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Fracture risk prediction: No benefit to repeat BMD testing in postmenopausal women
On the basis of the findings, published online in JAMA Internal Medicine, the authors recommend against routine repeat testing in postmenopausal women. Other experts, however, caution that the results may not be so broadly generalizable.
For the investigation, Carolyn J. Crandall, MD, of the division of general internal medicine and health services research at the University of California, Los Angeles, and colleagues analyzed data from 7,419 women enrolled in the prospective Women’s Health Initiative study and who underwent baseline and repeat dual-energy x-ray absorptiometry (DXA) between 1993 and 2010. The researchers excluded patients who reported using bisphosphonates, calcitonin, or selective estrogen-receptor modulators, those with a history of major osteoporotic fracture, or those who lacked follow-up visits. The mean body mass index (BMI) of the study population was 28.7 kg/m2, and the mean age was 66.1 years.
The mean follow-up after the repeat BMD test was 9.0 years, during which period 732 (9.9%) of the women experienced a major osteoporotic fracture, and 139 (1.9%) experienced hip fractures.
To determine whether repeat testing improved fracture risk discrimination, the researchers calculated area under the receiver operating characteristic curve (AUROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD.
With respect to any major osteoporotic fracture risk, the AUROC values for total hip BMD at baseline, change in total hip BMD at 3 years, and the combination of the two, respectively, were 0.61 (95% confidence interval, 0.59-0.63), 0.53 (95% CI, 0.51-0.55), and 0.61 (95% CI, 0.59-0.63). For hip fracture risk, the respective AUROC values were 0.71 (95% CI, 0.67-0.75), 0.61 (95% CI, 0.56-0.65), and 0.73 (95% CI, 0.69-0.77), the authors reported.
Similar results were observed for femoral neck and lumbar spine BMD measurements. The associations between BMD changes and fracture risk were consistent across age, race, ethnicity, BMI, and baseline BMD T-score subgroups.
Although baseline BMD and change in BMD were independently associated with incident fracture, the association was stronger for lower baseline BMD than the 3-year absolute change in BMD, the authors stated.
The findings, which are consistent with those of previous investigations that involved older adults, are notable because of the age range of the population, according to the authors. “To our knowledge, this is the first prospective study that addressed this issue in a study cohort that included younger postmenopausal U.S. women,” they wrote. “Forty-four percent of our study population was younger than 65 years.”
The authors wrote that, given the lack of benefit associated with repeat BMD testing, such tests should no longer be routinely performed. “Our findings further suggest that resources should be devoted to increasing the underuse of baseline BMD testing among women aged [between] 65 and 85 years, one-quarter of whom do not receive an initial BMD test.”
However, some experts are not comfortable with the broad recommendation to skip repeat testing in the general population. “This is a great study, and it gives important information. However, we know, even in the real world, that patients can lose BMD in this time frame and not really fracture. This does not mean that they will not fracture further down the road,” said Pauline Camacho, MD, director of Loyola University Medical Center’s Osteoporosis and Metabolic Bone Disease Center in Chicago,. “The value of doing BMD goes beyond predicting fracture risk. It also helps assess patient compliance and detect the presence of uncorrected secondary causes of osteoporosis that are limiting the response to therapy, including failure to absorb oral bisphosphonates, vitamin D deficiency, or hyperparathyroidism.”
In addition, patients for whom treatment is initiated would want to know whether it’s working. “Seeing the BMD response to therapy is helpful to both clinicians and patients,” Dr. Camacho said in an interview.
Another concern is the study population. “The study was designed to assess the clinical utility of repeating a screening BMD test in a population of low-risk women -- older postmenopausal women with remarkably good BMD on initial testing,” according to E. Michael Lewiecki, MD, vice president of the National Osteoporosis Foundation and director of the New Mexico Clinical Research and Osteoporosis Center in Albuquerque. “Not surprisingly, with what we know about the expected age-related rate of bone loss, there was only a modest decrease in BMD and little clinical utility in repeating DXA in 3 years. However, repeat testing is an important component in the care of many patients seen in clinical practice.”
There are numerous situations in clinical practice in which repeat BMD testing can enhance patient care and potentially improve outcomes, Dr. Lewiecki said in an interview. “Repeating BMD 1-2 years after starting osteoporosis therapy is a useful way to assess response and determine whether the patient is on a pathway to achieving an acceptable level of fracture risk with a strategy called treat to target.”
Additionally, patients starting high-dose glucocorticoids who are at high risk for rapid bone loss may benefit from undergoing baseline BMD testing and having a follow-up test 1 year later or even sooner, he said. Further, for early postmenopausal women, the rate of bone loss may be accelerated and may be faster than age-related bone loss later in life. For this reason, “close monitoring of BMD may be used to determine when a treatment threshold has been crossed and pharmacological therapy is indicated.”
The most important message from this study for clinicians and healthcare policymakers is not the relative value of the repeat BMD testing, Dr. Lewiecki stated. Rather, it is the call to action regarding the underuse of BMD testing. “There is a global crisis in the care of osteoporosis that is characterized by underdiagnosis and undertreatment of patients at risk for fracture. Many patients who could benefit from treatment to reduce fracture risk are not receiving it, resulting in disability and deaths from fractures that might have been prevented. We need more bone density testing in appropriately selected patients to identify high-risk patients and intervene to reduce fracture risk,” he said. “DXA is an inexpensive and highly versatile clinical tool with many applications in clinical practice. When used wisely, it can be extraordinarily useful to identify and monitor high-risk patients, with the goal of reducing the burden of osteoporotic fractures.”
The barriers to performing baseline BMD measurement in this population are poorly understood and not well researched, Dr. Crandall said in an interview. “I expect that they relate to the multiple competing demands on primary care physicians, who are, for example, trying to juggle hypertension, a sprained ankle, diabetes, and complex social situations simultaneously with identifying appropriate candidates for osteoporosis screening and considering numerous other screening guidelines.”
The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The study authors reported relationships with multiple companies, including Amgen, Pfizer, Bayer, Mithra, Norton Rose Fulbright, TherapeuticsMD, AbbVie, Radius, and Allergan. Dr. Camacho reported relationships with Amgen and Shire. Dr. Lewiecki reported relationships with Amgen, Radius Health, Alexion, Samsung Bioepis, Sandoz, Mereo, and Bindex.
A version of this article originally appeared on Medscape.com.
On the basis of the findings, published online in JAMA Internal Medicine, the authors recommend against routine repeat testing in postmenopausal women. Other experts, however, caution that the results may not be so broadly generalizable.
For the investigation, Carolyn J. Crandall, MD, of the division of general internal medicine and health services research at the University of California, Los Angeles, and colleagues analyzed data from 7,419 women enrolled in the prospective Women’s Health Initiative study and who underwent baseline and repeat dual-energy x-ray absorptiometry (DXA) between 1993 and 2010. The researchers excluded patients who reported using bisphosphonates, calcitonin, or selective estrogen-receptor modulators, those with a history of major osteoporotic fracture, or those who lacked follow-up visits. The mean body mass index (BMI) of the study population was 28.7 kg/m2, and the mean age was 66.1 years.
The mean follow-up after the repeat BMD test was 9.0 years, during which period 732 (9.9%) of the women experienced a major osteoporotic fracture, and 139 (1.9%) experienced hip fractures.
To determine whether repeat testing improved fracture risk discrimination, the researchers calculated area under the receiver operating characteristic curve (AUROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD.
With respect to any major osteoporotic fracture risk, the AUROC values for total hip BMD at baseline, change in total hip BMD at 3 years, and the combination of the two, respectively, were 0.61 (95% confidence interval, 0.59-0.63), 0.53 (95% CI, 0.51-0.55), and 0.61 (95% CI, 0.59-0.63). For hip fracture risk, the respective AUROC values were 0.71 (95% CI, 0.67-0.75), 0.61 (95% CI, 0.56-0.65), and 0.73 (95% CI, 0.69-0.77), the authors reported.
Similar results were observed for femoral neck and lumbar spine BMD measurements. The associations between BMD changes and fracture risk were consistent across age, race, ethnicity, BMI, and baseline BMD T-score subgroups.
Although baseline BMD and change in BMD were independently associated with incident fracture, the association was stronger for lower baseline BMD than the 3-year absolute change in BMD, the authors stated.
The findings, which are consistent with those of previous investigations that involved older adults, are notable because of the age range of the population, according to the authors. “To our knowledge, this is the first prospective study that addressed this issue in a study cohort that included younger postmenopausal U.S. women,” they wrote. “Forty-four percent of our study population was younger than 65 years.”
The authors wrote that, given the lack of benefit associated with repeat BMD testing, such tests should no longer be routinely performed. “Our findings further suggest that resources should be devoted to increasing the underuse of baseline BMD testing among women aged [between] 65 and 85 years, one-quarter of whom do not receive an initial BMD test.”
However, some experts are not comfortable with the broad recommendation to skip repeat testing in the general population. “This is a great study, and it gives important information. However, we know, even in the real world, that patients can lose BMD in this time frame and not really fracture. This does not mean that they will not fracture further down the road,” said Pauline Camacho, MD, director of Loyola University Medical Center’s Osteoporosis and Metabolic Bone Disease Center in Chicago,. “The value of doing BMD goes beyond predicting fracture risk. It also helps assess patient compliance and detect the presence of uncorrected secondary causes of osteoporosis that are limiting the response to therapy, including failure to absorb oral bisphosphonates, vitamin D deficiency, or hyperparathyroidism.”
In addition, patients for whom treatment is initiated would want to know whether it’s working. “Seeing the BMD response to therapy is helpful to both clinicians and patients,” Dr. Camacho said in an interview.
Another concern is the study population. “The study was designed to assess the clinical utility of repeating a screening BMD test in a population of low-risk women -- older postmenopausal women with remarkably good BMD on initial testing,” according to E. Michael Lewiecki, MD, vice president of the National Osteoporosis Foundation and director of the New Mexico Clinical Research and Osteoporosis Center in Albuquerque. “Not surprisingly, with what we know about the expected age-related rate of bone loss, there was only a modest decrease in BMD and little clinical utility in repeating DXA in 3 years. However, repeat testing is an important component in the care of many patients seen in clinical practice.”
There are numerous situations in clinical practice in which repeat BMD testing can enhance patient care and potentially improve outcomes, Dr. Lewiecki said in an interview. “Repeating BMD 1-2 years after starting osteoporosis therapy is a useful way to assess response and determine whether the patient is on a pathway to achieving an acceptable level of fracture risk with a strategy called treat to target.”
Additionally, patients starting high-dose glucocorticoids who are at high risk for rapid bone loss may benefit from undergoing baseline BMD testing and having a follow-up test 1 year later or even sooner, he said. Further, for early postmenopausal women, the rate of bone loss may be accelerated and may be faster than age-related bone loss later in life. For this reason, “close monitoring of BMD may be used to determine when a treatment threshold has been crossed and pharmacological therapy is indicated.”
The most important message from this study for clinicians and healthcare policymakers is not the relative value of the repeat BMD testing, Dr. Lewiecki stated. Rather, it is the call to action regarding the underuse of BMD testing. “There is a global crisis in the care of osteoporosis that is characterized by underdiagnosis and undertreatment of patients at risk for fracture. Many patients who could benefit from treatment to reduce fracture risk are not receiving it, resulting in disability and deaths from fractures that might have been prevented. We need more bone density testing in appropriately selected patients to identify high-risk patients and intervene to reduce fracture risk,” he said. “DXA is an inexpensive and highly versatile clinical tool with many applications in clinical practice. When used wisely, it can be extraordinarily useful to identify and monitor high-risk patients, with the goal of reducing the burden of osteoporotic fractures.”
The barriers to performing baseline BMD measurement in this population are poorly understood and not well researched, Dr. Crandall said in an interview. “I expect that they relate to the multiple competing demands on primary care physicians, who are, for example, trying to juggle hypertension, a sprained ankle, diabetes, and complex social situations simultaneously with identifying appropriate candidates for osteoporosis screening and considering numerous other screening guidelines.”
The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The study authors reported relationships with multiple companies, including Amgen, Pfizer, Bayer, Mithra, Norton Rose Fulbright, TherapeuticsMD, AbbVie, Radius, and Allergan. Dr. Camacho reported relationships with Amgen and Shire. Dr. Lewiecki reported relationships with Amgen, Radius Health, Alexion, Samsung Bioepis, Sandoz, Mereo, and Bindex.
A version of this article originally appeared on Medscape.com.
On the basis of the findings, published online in JAMA Internal Medicine, the authors recommend against routine repeat testing in postmenopausal women. Other experts, however, caution that the results may not be so broadly generalizable.
For the investigation, Carolyn J. Crandall, MD, of the division of general internal medicine and health services research at the University of California, Los Angeles, and colleagues analyzed data from 7,419 women enrolled in the prospective Women’s Health Initiative study and who underwent baseline and repeat dual-energy x-ray absorptiometry (DXA) between 1993 and 2010. The researchers excluded patients who reported using bisphosphonates, calcitonin, or selective estrogen-receptor modulators, those with a history of major osteoporotic fracture, or those who lacked follow-up visits. The mean body mass index (BMI) of the study population was 28.7 kg/m2, and the mean age was 66.1 years.
The mean follow-up after the repeat BMD test was 9.0 years, during which period 732 (9.9%) of the women experienced a major osteoporotic fracture, and 139 (1.9%) experienced hip fractures.
To determine whether repeat testing improved fracture risk discrimination, the researchers calculated area under the receiver operating characteristic curve (AUROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD.
With respect to any major osteoporotic fracture risk, the AUROC values for total hip BMD at baseline, change in total hip BMD at 3 years, and the combination of the two, respectively, were 0.61 (95% confidence interval, 0.59-0.63), 0.53 (95% CI, 0.51-0.55), and 0.61 (95% CI, 0.59-0.63). For hip fracture risk, the respective AUROC values were 0.71 (95% CI, 0.67-0.75), 0.61 (95% CI, 0.56-0.65), and 0.73 (95% CI, 0.69-0.77), the authors reported.
Similar results were observed for femoral neck and lumbar spine BMD measurements. The associations between BMD changes and fracture risk were consistent across age, race, ethnicity, BMI, and baseline BMD T-score subgroups.
Although baseline BMD and change in BMD were independently associated with incident fracture, the association was stronger for lower baseline BMD than the 3-year absolute change in BMD, the authors stated.
The findings, which are consistent with those of previous investigations that involved older adults, are notable because of the age range of the population, according to the authors. “To our knowledge, this is the first prospective study that addressed this issue in a study cohort that included younger postmenopausal U.S. women,” they wrote. “Forty-four percent of our study population was younger than 65 years.”
The authors wrote that, given the lack of benefit associated with repeat BMD testing, such tests should no longer be routinely performed. “Our findings further suggest that resources should be devoted to increasing the underuse of baseline BMD testing among women aged [between] 65 and 85 years, one-quarter of whom do not receive an initial BMD test.”
However, some experts are not comfortable with the broad recommendation to skip repeat testing in the general population. “This is a great study, and it gives important information. However, we know, even in the real world, that patients can lose BMD in this time frame and not really fracture. This does not mean that they will not fracture further down the road,” said Pauline Camacho, MD, director of Loyola University Medical Center’s Osteoporosis and Metabolic Bone Disease Center in Chicago,. “The value of doing BMD goes beyond predicting fracture risk. It also helps assess patient compliance and detect the presence of uncorrected secondary causes of osteoporosis that are limiting the response to therapy, including failure to absorb oral bisphosphonates, vitamin D deficiency, or hyperparathyroidism.”
In addition, patients for whom treatment is initiated would want to know whether it’s working. “Seeing the BMD response to therapy is helpful to both clinicians and patients,” Dr. Camacho said in an interview.
Another concern is the study population. “The study was designed to assess the clinical utility of repeating a screening BMD test in a population of low-risk women -- older postmenopausal women with remarkably good BMD on initial testing,” according to E. Michael Lewiecki, MD, vice president of the National Osteoporosis Foundation and director of the New Mexico Clinical Research and Osteoporosis Center in Albuquerque. “Not surprisingly, with what we know about the expected age-related rate of bone loss, there was only a modest decrease in BMD and little clinical utility in repeating DXA in 3 years. However, repeat testing is an important component in the care of many patients seen in clinical practice.”
There are numerous situations in clinical practice in which repeat BMD testing can enhance patient care and potentially improve outcomes, Dr. Lewiecki said in an interview. “Repeating BMD 1-2 years after starting osteoporosis therapy is a useful way to assess response and determine whether the patient is on a pathway to achieving an acceptable level of fracture risk with a strategy called treat to target.”
Additionally, patients starting high-dose glucocorticoids who are at high risk for rapid bone loss may benefit from undergoing baseline BMD testing and having a follow-up test 1 year later or even sooner, he said. Further, for early postmenopausal women, the rate of bone loss may be accelerated and may be faster than age-related bone loss later in life. For this reason, “close monitoring of BMD may be used to determine when a treatment threshold has been crossed and pharmacological therapy is indicated.”
The most important message from this study for clinicians and healthcare policymakers is not the relative value of the repeat BMD testing, Dr. Lewiecki stated. Rather, it is the call to action regarding the underuse of BMD testing. “There is a global crisis in the care of osteoporosis that is characterized by underdiagnosis and undertreatment of patients at risk for fracture. Many patients who could benefit from treatment to reduce fracture risk are not receiving it, resulting in disability and deaths from fractures that might have been prevented. We need more bone density testing in appropriately selected patients to identify high-risk patients and intervene to reduce fracture risk,” he said. “DXA is an inexpensive and highly versatile clinical tool with many applications in clinical practice. When used wisely, it can be extraordinarily useful to identify and monitor high-risk patients, with the goal of reducing the burden of osteoporotic fractures.”
The barriers to performing baseline BMD measurement in this population are poorly understood and not well researched, Dr. Crandall said in an interview. “I expect that they relate to the multiple competing demands on primary care physicians, who are, for example, trying to juggle hypertension, a sprained ankle, diabetes, and complex social situations simultaneously with identifying appropriate candidates for osteoporosis screening and considering numerous other screening guidelines.”
The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The study authors reported relationships with multiple companies, including Amgen, Pfizer, Bayer, Mithra, Norton Rose Fulbright, TherapeuticsMD, AbbVie, Radius, and Allergan. Dr. Camacho reported relationships with Amgen and Shire. Dr. Lewiecki reported relationships with Amgen, Radius Health, Alexion, Samsung Bioepis, Sandoz, Mereo, and Bindex.
A version of this article originally appeared on Medscape.com.
Unexpected rosuvastatin-canagliflozin adverse effect reported
A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).
The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.
“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.
“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.
“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
Sky high rosuvastatin levels
The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.
The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.
“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.
“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
Concern and skepticism
Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.
“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.
“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”
Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.
But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.
Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.
One in a million?
“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.
Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m2, respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m2 for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m2.
“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.
Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.
Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.
SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.
*Correction: This value was missing from the original article.
A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).
The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.
“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.
“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.
“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
Sky high rosuvastatin levels
The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.
The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.
“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.
“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
Concern and skepticism
Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.
“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.
“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”
Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.
But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.
Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.
One in a million?
“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.
Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m2, respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m2 for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m2.
“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.
Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.
Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.
SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.
*Correction: This value was missing from the original article.
A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).
The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.
“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.
“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.
“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
Sky high rosuvastatin levels
The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.
The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.
“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.
“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
Concern and skepticism
Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.
“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.
“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”
Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.
But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.
Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.
One in a million?
“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.
Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m2, respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m2 for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m2.
“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.
Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.
Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.
SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.
*Correction: This value was missing from the original article.
FROM ANNALS OF INTERNAL MEDICINE
COVID-19 taking financial toll on people in U.S. with diabetes
The COVID-19 pandemic is taking a particularly severe financial toll on people with diabetes, new research from the United States suggests.
Results from a national online survey of 5,000 people with diabetes conducted between June 26 and July 1, 2020, were posted July 29 on the American Diabetes Association website.
The survey, conducted by the diabetes research company dQ&A in association with the ADA, revealed that Americans with diabetes are experiencing extreme financial pressures, leading to medication and supply rationing.
A high proportion of respondents had either lost income or are working in jobs that place them at risk for catching the novel coronavirus.
“These new numbers show the urgency needed to adopt measures to protect and assist the millions of people with diabetes who are suffering through this pandemic,” Tracey D. Brown, CEO of the ADA, said in a statement.
She called for states to extend health care coverage to people who have lost their jobs, for the eradication of insulin copays during the pandemic, and for increased COVID-19 testing capacity in high-risk communities.
“If these actions aren’t taken immediately, we will continue to see devastating impacts and outcomes for millions of vulnerable Americans,” Ms. Brown stressed.
COVID-19 has worsened financial pressures for people with diabetes
In the survey, 24% of respondents reported having used savings, loans, or stimulus check money to pay for diabetes care in the past 3 months. Among those who have lost income, half are using savings or stimulus money.
A quarter of respondents said they have been self-rationing supplies to cut costs.
Extrapolating to the entire U.S. population with diabetes, dQ&A estimated that roughly 650,000 are skipping insulin doses or taking less than prescribed, and 3 million are skipping blood glucose tests.
In June, the unemployment rate for people with diabetes was 18%, higher than the national rate of 12%.
Also higher is the proportion of those working prior to the pandemic who have since lost income: 33%, compared with 29% for the general population.
Among those who are self-employed, 7 in 10 of those with diabetes have lost some or all of their income.
Many with diabetes who are employed are vulnerable to exposure
Of those who remain employed, half said they can’t work from home.
Of those, 60% work in essential industries, with 22% in health care. A large majority, 90%, reported lack of social distancing at work and nearly a third work in places that don’t require masks.
“People with diabetes are helping to provide the services we all depend on during this pandemic, even as it puts their own well-being at risk,” the report said.
It concluded that “these numbers represent a conservative estimate of the pandemic’s impact. They are generated from an ongoing online study of the diabetes population amongst people who have opted in to participate.”
A version of this article originally appeared on Medscape.com.
The COVID-19 pandemic is taking a particularly severe financial toll on people with diabetes, new research from the United States suggests.
Results from a national online survey of 5,000 people with diabetes conducted between June 26 and July 1, 2020, were posted July 29 on the American Diabetes Association website.
The survey, conducted by the diabetes research company dQ&A in association with the ADA, revealed that Americans with diabetes are experiencing extreme financial pressures, leading to medication and supply rationing.
A high proportion of respondents had either lost income or are working in jobs that place them at risk for catching the novel coronavirus.
“These new numbers show the urgency needed to adopt measures to protect and assist the millions of people with diabetes who are suffering through this pandemic,” Tracey D. Brown, CEO of the ADA, said in a statement.
She called for states to extend health care coverage to people who have lost their jobs, for the eradication of insulin copays during the pandemic, and for increased COVID-19 testing capacity in high-risk communities.
“If these actions aren’t taken immediately, we will continue to see devastating impacts and outcomes for millions of vulnerable Americans,” Ms. Brown stressed.
COVID-19 has worsened financial pressures for people with diabetes
In the survey, 24% of respondents reported having used savings, loans, or stimulus check money to pay for diabetes care in the past 3 months. Among those who have lost income, half are using savings or stimulus money.
A quarter of respondents said they have been self-rationing supplies to cut costs.
Extrapolating to the entire U.S. population with diabetes, dQ&A estimated that roughly 650,000 are skipping insulin doses or taking less than prescribed, and 3 million are skipping blood glucose tests.
In June, the unemployment rate for people with diabetes was 18%, higher than the national rate of 12%.
Also higher is the proportion of those working prior to the pandemic who have since lost income: 33%, compared with 29% for the general population.
Among those who are self-employed, 7 in 10 of those with diabetes have lost some or all of their income.
Many with diabetes who are employed are vulnerable to exposure
Of those who remain employed, half said they can’t work from home.
Of those, 60% work in essential industries, with 22% in health care. A large majority, 90%, reported lack of social distancing at work and nearly a third work in places that don’t require masks.
“People with diabetes are helping to provide the services we all depend on during this pandemic, even as it puts their own well-being at risk,” the report said.
It concluded that “these numbers represent a conservative estimate of the pandemic’s impact. They are generated from an ongoing online study of the diabetes population amongst people who have opted in to participate.”
A version of this article originally appeared on Medscape.com.
The COVID-19 pandemic is taking a particularly severe financial toll on people with diabetes, new research from the United States suggests.
Results from a national online survey of 5,000 people with diabetes conducted between June 26 and July 1, 2020, were posted July 29 on the American Diabetes Association website.
The survey, conducted by the diabetes research company dQ&A in association with the ADA, revealed that Americans with diabetes are experiencing extreme financial pressures, leading to medication and supply rationing.
A high proportion of respondents had either lost income or are working in jobs that place them at risk for catching the novel coronavirus.
“These new numbers show the urgency needed to adopt measures to protect and assist the millions of people with diabetes who are suffering through this pandemic,” Tracey D. Brown, CEO of the ADA, said in a statement.
She called for states to extend health care coverage to people who have lost their jobs, for the eradication of insulin copays during the pandemic, and for increased COVID-19 testing capacity in high-risk communities.
“If these actions aren’t taken immediately, we will continue to see devastating impacts and outcomes for millions of vulnerable Americans,” Ms. Brown stressed.
COVID-19 has worsened financial pressures for people with diabetes
In the survey, 24% of respondents reported having used savings, loans, or stimulus check money to pay for diabetes care in the past 3 months. Among those who have lost income, half are using savings or stimulus money.
A quarter of respondents said they have been self-rationing supplies to cut costs.
Extrapolating to the entire U.S. population with diabetes, dQ&A estimated that roughly 650,000 are skipping insulin doses or taking less than prescribed, and 3 million are skipping blood glucose tests.
In June, the unemployment rate for people with diabetes was 18%, higher than the national rate of 12%.
Also higher is the proportion of those working prior to the pandemic who have since lost income: 33%, compared with 29% for the general population.
Among those who are self-employed, 7 in 10 of those with diabetes have lost some or all of their income.
Many with diabetes who are employed are vulnerable to exposure
Of those who remain employed, half said they can’t work from home.
Of those, 60% work in essential industries, with 22% in health care. A large majority, 90%, reported lack of social distancing at work and nearly a third work in places that don’t require masks.
“People with diabetes are helping to provide the services we all depend on during this pandemic, even as it puts their own well-being at risk,” the report said.
It concluded that “these numbers represent a conservative estimate of the pandemic’s impact. They are generated from an ongoing online study of the diabetes population amongst people who have opted in to participate.”
A version of this article originally appeared on Medscape.com.
Low vitamin D linked to increased COVID-19 risk
Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.
Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.
The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.
The study was published online July 23 in The FEBS Journal.
Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.
Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.
Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.
Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.
Key findings
A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).
The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.
“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.
“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.
In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.
The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).
After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).
Implications and future plans
The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.
Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.
“A compelling case”
“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.
Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.
However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”
“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
More confounders likely?
“I think the study is of interest,” Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.
“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.
For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.
“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”
Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.
Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.
The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.
The study was published online July 23 in The FEBS Journal.
Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.
Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.
Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.
Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.
Key findings
A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).
The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.
“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.
“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.
In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.
The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).
After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).
Implications and future plans
The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.
Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.
“A compelling case”
“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.
Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.
However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”
“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
More confounders likely?
“I think the study is of interest,” Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.
“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.
For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.
“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”
Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.
Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.
The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.
The study was published online July 23 in The FEBS Journal.
Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.
Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.
Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.
Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.
Key findings
A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).
The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.
“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.
“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.
In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.
The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).
After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).
Implications and future plans
The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.
Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.
“A compelling case”
“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.
Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.
However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”
“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
More confounders likely?
“I think the study is of interest,” Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.
“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.
For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.
“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”
Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Postmenopausal use of estrogen alone lowers breast cancer cases, deaths
A new follow-up study of menopausal hormone therapy found that prior use of conjugated equine estrogen (CEE) decreased both breast cancer incidence and mortality, while prior use of CEE plus medroxyprogesterone acetate (MPA) was associated with an increase in incidence.
“Prior use of CEE alone is, to our knowledge, the first pharmacologic intervention demonstrated to be associated with a statistically significantly reduction in deaths from breast cancer,” wrote Rowan T. Chlebowski, MD, PhD, of the Lundquist Institute for Biomedical Innovation in Torrance, Calif., and his coauthors. The study was published July 28 in JAMA.
To further investigate the outcomes of the Women’s Health Initiative in regard to hormone therapy and breast cancer risk, the researchers analyzed the long-term follow-up of two randomized trials that included 27,347 postmenopausal women with no prior breast cancer and negative mammograms at baseline. Their mean (SD) age was 63.4 (7.2) years. Enrollment took place from 1993 to 1998; participants were contacted for follow-up every 6 months through 2005 and annually from then on. Mortality data were gathered from follow-up and the National Death Index.
The first trial included 16,608 women with a uterus. Among these women, 8,506 received 0.625 mg/day of CEE plus 2.5 mg/day of MPA, and 8,102 received placebo. The second trial included 10,739 women who’d gotten a hysterectomy, 5,310 of whom received 0.625 mg/day of CEE alone and 5,429 of whom received placebo. The first trial ended in 2002 after a median intervention period of 5.6 years, and the second trial ended in 2004 after a period of 7.2 years.
An analysis in 2015 found that CEE alone was associated with lower risk of breast cancer and CEE plus MPA was associated with increased risk.
The current analysis confirmed that, after a median of 20.3 years of follow-up, and with mortality data now available for more than 98% of participants, CEE alone was associated with fewer cases of breast cancer (238 cases, annualized rate 0.30%), compared with placebo (296 cases, annualized rate 0.37%; hazard ratio 0.78; 95% confidence interval, 0.65-0.93; P = .005).
Furthermore, CEE alone was also associated with lower mortality (30 deaths, annualized mortality rate 0.031%), compared with placebo (46 deaths, annualized mortality rate 0.046%; HR 0.60; 95% CI, 0.37-0.97; P = .04).
By comparison, CEE plus MPA was linked with more cases of breast cancer (584 cases, annualized rate 0.45%) than placebo (447 cases, annualized rate 0.36%; HR 1.28; 95% CI, 1.13-1.45; P < .001). In regard to mortality, there was no statistically significant difference between CEE plus MPA (71 deaths, annualized mortality rate 0.045%) and placebo (53 deaths, annualized mortality rate 0.035%; HR 1.35; 95% CI, 0.94-1.95; P = .11).
“The big thing to think about is estrogen alone reducing breast cancer mortality by 40%,” said Dr. Chlebowski in an interview. “None of the other interventions, including tamoxifen, had any change on mortality. This should change the way we look at breast cancer prevention, though we might have to be a little creative about it. I think you have to be a little away from menopause for it to reduce breast cancer. But we wanted to start that debate.
“On the other hand,” he said, “a woman takes estrogen plus progestin and when you look at that curve, it’s staying about 25% increased. You take it for 5.6 years and the increase continues through 20 years, so you’re maybe buying a lifetime of increase in breast cancer by taking estrogen plus progestin for 5 years.”
He also highlighted the comprehensiveness of the mortality data, noting that “when you hook up to the National Death Index, they find 98% of all deaths in the United States. That’s really remarkable; you retain the whole power of the randomization. It means our data, between the death index and our follow-up of participants, is essentially complete.”
Use of hormone therapy, and decoding the outcomes, remains ‘complex’
Decades after the data were gathered from the Women’s Health Initiative clinical trials, they continue to assist researchers and patients alike, wrote Christina A. Minami, MD, of Brigham and Women’s Hospital in Boston and Rachel A. Freedman, MD, of the Dana-Farber Cancer Institute in Boston, in an accompanying editorial.
That said, in regard to the findings of this latest analysis, “many questions still remain on whether (and how) a hormone therapy intervention that occurred many years earlier may continue to affect breast cancer risk and mortality at 20 years,” they wrote. They noted that it’s “impossible” to isolate how exposure to certain therapies can impact long-term outcomes, and that a high percentage of patients who discontinued the drugs during each trial muddy the waters even further.
“Decisions to initiate these medications remain complex,” they added, emphasizing that breast cancer risk is just one of many factors that physicians must consider when considering hormone therapy for their patients.
Dr. Chlebowski and his coauthors acknowledged their study’s limitations, including the use of very specifically administered and formulated dosages making their findings “not necessarily generalizable to other preparations.” In addition, they noted the significant percentage of patients – 54% with CEE alone and 42% with CEE plus MPA – who discontinued drug usage during their respective trials.
The Women’s Health Initiative is supported by the National Institutes of Health and the Department of Health and Human Services. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various government organizations, foundations, and pharmaceutical companies. The editorial’s authors reported no conflicts of interest.
SOURCE: Chlebowski RT et al. JAMA. 2020 Jul 28. doi: 10.1001/jama.2020.9482.
A new follow-up study of menopausal hormone therapy found that prior use of conjugated equine estrogen (CEE) decreased both breast cancer incidence and mortality, while prior use of CEE plus medroxyprogesterone acetate (MPA) was associated with an increase in incidence.
“Prior use of CEE alone is, to our knowledge, the first pharmacologic intervention demonstrated to be associated with a statistically significantly reduction in deaths from breast cancer,” wrote Rowan T. Chlebowski, MD, PhD, of the Lundquist Institute for Biomedical Innovation in Torrance, Calif., and his coauthors. The study was published July 28 in JAMA.
To further investigate the outcomes of the Women’s Health Initiative in regard to hormone therapy and breast cancer risk, the researchers analyzed the long-term follow-up of two randomized trials that included 27,347 postmenopausal women with no prior breast cancer and negative mammograms at baseline. Their mean (SD) age was 63.4 (7.2) years. Enrollment took place from 1993 to 1998; participants were contacted for follow-up every 6 months through 2005 and annually from then on. Mortality data were gathered from follow-up and the National Death Index.
The first trial included 16,608 women with a uterus. Among these women, 8,506 received 0.625 mg/day of CEE plus 2.5 mg/day of MPA, and 8,102 received placebo. The second trial included 10,739 women who’d gotten a hysterectomy, 5,310 of whom received 0.625 mg/day of CEE alone and 5,429 of whom received placebo. The first trial ended in 2002 after a median intervention period of 5.6 years, and the second trial ended in 2004 after a period of 7.2 years.
An analysis in 2015 found that CEE alone was associated with lower risk of breast cancer and CEE plus MPA was associated with increased risk.
The current analysis confirmed that, after a median of 20.3 years of follow-up, and with mortality data now available for more than 98% of participants, CEE alone was associated with fewer cases of breast cancer (238 cases, annualized rate 0.30%), compared with placebo (296 cases, annualized rate 0.37%; hazard ratio 0.78; 95% confidence interval, 0.65-0.93; P = .005).
Furthermore, CEE alone was also associated with lower mortality (30 deaths, annualized mortality rate 0.031%), compared with placebo (46 deaths, annualized mortality rate 0.046%; HR 0.60; 95% CI, 0.37-0.97; P = .04).
By comparison, CEE plus MPA was linked with more cases of breast cancer (584 cases, annualized rate 0.45%) than placebo (447 cases, annualized rate 0.36%; HR 1.28; 95% CI, 1.13-1.45; P < .001). In regard to mortality, there was no statistically significant difference between CEE plus MPA (71 deaths, annualized mortality rate 0.045%) and placebo (53 deaths, annualized mortality rate 0.035%; HR 1.35; 95% CI, 0.94-1.95; P = .11).
“The big thing to think about is estrogen alone reducing breast cancer mortality by 40%,” said Dr. Chlebowski in an interview. “None of the other interventions, including tamoxifen, had any change on mortality. This should change the way we look at breast cancer prevention, though we might have to be a little creative about it. I think you have to be a little away from menopause for it to reduce breast cancer. But we wanted to start that debate.
“On the other hand,” he said, “a woman takes estrogen plus progestin and when you look at that curve, it’s staying about 25% increased. You take it for 5.6 years and the increase continues through 20 years, so you’re maybe buying a lifetime of increase in breast cancer by taking estrogen plus progestin for 5 years.”
He also highlighted the comprehensiveness of the mortality data, noting that “when you hook up to the National Death Index, they find 98% of all deaths in the United States. That’s really remarkable; you retain the whole power of the randomization. It means our data, between the death index and our follow-up of participants, is essentially complete.”
Use of hormone therapy, and decoding the outcomes, remains ‘complex’
Decades after the data were gathered from the Women’s Health Initiative clinical trials, they continue to assist researchers and patients alike, wrote Christina A. Minami, MD, of Brigham and Women’s Hospital in Boston and Rachel A. Freedman, MD, of the Dana-Farber Cancer Institute in Boston, in an accompanying editorial.
That said, in regard to the findings of this latest analysis, “many questions still remain on whether (and how) a hormone therapy intervention that occurred many years earlier may continue to affect breast cancer risk and mortality at 20 years,” they wrote. They noted that it’s “impossible” to isolate how exposure to certain therapies can impact long-term outcomes, and that a high percentage of patients who discontinued the drugs during each trial muddy the waters even further.
“Decisions to initiate these medications remain complex,” they added, emphasizing that breast cancer risk is just one of many factors that physicians must consider when considering hormone therapy for their patients.
Dr. Chlebowski and his coauthors acknowledged their study’s limitations, including the use of very specifically administered and formulated dosages making their findings “not necessarily generalizable to other preparations.” In addition, they noted the significant percentage of patients – 54% with CEE alone and 42% with CEE plus MPA – who discontinued drug usage during their respective trials.
The Women’s Health Initiative is supported by the National Institutes of Health and the Department of Health and Human Services. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various government organizations, foundations, and pharmaceutical companies. The editorial’s authors reported no conflicts of interest.
SOURCE: Chlebowski RT et al. JAMA. 2020 Jul 28. doi: 10.1001/jama.2020.9482.
A new follow-up study of menopausal hormone therapy found that prior use of conjugated equine estrogen (CEE) decreased both breast cancer incidence and mortality, while prior use of CEE plus medroxyprogesterone acetate (MPA) was associated with an increase in incidence.
“Prior use of CEE alone is, to our knowledge, the first pharmacologic intervention demonstrated to be associated with a statistically significantly reduction in deaths from breast cancer,” wrote Rowan T. Chlebowski, MD, PhD, of the Lundquist Institute for Biomedical Innovation in Torrance, Calif., and his coauthors. The study was published July 28 in JAMA.
To further investigate the outcomes of the Women’s Health Initiative in regard to hormone therapy and breast cancer risk, the researchers analyzed the long-term follow-up of two randomized trials that included 27,347 postmenopausal women with no prior breast cancer and negative mammograms at baseline. Their mean (SD) age was 63.4 (7.2) years. Enrollment took place from 1993 to 1998; participants were contacted for follow-up every 6 months through 2005 and annually from then on. Mortality data were gathered from follow-up and the National Death Index.
The first trial included 16,608 women with a uterus. Among these women, 8,506 received 0.625 mg/day of CEE plus 2.5 mg/day of MPA, and 8,102 received placebo. The second trial included 10,739 women who’d gotten a hysterectomy, 5,310 of whom received 0.625 mg/day of CEE alone and 5,429 of whom received placebo. The first trial ended in 2002 after a median intervention period of 5.6 years, and the second trial ended in 2004 after a period of 7.2 years.
An analysis in 2015 found that CEE alone was associated with lower risk of breast cancer and CEE plus MPA was associated with increased risk.
The current analysis confirmed that, after a median of 20.3 years of follow-up, and with mortality data now available for more than 98% of participants, CEE alone was associated with fewer cases of breast cancer (238 cases, annualized rate 0.30%), compared with placebo (296 cases, annualized rate 0.37%; hazard ratio 0.78; 95% confidence interval, 0.65-0.93; P = .005).
Furthermore, CEE alone was also associated with lower mortality (30 deaths, annualized mortality rate 0.031%), compared with placebo (46 deaths, annualized mortality rate 0.046%; HR 0.60; 95% CI, 0.37-0.97; P = .04).
By comparison, CEE plus MPA was linked with more cases of breast cancer (584 cases, annualized rate 0.45%) than placebo (447 cases, annualized rate 0.36%; HR 1.28; 95% CI, 1.13-1.45; P < .001). In regard to mortality, there was no statistically significant difference between CEE plus MPA (71 deaths, annualized mortality rate 0.045%) and placebo (53 deaths, annualized mortality rate 0.035%; HR 1.35; 95% CI, 0.94-1.95; P = .11).
“The big thing to think about is estrogen alone reducing breast cancer mortality by 40%,” said Dr. Chlebowski in an interview. “None of the other interventions, including tamoxifen, had any change on mortality. This should change the way we look at breast cancer prevention, though we might have to be a little creative about it. I think you have to be a little away from menopause for it to reduce breast cancer. But we wanted to start that debate.
“On the other hand,” he said, “a woman takes estrogen plus progestin and when you look at that curve, it’s staying about 25% increased. You take it for 5.6 years and the increase continues through 20 years, so you’re maybe buying a lifetime of increase in breast cancer by taking estrogen plus progestin for 5 years.”
He also highlighted the comprehensiveness of the mortality data, noting that “when you hook up to the National Death Index, they find 98% of all deaths in the United States. That’s really remarkable; you retain the whole power of the randomization. It means our data, between the death index and our follow-up of participants, is essentially complete.”
Use of hormone therapy, and decoding the outcomes, remains ‘complex’
Decades after the data were gathered from the Women’s Health Initiative clinical trials, they continue to assist researchers and patients alike, wrote Christina A. Minami, MD, of Brigham and Women’s Hospital in Boston and Rachel A. Freedman, MD, of the Dana-Farber Cancer Institute in Boston, in an accompanying editorial.
That said, in regard to the findings of this latest analysis, “many questions still remain on whether (and how) a hormone therapy intervention that occurred many years earlier may continue to affect breast cancer risk and mortality at 20 years,” they wrote. They noted that it’s “impossible” to isolate how exposure to certain therapies can impact long-term outcomes, and that a high percentage of patients who discontinued the drugs during each trial muddy the waters even further.
“Decisions to initiate these medications remain complex,” they added, emphasizing that breast cancer risk is just one of many factors that physicians must consider when considering hormone therapy for their patients.
Dr. Chlebowski and his coauthors acknowledged their study’s limitations, including the use of very specifically administered and formulated dosages making their findings “not necessarily generalizable to other preparations.” In addition, they noted the significant percentage of patients – 54% with CEE alone and 42% with CEE plus MPA – who discontinued drug usage during their respective trials.
The Women’s Health Initiative is supported by the National Institutes of Health and the Department of Health and Human Services. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various government organizations, foundations, and pharmaceutical companies. The editorial’s authors reported no conflicts of interest.
SOURCE: Chlebowski RT et al. JAMA. 2020 Jul 28. doi: 10.1001/jama.2020.9482.
FROM JAMA
Real-world data show SGLT2 inhibitors for diabetes triple DKA risk
according to a new large database analysis.
The findings, which include data on the use of three different SGLT2 inhibitors in Canada and the United Kingdom and suggest a class effect, were published online July 27 in Annals of Internal Medicine by Antonios Douros, MD, PhD, of McGill University and the Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, and colleagues.
“Our results provide robust evidence that SGLT2 inhibitors are associated with an increased risk for DKA. Of note, increased risks were observed in all molecule-specific analyses, with canagliflozin [Invokana, Janssen] showing the highest effect estimate,” they noted.
And because the beneficial effects of SGLT2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the coming years, “Physicians should be aware of DKA as a potential adverse effect,” Dr. Douros and colleagues wrote.
Analysis “generally confirms what has already been published”
Asked for comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, said that the study “generally confirms what has already been published” on the topic. He noted that overall “the risk of SGLT2 inhibitor–induced ketoacidosis is quite low in type 2 diabetes, perhaps on the order of 1 episode per 1000 patient-years.”
However, Dr. Taylor cautioned: “Published evidence suggests that the risk of DKA is increased if patients are unable to eat,” such as when hospitalized patients are not permitted to eat.
“In that setting, it is probably prudent to discontinue an SGLT2 inhibitor. Also, it may be prudent not to prescribe SGLT2 inhibitors to patients with a history of DKA,” he added.
Dr. Taylor also advised: “Although not necessarily supported by this publication, I think that caution should be exercised in prescribing SGLT2 inhibitors to insulin-dependent type 2 diabetes patients. ... Some late-stage type 2 diabetes patients may have severe insulin deficiency, and their physiology may resemble that of a type 1 diabetes patient.”
Dr. Taylor has previously advised against using SGLT2 inhibitors altogether in patients with type 1 diabetes.
Increased DKA risk seen across all SGLT2 inhibitors
The study involved electronic health care databases from seven Canadian provinces and the United Kingdom, from which 208,757 new users of SGLT2 inhibitors were propensity-matched 1:1 to new dipeptidyl peptidase-4 (DPP-4) inhibitor users.
Of those taking an SGLT2 inhibitor, 42.3% took canagliflozin, 30.7% dapagliflozin (Farxiga/Forxiga, AstraZeneca), and 27.0% empagliflozin (Jardiance, Boehringer Ingelheim).
Over a mean 0.9-year follow-up, 521 patients were hospitalized with DKA, for an overall incidence rate of 1.41 per 1,000 person-years.
The rate with SGLT2 inhibitors, 2.03 per 1,000 person-years, was nearly three times that seen with DPP-4 inhibitors, at 0.75 per 1,000 person-years, a significant difference (hazard ratio, 2.85).
By individual SGLT2 inhibitor, the hazard ratios compared with DPP-4 inhibitors were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin, all statistically significant. Stratification by age, sex, and incident versus prevalent user did not change the association between SGLT2 inhibitors and DKA.
Asked about the higher rate for canagliflozin, Dr. Taylor commented: “It is hard to know whether there are real and reproducible differences in the risks of DKA among the various SGLT2 inhibitors. The differences are not huge and the populations are not well matched.”
But, he noted, “If canagliflozin triggers more glucosuria, it is not surprising that it would also induce more ketosis and possibly ketoacidosis.”
He also noted that the threefold relative increase in DKA with canagliflozin versus comparators is consistent with Janssen’s data, published in 2015.
“It is, of course, reassuring that both [randomized clinical trials] and epidemiology produce similar estimates of the risk of drug-induced adverse events. Interestingly, the incidence of DKA is approximately threefold higher in the Canadian [data] as compared to Janssen’s clinical trials.”
Dr. Taylor also pointed out that, in the Janssen studies, the risk of canagliflozin-induced DKA appeared to be higher among patients with anti-islet antibodies, which suggests that some may have actually had autoimmune (type 1) diabetes. “So the overall risk of SGLT2 inhibitor-induced DKA may depend at least in part on the mix of patients.”
In the current study, individuals who never used insulin had a greater relative increase in risk of DKA with SGLT2 inhibitors, compared with DPP-4 inhibitors, than did those who did use insulin (hazard ratios, 3.96 vs. 2.24, both compared with DPP-4 inhibitors). However, just among those taking SGLT2 inhibitors, the absolute risk for DKA was higher for those with prior insulin use (3.52 vs. 1.43 per 1,000 person-years).
The results of sensitivity analyses were consistent with those of the primary analysis.
The study was funded by the Canadian Institutes of Health Research and supported by ICES. Dr. Douros has reported receiving a salary support award from Fonds de recherche du Quebec – sante. Dr. Taylor was previously employed at Bristol-Myers Squibb. He is currently a consultant for Ionis Pharmaceuticals and has reported receiving research support provided to the University of Maryland School of Medicine by Regeneron.
A version of this article originally appeared on Medscape.com.
according to a new large database analysis.
The findings, which include data on the use of three different SGLT2 inhibitors in Canada and the United Kingdom and suggest a class effect, were published online July 27 in Annals of Internal Medicine by Antonios Douros, MD, PhD, of McGill University and the Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, and colleagues.
“Our results provide robust evidence that SGLT2 inhibitors are associated with an increased risk for DKA. Of note, increased risks were observed in all molecule-specific analyses, with canagliflozin [Invokana, Janssen] showing the highest effect estimate,” they noted.
And because the beneficial effects of SGLT2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the coming years, “Physicians should be aware of DKA as a potential adverse effect,” Dr. Douros and colleagues wrote.
Analysis “generally confirms what has already been published”
Asked for comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, said that the study “generally confirms what has already been published” on the topic. He noted that overall “the risk of SGLT2 inhibitor–induced ketoacidosis is quite low in type 2 diabetes, perhaps on the order of 1 episode per 1000 patient-years.”
However, Dr. Taylor cautioned: “Published evidence suggests that the risk of DKA is increased if patients are unable to eat,” such as when hospitalized patients are not permitted to eat.
“In that setting, it is probably prudent to discontinue an SGLT2 inhibitor. Also, it may be prudent not to prescribe SGLT2 inhibitors to patients with a history of DKA,” he added.
Dr. Taylor also advised: “Although not necessarily supported by this publication, I think that caution should be exercised in prescribing SGLT2 inhibitors to insulin-dependent type 2 diabetes patients. ... Some late-stage type 2 diabetes patients may have severe insulin deficiency, and their physiology may resemble that of a type 1 diabetes patient.”
Dr. Taylor has previously advised against using SGLT2 inhibitors altogether in patients with type 1 diabetes.
Increased DKA risk seen across all SGLT2 inhibitors
The study involved electronic health care databases from seven Canadian provinces and the United Kingdom, from which 208,757 new users of SGLT2 inhibitors were propensity-matched 1:1 to new dipeptidyl peptidase-4 (DPP-4) inhibitor users.
Of those taking an SGLT2 inhibitor, 42.3% took canagliflozin, 30.7% dapagliflozin (Farxiga/Forxiga, AstraZeneca), and 27.0% empagliflozin (Jardiance, Boehringer Ingelheim).
Over a mean 0.9-year follow-up, 521 patients were hospitalized with DKA, for an overall incidence rate of 1.41 per 1,000 person-years.
The rate with SGLT2 inhibitors, 2.03 per 1,000 person-years, was nearly three times that seen with DPP-4 inhibitors, at 0.75 per 1,000 person-years, a significant difference (hazard ratio, 2.85).
By individual SGLT2 inhibitor, the hazard ratios compared with DPP-4 inhibitors were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin, all statistically significant. Stratification by age, sex, and incident versus prevalent user did not change the association between SGLT2 inhibitors and DKA.
Asked about the higher rate for canagliflozin, Dr. Taylor commented: “It is hard to know whether there are real and reproducible differences in the risks of DKA among the various SGLT2 inhibitors. The differences are not huge and the populations are not well matched.”
But, he noted, “If canagliflozin triggers more glucosuria, it is not surprising that it would also induce more ketosis and possibly ketoacidosis.”
He also noted that the threefold relative increase in DKA with canagliflozin versus comparators is consistent with Janssen’s data, published in 2015.
“It is, of course, reassuring that both [randomized clinical trials] and epidemiology produce similar estimates of the risk of drug-induced adverse events. Interestingly, the incidence of DKA is approximately threefold higher in the Canadian [data] as compared to Janssen’s clinical trials.”
Dr. Taylor also pointed out that, in the Janssen studies, the risk of canagliflozin-induced DKA appeared to be higher among patients with anti-islet antibodies, which suggests that some may have actually had autoimmune (type 1) diabetes. “So the overall risk of SGLT2 inhibitor-induced DKA may depend at least in part on the mix of patients.”
In the current study, individuals who never used insulin had a greater relative increase in risk of DKA with SGLT2 inhibitors, compared with DPP-4 inhibitors, than did those who did use insulin (hazard ratios, 3.96 vs. 2.24, both compared with DPP-4 inhibitors). However, just among those taking SGLT2 inhibitors, the absolute risk for DKA was higher for those with prior insulin use (3.52 vs. 1.43 per 1,000 person-years).
The results of sensitivity analyses were consistent with those of the primary analysis.
The study was funded by the Canadian Institutes of Health Research and supported by ICES. Dr. Douros has reported receiving a salary support award from Fonds de recherche du Quebec – sante. Dr. Taylor was previously employed at Bristol-Myers Squibb. He is currently a consultant for Ionis Pharmaceuticals and has reported receiving research support provided to the University of Maryland School of Medicine by Regeneron.
A version of this article originally appeared on Medscape.com.
according to a new large database analysis.
The findings, which include data on the use of three different SGLT2 inhibitors in Canada and the United Kingdom and suggest a class effect, were published online July 27 in Annals of Internal Medicine by Antonios Douros, MD, PhD, of McGill University and the Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, and colleagues.
“Our results provide robust evidence that SGLT2 inhibitors are associated with an increased risk for DKA. Of note, increased risks were observed in all molecule-specific analyses, with canagliflozin [Invokana, Janssen] showing the highest effect estimate,” they noted.
And because the beneficial effects of SGLT2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the coming years, “Physicians should be aware of DKA as a potential adverse effect,” Dr. Douros and colleagues wrote.
Analysis “generally confirms what has already been published”
Asked for comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, said that the study “generally confirms what has already been published” on the topic. He noted that overall “the risk of SGLT2 inhibitor–induced ketoacidosis is quite low in type 2 diabetes, perhaps on the order of 1 episode per 1000 patient-years.”
However, Dr. Taylor cautioned: “Published evidence suggests that the risk of DKA is increased if patients are unable to eat,” such as when hospitalized patients are not permitted to eat.
“In that setting, it is probably prudent to discontinue an SGLT2 inhibitor. Also, it may be prudent not to prescribe SGLT2 inhibitors to patients with a history of DKA,” he added.
Dr. Taylor also advised: “Although not necessarily supported by this publication, I think that caution should be exercised in prescribing SGLT2 inhibitors to insulin-dependent type 2 diabetes patients. ... Some late-stage type 2 diabetes patients may have severe insulin deficiency, and their physiology may resemble that of a type 1 diabetes patient.”
Dr. Taylor has previously advised against using SGLT2 inhibitors altogether in patients with type 1 diabetes.
Increased DKA risk seen across all SGLT2 inhibitors
The study involved electronic health care databases from seven Canadian provinces and the United Kingdom, from which 208,757 new users of SGLT2 inhibitors were propensity-matched 1:1 to new dipeptidyl peptidase-4 (DPP-4) inhibitor users.
Of those taking an SGLT2 inhibitor, 42.3% took canagliflozin, 30.7% dapagliflozin (Farxiga/Forxiga, AstraZeneca), and 27.0% empagliflozin (Jardiance, Boehringer Ingelheim).
Over a mean 0.9-year follow-up, 521 patients were hospitalized with DKA, for an overall incidence rate of 1.41 per 1,000 person-years.
The rate with SGLT2 inhibitors, 2.03 per 1,000 person-years, was nearly three times that seen with DPP-4 inhibitors, at 0.75 per 1,000 person-years, a significant difference (hazard ratio, 2.85).
By individual SGLT2 inhibitor, the hazard ratios compared with DPP-4 inhibitors were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin, all statistically significant. Stratification by age, sex, and incident versus prevalent user did not change the association between SGLT2 inhibitors and DKA.
Asked about the higher rate for canagliflozin, Dr. Taylor commented: “It is hard to know whether there are real and reproducible differences in the risks of DKA among the various SGLT2 inhibitors. The differences are not huge and the populations are not well matched.”
But, he noted, “If canagliflozin triggers more glucosuria, it is not surprising that it would also induce more ketosis and possibly ketoacidosis.”
He also noted that the threefold relative increase in DKA with canagliflozin versus comparators is consistent with Janssen’s data, published in 2015.
“It is, of course, reassuring that both [randomized clinical trials] and epidemiology produce similar estimates of the risk of drug-induced adverse events. Interestingly, the incidence of DKA is approximately threefold higher in the Canadian [data] as compared to Janssen’s clinical trials.”
Dr. Taylor also pointed out that, in the Janssen studies, the risk of canagliflozin-induced DKA appeared to be higher among patients with anti-islet antibodies, which suggests that some may have actually had autoimmune (type 1) diabetes. “So the overall risk of SGLT2 inhibitor-induced DKA may depend at least in part on the mix of patients.”
In the current study, individuals who never used insulin had a greater relative increase in risk of DKA with SGLT2 inhibitors, compared with DPP-4 inhibitors, than did those who did use insulin (hazard ratios, 3.96 vs. 2.24, both compared with DPP-4 inhibitors). However, just among those taking SGLT2 inhibitors, the absolute risk for DKA was higher for those with prior insulin use (3.52 vs. 1.43 per 1,000 person-years).
The results of sensitivity analyses were consistent with those of the primary analysis.
The study was funded by the Canadian Institutes of Health Research and supported by ICES. Dr. Douros has reported receiving a salary support award from Fonds de recherche du Quebec – sante. Dr. Taylor was previously employed at Bristol-Myers Squibb. He is currently a consultant for Ionis Pharmaceuticals and has reported receiving research support provided to the University of Maryland School of Medicine by Regeneron.
A version of this article originally appeared on Medscape.com.
Dapagliflozin Improves Cardiovascular Outcomes in Patients With Heart Failure and Reduced Ejection Fraction
Study Overview
Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.
Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.
Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.
Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.
Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.
Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.
Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
Commentary
Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.1 This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.2,3
While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.
DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.
There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.
Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.
Applications for Clinical Practice
SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.
—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
Study Overview
Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.
Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.
Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.
Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.
Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.
Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.
Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
Commentary
Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.1 This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.2,3
While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.
DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.
There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.
Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.
Applications for Clinical Practice
SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.
—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO
Study Overview
Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.
Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.
Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.
Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.
Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.
Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.
Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
Commentary
Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.1 This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.2,3
While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.
DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.
There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.
Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.
Applications for Clinical Practice
SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.
—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
Part 5: Screening for “Opathies” in Diabetes Patients
Previously, we discussed monitoring for chronic kidney disease in patients with diabetes. In this final part of our series, we’ll discuss screening to prevent impairment to the patient’s mobility and sight.
CASE CONTINUED
Mr. W is appreciative of your efforts to improve his health, but he fears his quality of life with diabetes will suffer. Because his father experienced impaired sight and limited mobility during the final years of his life, Mr. W is concerned he will endure similar complications from his diabetes. What can you do to help safeguard his abilities for sight and mobility?
Detecting peripheral neuropathy
Evaluation of Mr. W’s feet is an appropriate first step in the right direction. Peripheral neuropathy—one of the most common complications in diabetes—occurs in up to 50% of patients with diabetes, and about 50% of peripheral neuropathies may be asymptomatic.40 It is the most significant risk factor for foot ulceration, which in turn is the leading cause of amputation in patients with diabetes.40 Therefore, early identification of peripheral neuropathy is important because it provides an opportunity for patient education on preventive practices and prompts podiatric care.
Screening for peripheral neuropathy should include a detailed history of the risk factors and a thorough physical exam, including pinprick sensation (small sensory fiber function), vibration perception (large sensory fiber function), and 10-g monofilament testing.7,8,40 Clinicians should screen their patients within 5 years of the diagnosis of type 1 diabetes and at the time of diagnosis of type 2 diabetes, subsequently scheduling at least annual screening with a full foot exam.7,8
Further assessment to identify risk factors for diabetic foot wounds should include evaluation for foot deformities and vascular disease.7,8 Findings that indicate vascular disease should prompt ankle-brachial index testing.7,8
Patients are considered at high-risk for peripheral neuropathy if they have sensory impairment, a history of podiatric complications, or foot deformities, or if they actively smoke.8 Such patients should have a thorough foot exam during each visit with their primary care provider, and referral to a foot care specialist would be appropriate.8 High-risk individuals would benefit from close surveillance to prevent complications, and specialized footwear may be helpful.8
How to Screen for Diabetic Retinopathy
Also high on the list of Mr. W’s priorities is maintaining his eyesight. All patients with diabetes require adequate screening for diabetic retinopathy, which is a contributing factor in the progression to blindness.41 Referral to an optometrist or ophthalmologist for a dilated fundoscopic eye exam is recommended for patients within 5 years of a diagnosis of type 1 diabetes and for patients with type 2 diabetes at the time of diagnosis.2,7,8 Prompt referral is need for patients with macular edema, severe nonproliferative diabetic retinopathy, or proliferative diabetic retinopathy. The ADA considers the use of retinal photography in detecting diabetic retinopathy an appropriate component of the fundoscopic exam because it has high sensitivity, specificity, and inter- and intra-examination agreement.8,41,42
Continue to: For patients with...
For patients with poorly controlled diabetes or known diabetic retinopathy, dilated retinal examinations should be scheduled on at least an annual basis.2 For those with well-controlled diabetes and no signs of retinopathy, repeat screening no less frequently than every 2 years may be appropriate.2 This allows prompt diagnosis and treatment of a potentially sight-limiting disease before irreversible damage is caused.
In Conclusion: Empowering Patients with Diabetes
The more Mr. W knows about how to maintain his health, the more control he has over his future with diabetes. Providing patients with knowledge of the risks and empowering them through evidence-based methods is invaluable. DSMES programs help achieve this goal and should be considered at multiple stages in the patient’s disease course, including at the time of initial diagnosis, annually, and when complications or transitions in treatment occur.2,9 Involving patients in their own medical care and management helps them to advocate for their well-being. The patient as a fellow collaborator in treatment can help the clinician design a successful management plan that increases the likelihood of better outcomes for patients such as Mr. W.
To review the important areas of prevention of and screening for complications in patients with diabetes, see the Table. Additional guidance can be found in the ADA and AACE recommendations.2,8
1. Centers for Disease Control and Prevention. Diabetes incidence and prevalence. Diabetes Report Card 2017. www.cdc.gov/diabetes/library/reports/reportcard/incidence-2017.html. Published 2018. Accessed June 18, 2020.
2. Standards of Medical Care in Diabetes—2020 Abridged for Primary Care Providers. American Diabetes Association Clinical Diabetes. 2020;38(1):10-38.
3. Chen Y, Sloan FA, Yashkin AP. Adherence to diabetes guidelines for screening, physical activity and medication and onset of complications and death. J Diabetes Complications. 2015;29(8):1228-1233.
4. Mehta S, Mocarski M, Wisniewski T, et al. Primary care physicians’ utilization of type 2 diabetes screening guidelines and referrals to behavioral interventions: a survey-linked retrospective study. BMJ Open Diabetes Res Care. 2017;5(1):e000406.
5. Center for Disease Control and Prevention. Preventive care practices. Diabetes Report Card 2017. www.cdc.gov/diabetes/library/reports/reportcard/preventive-care.html. Published 2018. Accessed June 18, 2020.
6. Arnold SV, de Lemos JA, Rosenson RS, et al; GOULD Investigators. Use of guideline-recommended risk reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease. Circulation. 2019;140(7):618-620.
7. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary. Endocr Pract Endocr Pract. 2020;26(1):107-139.
8. American Diabetes Association. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes—2020. Diabetes Care. 2020;43(suppl 1):S37-S47.
9. Beck J, Greenwood DA, Blanton L, et al; 2017 Standards Revision Task Force. 2017 National Standards for diabetes self-management education and support. Diabetes Educ. 2017;43(5): 449-464.
10. Chrvala CA, Sherr D, Lipman RD. Diabetes self-management education for adults with type 2 diabetes mellitus: a systematic review of the effect on glycemic control. Patient Educ Couns. 2016;99(6):926-943.
11. Association of Diabetes Care & Education Specialists. Find a diabetes education program in your area. www.diabeteseducator.org/living-with-diabetes/find-an-education-program. Accessed June 15, 2020.
12. Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. NEJM. 2018;378(25):e34.
13. Centers for Disease Control and Prevention. Tips for better sleep. Sleep and sleep disorders. www.cdc.gov/sleep/about_sleep/sleep_hygiene.html. Reviewed July 15, 2016. Accessed June 18, 2020.
14. Doumit J, Prasad B. Sleep Apnea in Type 2 Diabetes. Diabetes Spectrum. 2016; 29(1): 14-19.
15. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.
16. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306.
17. Trends in Blood pressure control and treatment among type 2 diabetes with comorbid hypertension in the United States: 1988-2004. J Hypertens. 2009;27(9):1908-1916.
18. Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015;313(6):603-615.
19. Vouri SM, Shaw RF, Waterbury NV, et al. Prevalence of achievement of A1c, blood pressure, and cholesterol (ABC) goal in veterans with diabetes. J Manag Care Pharm. 2011;17(4):304-312.
20. Kudo N, Yokokawa H, Fukuda H, et al. Achievement of target blood pressure levels among Japanese workers with hypertension and healthy lifestyle characteristics associated with therapeutic failure. Plos One. 2015;10(7):e0133641.
21. Carey RM, Whelton PK; 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension guideline. Ann Intern Med. 2018;168(5):351-358.
22. Deedwania PC. Blood pressure control in diabetes mellitus. Circulation. 2011;123:2776–2778.
23. Catalá-López F, Saint-Gerons DM, González-Bermejo D, et al. Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: a systematic review with network meta-analyses. PLoS Med. 2016;13(3):e1001971.
24. Furberg CD, Wright JT Jr, Davis BR, et al; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997.
25. Sleight P. The HOPE Study (Heart Outcomes Prevention Evaluation). J Renin-Angiotensin-Aldosterone Syst. 2000;1(1):18-20.
26. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21(4):597-603.
27. Schrier RW, Estacio RO, Jeffers B. Appropriate Blood Pressure Control in NIDDM (ABCD) Trial. Diabetologia. 1996;39(12):1646-1654.
28. Hansson L, Zanchetti A, Carruthers SG, et al; HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) Randomised Trial. Lancet. 1998;351(9118):1755-1762.
29. Baigent C, Blackwell L, Emberson J, et al; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
30. Fu AZ, Zhang Q, Davies MJ, et al. Underutilization of statins in patients with type 2 diabetes in US clinical practice: a retrospective cohort study. Curr Med Res Opin. 2011;27(5):1035-1040.
31. Cannon CP, Blazing MA, Giugliano RP, et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372:2387-2397
32. Sabatine MS, Giugliano RP, Keech AC, et al; the FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
33. Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome | NEJM. N Engl J Med. 2018;379:2097-2107.
34. Icosapent ethyl [package insert]. Bridgewater, NJ: Amarin Pharma, Inc.; 2019.
35. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22
36. Bolton WK. Renal Physicians Association Clinical practice guideline: appropriate patient preparation for renal replacement therapy: guideline number 3. J Am Soc Nephrol. 2003;14(5):1406-1410.
37. American Diabetes Association. Pharmacologic Approaches to glycemic treatment: standards of medical care in diabetes—2020. Diabetes Care. 2020;43(suppl 1):S98-S110.
38. Qaseem A, Barry MJ, Humphrey LL, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279-290.
39. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011). 2017;7(1):1-59.
40. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154.
41. Gupta V, Bansal R, Gupta A, Bhansali A. The sensitivity and specificity of nonmydriatic digital stereoscopic retinal imaging in detecting diabetic retinopathy. Indian J Ophthalmol. 2014;62(8):851-856.
42. Pérez MA, Bruce BB, Newman NJ, Biousse V. The use of retinal photography in non-ophthalmic settings and its potential for neurology. The Neurologist. 2012;18(6):350-355.
Clinician Reviews in partnership with
Courtney Bennett Wilke is an Assistant Professor at Florida State University College of Medicine, School of Physician Assistant Practice, Tallahassee.
Clinician Reviews in partnership with
Courtney Bennett Wilke is an Assistant Professor at Florida State University College of Medicine, School of Physician Assistant Practice, Tallahassee.
Clinician Reviews in partnership with
Courtney Bennett Wilke is an Assistant Professor at Florida State University College of Medicine, School of Physician Assistant Practice, Tallahassee.
Previously, we discussed monitoring for chronic kidney disease in patients with diabetes. In this final part of our series, we’ll discuss screening to prevent impairment to the patient’s mobility and sight.
CASE CONTINUED
Mr. W is appreciative of your efforts to improve his health, but he fears his quality of life with diabetes will suffer. Because his father experienced impaired sight and limited mobility during the final years of his life, Mr. W is concerned he will endure similar complications from his diabetes. What can you do to help safeguard his abilities for sight and mobility?
Detecting peripheral neuropathy
Evaluation of Mr. W’s feet is an appropriate first step in the right direction. Peripheral neuropathy—one of the most common complications in diabetes—occurs in up to 50% of patients with diabetes, and about 50% of peripheral neuropathies may be asymptomatic.40 It is the most significant risk factor for foot ulceration, which in turn is the leading cause of amputation in patients with diabetes.40 Therefore, early identification of peripheral neuropathy is important because it provides an opportunity for patient education on preventive practices and prompts podiatric care.
Screening for peripheral neuropathy should include a detailed history of the risk factors and a thorough physical exam, including pinprick sensation (small sensory fiber function), vibration perception (large sensory fiber function), and 10-g monofilament testing.7,8,40 Clinicians should screen their patients within 5 years of the diagnosis of type 1 diabetes and at the time of diagnosis of type 2 diabetes, subsequently scheduling at least annual screening with a full foot exam.7,8
Further assessment to identify risk factors for diabetic foot wounds should include evaluation for foot deformities and vascular disease.7,8 Findings that indicate vascular disease should prompt ankle-brachial index testing.7,8
Patients are considered at high-risk for peripheral neuropathy if they have sensory impairment, a history of podiatric complications, or foot deformities, or if they actively smoke.8 Such patients should have a thorough foot exam during each visit with their primary care provider, and referral to a foot care specialist would be appropriate.8 High-risk individuals would benefit from close surveillance to prevent complications, and specialized footwear may be helpful.8
How to Screen for Diabetic Retinopathy
Also high on the list of Mr. W’s priorities is maintaining his eyesight. All patients with diabetes require adequate screening for diabetic retinopathy, which is a contributing factor in the progression to blindness.41 Referral to an optometrist or ophthalmologist for a dilated fundoscopic eye exam is recommended for patients within 5 years of a diagnosis of type 1 diabetes and for patients with type 2 diabetes at the time of diagnosis.2,7,8 Prompt referral is need for patients with macular edema, severe nonproliferative diabetic retinopathy, or proliferative diabetic retinopathy. The ADA considers the use of retinal photography in detecting diabetic retinopathy an appropriate component of the fundoscopic exam because it has high sensitivity, specificity, and inter- and intra-examination agreement.8,41,42
Continue to: For patients with...
For patients with poorly controlled diabetes or known diabetic retinopathy, dilated retinal examinations should be scheduled on at least an annual basis.2 For those with well-controlled diabetes and no signs of retinopathy, repeat screening no less frequently than every 2 years may be appropriate.2 This allows prompt diagnosis and treatment of a potentially sight-limiting disease before irreversible damage is caused.
In Conclusion: Empowering Patients with Diabetes
The more Mr. W knows about how to maintain his health, the more control he has over his future with diabetes. Providing patients with knowledge of the risks and empowering them through evidence-based methods is invaluable. DSMES programs help achieve this goal and should be considered at multiple stages in the patient’s disease course, including at the time of initial diagnosis, annually, and when complications or transitions in treatment occur.2,9 Involving patients in their own medical care and management helps them to advocate for their well-being. The patient as a fellow collaborator in treatment can help the clinician design a successful management plan that increases the likelihood of better outcomes for patients such as Mr. W.
To review the important areas of prevention of and screening for complications in patients with diabetes, see the Table. Additional guidance can be found in the ADA and AACE recommendations.2,8
Previously, we discussed monitoring for chronic kidney disease in patients with diabetes. In this final part of our series, we’ll discuss screening to prevent impairment to the patient’s mobility and sight.
CASE CONTINUED
Mr. W is appreciative of your efforts to improve his health, but he fears his quality of life with diabetes will suffer. Because his father experienced impaired sight and limited mobility during the final years of his life, Mr. W is concerned he will endure similar complications from his diabetes. What can you do to help safeguard his abilities for sight and mobility?
Detecting peripheral neuropathy
Evaluation of Mr. W’s feet is an appropriate first step in the right direction. Peripheral neuropathy—one of the most common complications in diabetes—occurs in up to 50% of patients with diabetes, and about 50% of peripheral neuropathies may be asymptomatic.40 It is the most significant risk factor for foot ulceration, which in turn is the leading cause of amputation in patients with diabetes.40 Therefore, early identification of peripheral neuropathy is important because it provides an opportunity for patient education on preventive practices and prompts podiatric care.
Screening for peripheral neuropathy should include a detailed history of the risk factors and a thorough physical exam, including pinprick sensation (small sensory fiber function), vibration perception (large sensory fiber function), and 10-g monofilament testing.7,8,40 Clinicians should screen their patients within 5 years of the diagnosis of type 1 diabetes and at the time of diagnosis of type 2 diabetes, subsequently scheduling at least annual screening with a full foot exam.7,8
Further assessment to identify risk factors for diabetic foot wounds should include evaluation for foot deformities and vascular disease.7,8 Findings that indicate vascular disease should prompt ankle-brachial index testing.7,8
Patients are considered at high-risk for peripheral neuropathy if they have sensory impairment, a history of podiatric complications, or foot deformities, or if they actively smoke.8 Such patients should have a thorough foot exam during each visit with their primary care provider, and referral to a foot care specialist would be appropriate.8 High-risk individuals would benefit from close surveillance to prevent complications, and specialized footwear may be helpful.8
How to Screen for Diabetic Retinopathy
Also high on the list of Mr. W’s priorities is maintaining his eyesight. All patients with diabetes require adequate screening for diabetic retinopathy, which is a contributing factor in the progression to blindness.41 Referral to an optometrist or ophthalmologist for a dilated fundoscopic eye exam is recommended for patients within 5 years of a diagnosis of type 1 diabetes and for patients with type 2 diabetes at the time of diagnosis.2,7,8 Prompt referral is need for patients with macular edema, severe nonproliferative diabetic retinopathy, or proliferative diabetic retinopathy. The ADA considers the use of retinal photography in detecting diabetic retinopathy an appropriate component of the fundoscopic exam because it has high sensitivity, specificity, and inter- and intra-examination agreement.8,41,42
Continue to: For patients with...
For patients with poorly controlled diabetes or known diabetic retinopathy, dilated retinal examinations should be scheduled on at least an annual basis.2 For those with well-controlled diabetes and no signs of retinopathy, repeat screening no less frequently than every 2 years may be appropriate.2 This allows prompt diagnosis and treatment of a potentially sight-limiting disease before irreversible damage is caused.
In Conclusion: Empowering Patients with Diabetes
The more Mr. W knows about how to maintain his health, the more control he has over his future with diabetes. Providing patients with knowledge of the risks and empowering them through evidence-based methods is invaluable. DSMES programs help achieve this goal and should be considered at multiple stages in the patient’s disease course, including at the time of initial diagnosis, annually, and when complications or transitions in treatment occur.2,9 Involving patients in their own medical care and management helps them to advocate for their well-being. The patient as a fellow collaborator in treatment can help the clinician design a successful management plan that increases the likelihood of better outcomes for patients such as Mr. W.
To review the important areas of prevention of and screening for complications in patients with diabetes, see the Table. Additional guidance can be found in the ADA and AACE recommendations.2,8
1. Centers for Disease Control and Prevention. Diabetes incidence and prevalence. Diabetes Report Card 2017. www.cdc.gov/diabetes/library/reports/reportcard/incidence-2017.html. Published 2018. Accessed June 18, 2020.
2. Standards of Medical Care in Diabetes—2020 Abridged for Primary Care Providers. American Diabetes Association Clinical Diabetes. 2020;38(1):10-38.
3. Chen Y, Sloan FA, Yashkin AP. Adherence to diabetes guidelines for screening, physical activity and medication and onset of complications and death. J Diabetes Complications. 2015;29(8):1228-1233.
4. Mehta S, Mocarski M, Wisniewski T, et al. Primary care physicians’ utilization of type 2 diabetes screening guidelines and referrals to behavioral interventions: a survey-linked retrospective study. BMJ Open Diabetes Res Care. 2017;5(1):e000406.
5. Center for Disease Control and Prevention. Preventive care practices. Diabetes Report Card 2017. www.cdc.gov/diabetes/library/reports/reportcard/preventive-care.html. Published 2018. Accessed June 18, 2020.
6. Arnold SV, de Lemos JA, Rosenson RS, et al; GOULD Investigators. Use of guideline-recommended risk reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease. Circulation. 2019;140(7):618-620.
7. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary. Endocr Pract Endocr Pract. 2020;26(1):107-139.
8. American Diabetes Association. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes—2020. Diabetes Care. 2020;43(suppl 1):S37-S47.
9. Beck J, Greenwood DA, Blanton L, et al; 2017 Standards Revision Task Force. 2017 National Standards for diabetes self-management education and support. Diabetes Educ. 2017;43(5): 449-464.
10. Chrvala CA, Sherr D, Lipman RD. Diabetes self-management education for adults with type 2 diabetes mellitus: a systematic review of the effect on glycemic control. Patient Educ Couns. 2016;99(6):926-943.
11. Association of Diabetes Care & Education Specialists. Find a diabetes education program in your area. www.diabeteseducator.org/living-with-diabetes/find-an-education-program. Accessed June 15, 2020.
12. Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. NEJM. 2018;378(25):e34.
13. Centers for Disease Control and Prevention. Tips for better sleep. Sleep and sleep disorders. www.cdc.gov/sleep/about_sleep/sleep_hygiene.html. Reviewed July 15, 2016. Accessed June 18, 2020.
14. Doumit J, Prasad B. Sleep Apnea in Type 2 Diabetes. Diabetes Spectrum. 2016; 29(1): 14-19.
15. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.
16. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306.
17. Trends in Blood pressure control and treatment among type 2 diabetes with comorbid hypertension in the United States: 1988-2004. J Hypertens. 2009;27(9):1908-1916.
18. Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015;313(6):603-615.
19. Vouri SM, Shaw RF, Waterbury NV, et al. Prevalence of achievement of A1c, blood pressure, and cholesterol (ABC) goal in veterans with diabetes. J Manag Care Pharm. 2011;17(4):304-312.
20. Kudo N, Yokokawa H, Fukuda H, et al. Achievement of target blood pressure levels among Japanese workers with hypertension and healthy lifestyle characteristics associated with therapeutic failure. Plos One. 2015;10(7):e0133641.
21. Carey RM, Whelton PK; 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension guideline. Ann Intern Med. 2018;168(5):351-358.
22. Deedwania PC. Blood pressure control in diabetes mellitus. Circulation. 2011;123:2776–2778.
23. Catalá-López F, Saint-Gerons DM, González-Bermejo D, et al. Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: a systematic review with network meta-analyses. PLoS Med. 2016;13(3):e1001971.
24. Furberg CD, Wright JT Jr, Davis BR, et al; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997.
25. Sleight P. The HOPE Study (Heart Outcomes Prevention Evaluation). J Renin-Angiotensin-Aldosterone Syst. 2000;1(1):18-20.
26. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21(4):597-603.
27. Schrier RW, Estacio RO, Jeffers B. Appropriate Blood Pressure Control in NIDDM (ABCD) Trial. Diabetologia. 1996;39(12):1646-1654.
28. Hansson L, Zanchetti A, Carruthers SG, et al; HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) Randomised Trial. Lancet. 1998;351(9118):1755-1762.
29. Baigent C, Blackwell L, Emberson J, et al; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
30. Fu AZ, Zhang Q, Davies MJ, et al. Underutilization of statins in patients with type 2 diabetes in US clinical practice: a retrospective cohort study. Curr Med Res Opin. 2011;27(5):1035-1040.
31. Cannon CP, Blazing MA, Giugliano RP, et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372:2387-2397
32. Sabatine MS, Giugliano RP, Keech AC, et al; the FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
33. Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome | NEJM. N Engl J Med. 2018;379:2097-2107.
34. Icosapent ethyl [package insert]. Bridgewater, NJ: Amarin Pharma, Inc.; 2019.
35. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22
36. Bolton WK. Renal Physicians Association Clinical practice guideline: appropriate patient preparation for renal replacement therapy: guideline number 3. J Am Soc Nephrol. 2003;14(5):1406-1410.
37. American Diabetes Association. Pharmacologic Approaches to glycemic treatment: standards of medical care in diabetes—2020. Diabetes Care. 2020;43(suppl 1):S98-S110.
38. Qaseem A, Barry MJ, Humphrey LL, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279-290.
39. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011). 2017;7(1):1-59.
40. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154.
41. Gupta V, Bansal R, Gupta A, Bhansali A. The sensitivity and specificity of nonmydriatic digital stereoscopic retinal imaging in detecting diabetic retinopathy. Indian J Ophthalmol. 2014;62(8):851-856.
42. Pérez MA, Bruce BB, Newman NJ, Biousse V. The use of retinal photography in non-ophthalmic settings and its potential for neurology. The Neurologist. 2012;18(6):350-355.
1. Centers for Disease Control and Prevention. Diabetes incidence and prevalence. Diabetes Report Card 2017. www.cdc.gov/diabetes/library/reports/reportcard/incidence-2017.html. Published 2018. Accessed June 18, 2020.
2. Standards of Medical Care in Diabetes—2020 Abridged for Primary Care Providers. American Diabetes Association Clinical Diabetes. 2020;38(1):10-38.
3. Chen Y, Sloan FA, Yashkin AP. Adherence to diabetes guidelines for screening, physical activity and medication and onset of complications and death. J Diabetes Complications. 2015;29(8):1228-1233.
4. Mehta S, Mocarski M, Wisniewski T, et al. Primary care physicians’ utilization of type 2 diabetes screening guidelines and referrals to behavioral interventions: a survey-linked retrospective study. BMJ Open Diabetes Res Care. 2017;5(1):e000406.
5. Center for Disease Control and Prevention. Preventive care practices. Diabetes Report Card 2017. www.cdc.gov/diabetes/library/reports/reportcard/preventive-care.html. Published 2018. Accessed June 18, 2020.
6. Arnold SV, de Lemos JA, Rosenson RS, et al; GOULD Investigators. Use of guideline-recommended risk reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease. Circulation. 2019;140(7):618-620.
7. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary. Endocr Pract Endocr Pract. 2020;26(1):107-139.
8. American Diabetes Association. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes—2020. Diabetes Care. 2020;43(suppl 1):S37-S47.
9. Beck J, Greenwood DA, Blanton L, et al; 2017 Standards Revision Task Force. 2017 National Standards for diabetes self-management education and support. Diabetes Educ. 2017;43(5): 449-464.
10. Chrvala CA, Sherr D, Lipman RD. Diabetes self-management education for adults with type 2 diabetes mellitus: a systematic review of the effect on glycemic control. Patient Educ Couns. 2016;99(6):926-943.
11. Association of Diabetes Care & Education Specialists. Find a diabetes education program in your area. www.diabeteseducator.org/living-with-diabetes/find-an-education-program. Accessed June 15, 2020.
12. Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. NEJM. 2018;378(25):e34.
13. Centers for Disease Control and Prevention. Tips for better sleep. Sleep and sleep disorders. www.cdc.gov/sleep/about_sleep/sleep_hygiene.html. Reviewed July 15, 2016. Accessed June 18, 2020.
14. Doumit J, Prasad B. Sleep Apnea in Type 2 Diabetes. Diabetes Spectrum. 2016; 29(1): 14-19.
15. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.
16. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306.
17. Trends in Blood pressure control and treatment among type 2 diabetes with comorbid hypertension in the United States: 1988-2004. J Hypertens. 2009;27(9):1908-1916.
18. Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015;313(6):603-615.
19. Vouri SM, Shaw RF, Waterbury NV, et al. Prevalence of achievement of A1c, blood pressure, and cholesterol (ABC) goal in veterans with diabetes. J Manag Care Pharm. 2011;17(4):304-312.
20. Kudo N, Yokokawa H, Fukuda H, et al. Achievement of target blood pressure levels among Japanese workers with hypertension and healthy lifestyle characteristics associated with therapeutic failure. Plos One. 2015;10(7):e0133641.
21. Carey RM, Whelton PK; 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension guideline. Ann Intern Med. 2018;168(5):351-358.
22. Deedwania PC. Blood pressure control in diabetes mellitus. Circulation. 2011;123:2776–2778.
23. Catalá-López F, Saint-Gerons DM, González-Bermejo D, et al. Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: a systematic review with network meta-analyses. PLoS Med. 2016;13(3):e1001971.
24. Furberg CD, Wright JT Jr, Davis BR, et al; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997.
25. Sleight P. The HOPE Study (Heart Outcomes Prevention Evaluation). J Renin-Angiotensin-Aldosterone Syst. 2000;1(1):18-20.
26. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21(4):597-603.
27. Schrier RW, Estacio RO, Jeffers B. Appropriate Blood Pressure Control in NIDDM (ABCD) Trial. Diabetologia. 1996;39(12):1646-1654.
28. Hansson L, Zanchetti A, Carruthers SG, et al; HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) Randomised Trial. Lancet. 1998;351(9118):1755-1762.
29. Baigent C, Blackwell L, Emberson J, et al; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
30. Fu AZ, Zhang Q, Davies MJ, et al. Underutilization of statins in patients with type 2 diabetes in US clinical practice: a retrospective cohort study. Curr Med Res Opin. 2011;27(5):1035-1040.
31. Cannon CP, Blazing MA, Giugliano RP, et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372:2387-2397
32. Sabatine MS, Giugliano RP, Keech AC, et al; the FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
33. Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome | NEJM. N Engl J Med. 2018;379:2097-2107.
34. Icosapent ethyl [package insert]. Bridgewater, NJ: Amarin Pharma, Inc.; 2019.
35. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22
36. Bolton WK. Renal Physicians Association Clinical practice guideline: appropriate patient preparation for renal replacement therapy: guideline number 3. J Am Soc Nephrol. 2003;14(5):1406-1410.
37. American Diabetes Association. Pharmacologic Approaches to glycemic treatment: standards of medical care in diabetes—2020. Diabetes Care. 2020;43(suppl 1):S98-S110.
38. Qaseem A, Barry MJ, Humphrey LL, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279-290.
39. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011). 2017;7(1):1-59.
40. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154.
41. Gupta V, Bansal R, Gupta A, Bhansali A. The sensitivity and specificity of nonmydriatic digital stereoscopic retinal imaging in detecting diabetic retinopathy. Indian J Ophthalmol. 2014;62(8):851-856.
42. Pérez MA, Bruce BB, Newman NJ, Biousse V. The use of retinal photography in non-ophthalmic settings and its potential for neurology. The Neurologist. 2012;18(6):350-355.
Delaying denosumab dose boosts risk for vertebral fractures
a new study confirms. Physicians say they are especially concerned about the risk facing patients who are delaying the treatment during the coronavirus pandemic.
The recommended doses of denosumab are at 6-month intervals. Patients who delayed a dose by more than 16 weeks were nearly four times more likely to suffer vertebral fractures, compared with those who received on-time injections, according to the study, which was published in Annals of Internal Medicine.
“Because patients who used denosumab were at high risk for vertebral fracture, strategies to improve timely administration of denosumab in routine clinical settings are needed,” wrote the study authors, led by Houchen Lyu, MD, PhD, of National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation at General Hospital of Chinese PLA in Beijing.
Denosumab, a human monoclonal antibody, is used to reduce bone loss in osteoporosis. The manufacturer of Prolia, a brand of the drug, recommends it be given every 6 months, but the study reports that it’s common for injections to be delayed.
Researchers have linked cessation of denosumab to higher risk of fractures, and Dr. Lyu led a study published earlier this year that linked less-frequent doses to less bone mineral density improvement. “However,” the authors of the new study wrote, “whether delaying subsequent injections beyond the recommended 6-month interval is associated with fractures is unknown.”
For their new study, researchers retrospectively analyzed data from 2,594 patients in the U.K. 45 years or older (mean age, 76; 94% female; 53% with a history of major osteoporotic fracture) who began taking denosumab between 2010 and 2019. They used a design that aimed to emulate a clinical trial, comparing three dosing intervals: “on time” (within 4 weeks of the recommended 6-month interval), “short delay” (within 4-16 weeks) and “long delay” (16 weeks to 6 months).
The study found that the risk of composite fracture over 6 months out of 1,000 was 27.3 for on-time dosing, 32.2 for short-delay dosing, and 42.4 for long-delay dosing. The hazard ratio for long-delay versus on-time was 1.44 (95% confidence interval, 0.96-2.17; P = .093).
Vertebral fractures were less likely, but delays boosted the risk significantly: Over 6 months, it grew from 2.2 in 1,000 (on time) to 3.6 in 1,000 (short delay) and 10.1 in 1,000 (long delay). The HR for long delay versus on time was 3.91 (95% CI, 1.62-9.45; P = .005).
“This study had limited statistical power for composite fracture and several secondary end points ... except for vertebral fracture. Thus, evidence was insufficient to conclude that fracture risk was increased at other anatomical sites.”
In an accompanying editorial, two physicians from the University of Minnesota, Minneapolis, noted that the study is “timely and relevant” since the coronavirus pandemic may disrupt dosage schedules more than usual. While the study has limitations, the “findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation, wrote Kristine E. Ensrud, MD, MPH, who is also of Minneapolis VA Health Care System, and John T. Schousboe, MD, PhD, who is also of HealthPartners Institute.
The editorial authors noted that, in light of the pandemic, “some organizations recommend temporary transition to an oral bisphosphonate in patients receiving denosumab treatment for whom continued treatment is not feasible within 7 to 8 months of their most recent injection.”
In an interview, endocrinologist and osteoporosis specialist Ethel Siris, MD, of Columbia University, New York, said many of her patients aren’t coming in for denosumab injections during the pandemic. “It’s hard enough to get people to show up every 6 months to get their shot when things are going nicely,” she said. “We’re talking older women who may be on a lot of other medications. People forget, and it’s difficult for the office to constantly remind some of them to get their shots at an infusion center.”
The lack of symptoms is another challenge to getting patients to return for doses, she said. “In osteoporosis, the only time something hurts is if you break it.”
Since the pandemic began, many patients have been avoiding medical offices because of fear of getting the coronavirus.
The new research is helpful because it shows that patients are “more likely to fracture if they delay,” Dr. Siris noted. The endocrinologist added that she has successfully convinced some patients to give themselves subcutaneous injections in the abdomen at home.
Dr. Siris said she has been able to watch patients do these injections on video to check their technique. Her patients have been impressed by “how easy it is and delighted to have accomplished it,” she said.
The study was funded by the National Institutes of Health China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. The study authors, commentary authors, and Dr. Siris report no relevant disclosures.
SOURCE: Lyu H et al. Ann Intern Med. 2020 Jul 28. doi: 10.7326/M20-0882.
a new study confirms. Physicians say they are especially concerned about the risk facing patients who are delaying the treatment during the coronavirus pandemic.
The recommended doses of denosumab are at 6-month intervals. Patients who delayed a dose by more than 16 weeks were nearly four times more likely to suffer vertebral fractures, compared with those who received on-time injections, according to the study, which was published in Annals of Internal Medicine.
“Because patients who used denosumab were at high risk for vertebral fracture, strategies to improve timely administration of denosumab in routine clinical settings are needed,” wrote the study authors, led by Houchen Lyu, MD, PhD, of National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation at General Hospital of Chinese PLA in Beijing.
Denosumab, a human monoclonal antibody, is used to reduce bone loss in osteoporosis. The manufacturer of Prolia, a brand of the drug, recommends it be given every 6 months, but the study reports that it’s common for injections to be delayed.
Researchers have linked cessation of denosumab to higher risk of fractures, and Dr. Lyu led a study published earlier this year that linked less-frequent doses to less bone mineral density improvement. “However,” the authors of the new study wrote, “whether delaying subsequent injections beyond the recommended 6-month interval is associated with fractures is unknown.”
For their new study, researchers retrospectively analyzed data from 2,594 patients in the U.K. 45 years or older (mean age, 76; 94% female; 53% with a history of major osteoporotic fracture) who began taking denosumab between 2010 and 2019. They used a design that aimed to emulate a clinical trial, comparing three dosing intervals: “on time” (within 4 weeks of the recommended 6-month interval), “short delay” (within 4-16 weeks) and “long delay” (16 weeks to 6 months).
The study found that the risk of composite fracture over 6 months out of 1,000 was 27.3 for on-time dosing, 32.2 for short-delay dosing, and 42.4 for long-delay dosing. The hazard ratio for long-delay versus on-time was 1.44 (95% confidence interval, 0.96-2.17; P = .093).
Vertebral fractures were less likely, but delays boosted the risk significantly: Over 6 months, it grew from 2.2 in 1,000 (on time) to 3.6 in 1,000 (short delay) and 10.1 in 1,000 (long delay). The HR for long delay versus on time was 3.91 (95% CI, 1.62-9.45; P = .005).
“This study had limited statistical power for composite fracture and several secondary end points ... except for vertebral fracture. Thus, evidence was insufficient to conclude that fracture risk was increased at other anatomical sites.”
In an accompanying editorial, two physicians from the University of Minnesota, Minneapolis, noted that the study is “timely and relevant” since the coronavirus pandemic may disrupt dosage schedules more than usual. While the study has limitations, the “findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation, wrote Kristine E. Ensrud, MD, MPH, who is also of Minneapolis VA Health Care System, and John T. Schousboe, MD, PhD, who is also of HealthPartners Institute.
The editorial authors noted that, in light of the pandemic, “some organizations recommend temporary transition to an oral bisphosphonate in patients receiving denosumab treatment for whom continued treatment is not feasible within 7 to 8 months of their most recent injection.”
In an interview, endocrinologist and osteoporosis specialist Ethel Siris, MD, of Columbia University, New York, said many of her patients aren’t coming in for denosumab injections during the pandemic. “It’s hard enough to get people to show up every 6 months to get their shot when things are going nicely,” she said. “We’re talking older women who may be on a lot of other medications. People forget, and it’s difficult for the office to constantly remind some of them to get their shots at an infusion center.”
The lack of symptoms is another challenge to getting patients to return for doses, she said. “In osteoporosis, the only time something hurts is if you break it.”
Since the pandemic began, many patients have been avoiding medical offices because of fear of getting the coronavirus.
The new research is helpful because it shows that patients are “more likely to fracture if they delay,” Dr. Siris noted. The endocrinologist added that she has successfully convinced some patients to give themselves subcutaneous injections in the abdomen at home.
Dr. Siris said she has been able to watch patients do these injections on video to check their technique. Her patients have been impressed by “how easy it is and delighted to have accomplished it,” she said.
The study was funded by the National Institutes of Health China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. The study authors, commentary authors, and Dr. Siris report no relevant disclosures.
SOURCE: Lyu H et al. Ann Intern Med. 2020 Jul 28. doi: 10.7326/M20-0882.
a new study confirms. Physicians say they are especially concerned about the risk facing patients who are delaying the treatment during the coronavirus pandemic.
The recommended doses of denosumab are at 6-month intervals. Patients who delayed a dose by more than 16 weeks were nearly four times more likely to suffer vertebral fractures, compared with those who received on-time injections, according to the study, which was published in Annals of Internal Medicine.
“Because patients who used denosumab were at high risk for vertebral fracture, strategies to improve timely administration of denosumab in routine clinical settings are needed,” wrote the study authors, led by Houchen Lyu, MD, PhD, of National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation at General Hospital of Chinese PLA in Beijing.
Denosumab, a human monoclonal antibody, is used to reduce bone loss in osteoporosis. The manufacturer of Prolia, a brand of the drug, recommends it be given every 6 months, but the study reports that it’s common for injections to be delayed.
Researchers have linked cessation of denosumab to higher risk of fractures, and Dr. Lyu led a study published earlier this year that linked less-frequent doses to less bone mineral density improvement. “However,” the authors of the new study wrote, “whether delaying subsequent injections beyond the recommended 6-month interval is associated with fractures is unknown.”
For their new study, researchers retrospectively analyzed data from 2,594 patients in the U.K. 45 years or older (mean age, 76; 94% female; 53% with a history of major osteoporotic fracture) who began taking denosumab between 2010 and 2019. They used a design that aimed to emulate a clinical trial, comparing three dosing intervals: “on time” (within 4 weeks of the recommended 6-month interval), “short delay” (within 4-16 weeks) and “long delay” (16 weeks to 6 months).
The study found that the risk of composite fracture over 6 months out of 1,000 was 27.3 for on-time dosing, 32.2 for short-delay dosing, and 42.4 for long-delay dosing. The hazard ratio for long-delay versus on-time was 1.44 (95% confidence interval, 0.96-2.17; P = .093).
Vertebral fractures were less likely, but delays boosted the risk significantly: Over 6 months, it grew from 2.2 in 1,000 (on time) to 3.6 in 1,000 (short delay) and 10.1 in 1,000 (long delay). The HR for long delay versus on time was 3.91 (95% CI, 1.62-9.45; P = .005).
“This study had limited statistical power for composite fracture and several secondary end points ... except for vertebral fracture. Thus, evidence was insufficient to conclude that fracture risk was increased at other anatomical sites.”
In an accompanying editorial, two physicians from the University of Minnesota, Minneapolis, noted that the study is “timely and relevant” since the coronavirus pandemic may disrupt dosage schedules more than usual. While the study has limitations, the “findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation, wrote Kristine E. Ensrud, MD, MPH, who is also of Minneapolis VA Health Care System, and John T. Schousboe, MD, PhD, who is also of HealthPartners Institute.
The editorial authors noted that, in light of the pandemic, “some organizations recommend temporary transition to an oral bisphosphonate in patients receiving denosumab treatment for whom continued treatment is not feasible within 7 to 8 months of their most recent injection.”
In an interview, endocrinologist and osteoporosis specialist Ethel Siris, MD, of Columbia University, New York, said many of her patients aren’t coming in for denosumab injections during the pandemic. “It’s hard enough to get people to show up every 6 months to get their shot when things are going nicely,” she said. “We’re talking older women who may be on a lot of other medications. People forget, and it’s difficult for the office to constantly remind some of them to get their shots at an infusion center.”
The lack of symptoms is another challenge to getting patients to return for doses, she said. “In osteoporosis, the only time something hurts is if you break it.”
Since the pandemic began, many patients have been avoiding medical offices because of fear of getting the coronavirus.
The new research is helpful because it shows that patients are “more likely to fracture if they delay,” Dr. Siris noted. The endocrinologist added that she has successfully convinced some patients to give themselves subcutaneous injections in the abdomen at home.
Dr. Siris said she has been able to watch patients do these injections on video to check their technique. Her patients have been impressed by “how easy it is and delighted to have accomplished it,” she said.
The study was funded by the National Institutes of Health China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. The study authors, commentary authors, and Dr. Siris report no relevant disclosures.
SOURCE: Lyu H et al. Ann Intern Med. 2020 Jul 28. doi: 10.7326/M20-0882.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: Patients with osteoporosis who delay denosumab doses are at much higher risk for vertebral fractures.
Major finding: Over 6 months, the risk of vertebral fractures grew from 2.2 in 1,000 (on-time doses) to 10.1 in 1,000 (delay of more than 16 weeks) – a hazard ratio of 3.91 (confidence interval, 1.62 to 9.45; P = .005).
Study details: Retrospective analysis of 2,594 patients in the U.K. 45 years or older who began taking denosumab between 2010 and 2019.
Disclosures: The study was funded by the National Institutes of Health China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. The study authors report no relevant disclosures.
Source: Lyu H et al. Ann Intern Med. 2020 Jul 28. doi: 10.7326/M20-0882.
Cleaner data confirm severe COVID-19 link to diabetes, hypertension
Further refinement of data from patients hospitalized worldwide for COVID-19 disease showed a 12% prevalence rate of patients with diabetes in this population and a 17% prevalence rate for hypertension.
These are lower rates than previously reported for COVID-19 patients with either of these two comorbidities, yet the findings still document important epidemiologic links between diabetes, hypertension, and COVID-19, said the study’s authors.
A meta-analysis of data from 15,794 patients hospitalized because of COVID-19 disease that was drawn from 65 carefully curated reports published from December 1, 2019, to April 6, 2020, also showed that, among the hospitalized COVID-19 patients with diabetes (either type 1 or type 2), the rate of patients who required ICU admission was 96% higher than among those without diabetes and mortality was 2.78-fold higher, both statistically significant differences.
The rate of ICU admissions among those hospitalized with COVID-19 who also had hypertension was 2.95-fold above those without hypertension, and mortality was 2.39-fold higher, also statistically significant differences, reported a team of researchers in the recently published report.
The new meta-analysis was notable for the extra effort investigators employed to eliminate duplicated patients from their database of COVID-19 patients included in various published reports, a potential source of bias that likely introduced errors into prior meta-analyses that used similar data. “We found an overwhelming proportion of studies at high risk of data repetition,” the report said. Virtually all of the included studies were retrospective case studies, nearly two-thirds had data from a single center, and 71% of the studies included only patients in China.
“We developed a method to identify reports that had a high risk for repetitions” of included patients, said Fady Hannah-Shmouni, MD, a senior author of the study. “We also used methods to minimize bias, we excluded certain patients populations, and we applied a uniform definition of COVID-19 disease severity,” specifically patients who died or needed ICU admission, because the definitions used originally by many of the reports were very heterogeneous, said Dr. Hannah-Shmouni, principal investigator for Endocrine, Genetics, and Hypertension at the National Institute of Child Health and Human Development.
Despite the effort to eliminate case duplications, the analysis remains subject to additional confounders, in part because of a lack of comprehensive patient information on factors such as smoking, body mass index, socioeconomic status, and the specific type of diabetes or hypertension a patient had. “Even with these limitations, we were able to show that the prevalence of hypertension and diabetes is elevated in patients with COVID-19, that patients with diabetes have increased risk for both death and ICU admissions, and that there is the potential for reverse causality in the reporting of hypertension as a risk factor for COVID-19,” Dr. Hannah-Shmouni said in an interview. “We believe the explosion of data that associated hypertension and COVID-19 may be partially the result of reverse causality.”
One possible example of this reverse causality is the overlap between hypertension and age as potential risk factors for COVID-19 disease or increased infection severity. People “older than 80 frequently develop severe disease if infected with the novel coronavirus, and 80% of people older than 80 have hypertension, so it’s not surprising that hypertension is highly prevalent among hospitalized COVID-19 patients,” but this “does not imply a causal relationship between hypertension and severe COVID-19; the risk of hypertension probably depends on older age,” noted Ernesto L. Schiffrin, MD, a coauthor of the study, as well as professor of medicine at McGill University and director of the Hypertension and Vascular Research Unit at the Lady Davis Institute for Medical Research, both in Montreal. “My current opinion, on the basis of the totality of data, is that hypertension does not worsen [COVID-19] outcomes, but patients who are elderly, obese, diabetic, or immunocompromised are susceptible to more severe COVID-19 and worse outcomes,” said Dr. Schiffrin in an interview.
The new findings show “there is certainly an interplay between the virus, diabetes, and hypertension and other risk factors,” and while still limited by biases, the new findings “get closer” to correctly estimating the COVID-19 risks associated with these comorbidities,” Dr. Hannah-Shmouni said.
The connections identified between COVID-19, diabetes, and hypertension mean that patients with these chronic diseases should receive education about their COVID-19 risks and should have adequate access to the drugs and supplies they need to control blood pressure and hyperglycemia. Patients with diabetes also need to be current on vaccinations to reduce their risk for pneumonia. And recognition of the heightened COVID-19 risk for people with these comorbidities is important among people who work in relevant government agencies, health care workers, and patient advocacy groups, he added.
The study received no commercial funding. Dr. Hannah-Shmouni and Dr. Schiffrin had no disclosures.
SOURCE: Barrera FJ et al. J Endocn Soc. 2020 July 21. doi: 10.1210/jendso/bvaa102.
Further refinement of data from patients hospitalized worldwide for COVID-19 disease showed a 12% prevalence rate of patients with diabetes in this population and a 17% prevalence rate for hypertension.
These are lower rates than previously reported for COVID-19 patients with either of these two comorbidities, yet the findings still document important epidemiologic links between diabetes, hypertension, and COVID-19, said the study’s authors.
A meta-analysis of data from 15,794 patients hospitalized because of COVID-19 disease that was drawn from 65 carefully curated reports published from December 1, 2019, to April 6, 2020, also showed that, among the hospitalized COVID-19 patients with diabetes (either type 1 or type 2), the rate of patients who required ICU admission was 96% higher than among those without diabetes and mortality was 2.78-fold higher, both statistically significant differences.
The rate of ICU admissions among those hospitalized with COVID-19 who also had hypertension was 2.95-fold above those without hypertension, and mortality was 2.39-fold higher, also statistically significant differences, reported a team of researchers in the recently published report.
The new meta-analysis was notable for the extra effort investigators employed to eliminate duplicated patients from their database of COVID-19 patients included in various published reports, a potential source of bias that likely introduced errors into prior meta-analyses that used similar data. “We found an overwhelming proportion of studies at high risk of data repetition,” the report said. Virtually all of the included studies were retrospective case studies, nearly two-thirds had data from a single center, and 71% of the studies included only patients in China.
“We developed a method to identify reports that had a high risk for repetitions” of included patients, said Fady Hannah-Shmouni, MD, a senior author of the study. “We also used methods to minimize bias, we excluded certain patients populations, and we applied a uniform definition of COVID-19 disease severity,” specifically patients who died or needed ICU admission, because the definitions used originally by many of the reports were very heterogeneous, said Dr. Hannah-Shmouni, principal investigator for Endocrine, Genetics, and Hypertension at the National Institute of Child Health and Human Development.
Despite the effort to eliminate case duplications, the analysis remains subject to additional confounders, in part because of a lack of comprehensive patient information on factors such as smoking, body mass index, socioeconomic status, and the specific type of diabetes or hypertension a patient had. “Even with these limitations, we were able to show that the prevalence of hypertension and diabetes is elevated in patients with COVID-19, that patients with diabetes have increased risk for both death and ICU admissions, and that there is the potential for reverse causality in the reporting of hypertension as a risk factor for COVID-19,” Dr. Hannah-Shmouni said in an interview. “We believe the explosion of data that associated hypertension and COVID-19 may be partially the result of reverse causality.”
One possible example of this reverse causality is the overlap between hypertension and age as potential risk factors for COVID-19 disease or increased infection severity. People “older than 80 frequently develop severe disease if infected with the novel coronavirus, and 80% of people older than 80 have hypertension, so it’s not surprising that hypertension is highly prevalent among hospitalized COVID-19 patients,” but this “does not imply a causal relationship between hypertension and severe COVID-19; the risk of hypertension probably depends on older age,” noted Ernesto L. Schiffrin, MD, a coauthor of the study, as well as professor of medicine at McGill University and director of the Hypertension and Vascular Research Unit at the Lady Davis Institute for Medical Research, both in Montreal. “My current opinion, on the basis of the totality of data, is that hypertension does not worsen [COVID-19] outcomes, but patients who are elderly, obese, diabetic, or immunocompromised are susceptible to more severe COVID-19 and worse outcomes,” said Dr. Schiffrin in an interview.
The new findings show “there is certainly an interplay between the virus, diabetes, and hypertension and other risk factors,” and while still limited by biases, the new findings “get closer” to correctly estimating the COVID-19 risks associated with these comorbidities,” Dr. Hannah-Shmouni said.
The connections identified between COVID-19, diabetes, and hypertension mean that patients with these chronic diseases should receive education about their COVID-19 risks and should have adequate access to the drugs and supplies they need to control blood pressure and hyperglycemia. Patients with diabetes also need to be current on vaccinations to reduce their risk for pneumonia. And recognition of the heightened COVID-19 risk for people with these comorbidities is important among people who work in relevant government agencies, health care workers, and patient advocacy groups, he added.
The study received no commercial funding. Dr. Hannah-Shmouni and Dr. Schiffrin had no disclosures.
SOURCE: Barrera FJ et al. J Endocn Soc. 2020 July 21. doi: 10.1210/jendso/bvaa102.
Further refinement of data from patients hospitalized worldwide for COVID-19 disease showed a 12% prevalence rate of patients with diabetes in this population and a 17% prevalence rate for hypertension.
These are lower rates than previously reported for COVID-19 patients with either of these two comorbidities, yet the findings still document important epidemiologic links between diabetes, hypertension, and COVID-19, said the study’s authors.
A meta-analysis of data from 15,794 patients hospitalized because of COVID-19 disease that was drawn from 65 carefully curated reports published from December 1, 2019, to April 6, 2020, also showed that, among the hospitalized COVID-19 patients with diabetes (either type 1 or type 2), the rate of patients who required ICU admission was 96% higher than among those without diabetes and mortality was 2.78-fold higher, both statistically significant differences.
The rate of ICU admissions among those hospitalized with COVID-19 who also had hypertension was 2.95-fold above those without hypertension, and mortality was 2.39-fold higher, also statistically significant differences, reported a team of researchers in the recently published report.
The new meta-analysis was notable for the extra effort investigators employed to eliminate duplicated patients from their database of COVID-19 patients included in various published reports, a potential source of bias that likely introduced errors into prior meta-analyses that used similar data. “We found an overwhelming proportion of studies at high risk of data repetition,” the report said. Virtually all of the included studies were retrospective case studies, nearly two-thirds had data from a single center, and 71% of the studies included only patients in China.
“We developed a method to identify reports that had a high risk for repetitions” of included patients, said Fady Hannah-Shmouni, MD, a senior author of the study. “We also used methods to minimize bias, we excluded certain patients populations, and we applied a uniform definition of COVID-19 disease severity,” specifically patients who died or needed ICU admission, because the definitions used originally by many of the reports were very heterogeneous, said Dr. Hannah-Shmouni, principal investigator for Endocrine, Genetics, and Hypertension at the National Institute of Child Health and Human Development.
Despite the effort to eliminate case duplications, the analysis remains subject to additional confounders, in part because of a lack of comprehensive patient information on factors such as smoking, body mass index, socioeconomic status, and the specific type of diabetes or hypertension a patient had. “Even with these limitations, we were able to show that the prevalence of hypertension and diabetes is elevated in patients with COVID-19, that patients with diabetes have increased risk for both death and ICU admissions, and that there is the potential for reverse causality in the reporting of hypertension as a risk factor for COVID-19,” Dr. Hannah-Shmouni said in an interview. “We believe the explosion of data that associated hypertension and COVID-19 may be partially the result of reverse causality.”
One possible example of this reverse causality is the overlap between hypertension and age as potential risk factors for COVID-19 disease or increased infection severity. People “older than 80 frequently develop severe disease if infected with the novel coronavirus, and 80% of people older than 80 have hypertension, so it’s not surprising that hypertension is highly prevalent among hospitalized COVID-19 patients,” but this “does not imply a causal relationship between hypertension and severe COVID-19; the risk of hypertension probably depends on older age,” noted Ernesto L. Schiffrin, MD, a coauthor of the study, as well as professor of medicine at McGill University and director of the Hypertension and Vascular Research Unit at the Lady Davis Institute for Medical Research, both in Montreal. “My current opinion, on the basis of the totality of data, is that hypertension does not worsen [COVID-19] outcomes, but patients who are elderly, obese, diabetic, or immunocompromised are susceptible to more severe COVID-19 and worse outcomes,” said Dr. Schiffrin in an interview.
The new findings show “there is certainly an interplay between the virus, diabetes, and hypertension and other risk factors,” and while still limited by biases, the new findings “get closer” to correctly estimating the COVID-19 risks associated with these comorbidities,” Dr. Hannah-Shmouni said.
The connections identified between COVID-19, diabetes, and hypertension mean that patients with these chronic diseases should receive education about their COVID-19 risks and should have adequate access to the drugs and supplies they need to control blood pressure and hyperglycemia. Patients with diabetes also need to be current on vaccinations to reduce their risk for pneumonia. And recognition of the heightened COVID-19 risk for people with these comorbidities is important among people who work in relevant government agencies, health care workers, and patient advocacy groups, he added.
The study received no commercial funding. Dr. Hannah-Shmouni and Dr. Schiffrin had no disclosures.
SOURCE: Barrera FJ et al. J Endocn Soc. 2020 July 21. doi: 10.1210/jendso/bvaa102.
FROM JOURNAL OF THE ENDOCRINE SOCIETY