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EMPEROR-Reduced: Empagliflozin’s HFrEF benefit solidifies class effects
The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients with heart failure with reduced ejection fraction and no diabetes, with results from a second large, controlled trial showing clear efficacy and safety in this population.
Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) had a statistically significant 25% relative cut in their incidence of cardiovascular death or first heart failure hospitalization, compared with placebo-treated controls when added on top of standard HFrEF treatment, and this benefit was consistent regardless of whether the treated patients also had type 2 diabetes, Milton Packer, MD, reported at the virtual annual congress of the European Society of Cardiology.
This 25% drop in the primary endpoint with empagliflozin treatment in the EMPEROR-Reduced trial exactly matched the cut in incidence of cardiovascular death or heart failure hospitalization produced by treatment with a another SGLT2 inhibitor, dapagliflozin (Farxiga), in the DAPA-HF trial (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).
The performance of these two SGLT2 inhibitors was “incredibly consistent” across the their respective trials run in HFrEF patients with and without type 2 diabetes, and the combined evidence base of the two trials makes for “really compelling evidence” of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment, Dr. Packer said.
Results plant drug class firmly as HFrEF treatment
Dr. Packer stressed in his presentation that optimal treatment of patients with HFrEF now demands use of one of these two SGLT2 inhibitors, as well as sacubitril plus valsartan (Entresto), a beta-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many HFrEF patients who also need treatment for fluid overload. He further advocated for rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives a HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less while acknowledging that optimal up-titration of the beta-blocker would likely take longer.
The order in which a patient starts these drugs shouldn’t matter, and there currently seems to be no evidence that clearly points toward using either dapagliflozin or empagliflozin over the other, Dr. Packer added.
In recognition of the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in HFrEF patients, the American College of Cardiology and American Heart Association are now drafting an “expert decision pathway” to help clinicians as they enter this new prescribing space. This interim guidance should come out before the end of 2020, prior to release of fully revised HFrEF management guidelines in 2021, said Athena Poppas, MD, president of the ACC, in an interview.
“There is clearly need for education” that can help guide physicians who care for HFrEF patients on how to introduce an SGLT2 inhibitor along with the additional, lengthy list of drug classes proven to benefit these patients, noted Dr. Poppas, who is also a professor and chief of cardiology at the Brown University in Providence, R.I. Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in HFrEF patients because recent history has shown substantial pushback from third-party payers in reimbursing for these relatively expensive drugs, Dr. Poppas noted. She added that this is a problem that may be compounded when patients should ideally get both drug classes.
Physicians who care for heart failure patients have their own history of dragging their feet when adding new drugs to the regimens HFrEF patients receive. The angiotensin converting enzyme inhibitors and beta-blockers took about 17 years each to start reaching a majority of U.S. HFrEF patients, and sacubitril plus valsartan is now used on perhaps a quarter to a third of HFrEF patients despite receiving Food and Drug Administration approval for these patients in mid 2015, noted Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Va.
Despite dapagliflozin receiving FDA approval in May 2020 for treating HFrEF in patients without diabetes, early uptake in U.S. practice has been very slow, with findings from large U.S. patient registries suggesting that perhaps 1% of suitable HFrEF patients currently get the drug, estimated Dr. O’Connor in an interview.
Given how strong the evidence now is for benefit and safety from dapagliflozin and empagliflozin, it may take as little as 5 years to reach greater than 50% penetration of one of these drugs into U.S. HFrEF patient populations, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.
EMPEROR-Reduced outcomes
The road to routine use of these SGLT2 inhibitor drugs should be hastened by empagliflozin’s impressive performance in EMPEROR-Reduced, in which the drug scored highly significant benefits over placebo for the prespecified primary and two major secondary endpoints, one of which was a measure of preserved renal function.
The trial randomized 3,730 patients at 520 sites in 20 countries during 2017-2019 and followed them on treatment for a median of 16 months. All patients had a left ventricular ejection fraction of 40% or less, and roughly three-quarters had New York Heart Association (NYHA) class II function, nearly one-quarter had class III function, and fewer than 1% of patients fell into the class IV category.
The primary endpoint occurred in 19% of the empagliflozin-treated patients and in 25% of those who received placebo. Among the half of patients with diabetes in the trial, the relative risk reduction by empagliflozin compared with placebo was a statistically significant 28%; among those without diabetes, it was a statistically significant 22%. Concurrently with Dr. Packer’s report, the results appeared in an article posted online (N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190).
The study also had two main prespecified secondary endpoints: the incidence of total hospitalizations for heart failure, both first and recurrent, which fell by 30% in the empagliflozin-treated patients, compared with placebo, and the rate of declining renal function during the 16 months of the study as measured by estimated glomerular filtration rate, which dropped by roughly 1 mL/min per 1.73 m2 among the empagliflozin recipients and by about 4 mL/min/ per 1.73 m2 in the placebo patients.
Treatment with empagliflozin also achieved a notable, statistically significant 50% drop in major adverse renal events, consistent with the performance of other drugs in the class.
“Renal protection is a big plus” of empagliflozin in this trial and from the other SGLT2 inhibitors in prior studies, noted Dr. O’Connor.
The EMPEROR-Reduced results also showed an important benefit for HFrEF patients from empagliflozin not previously seen as quickly with any other drug class, noted Dr. Packer. The SGLT2 inhibitor led to statistically a significant slowing in the progression of patients from NYHA class II function to class III, compared with placebo, and it also significantly promoted the recovery of patients from NYHA class III to class II, an effect that became apparent within the first month on treatment and a benefit that is a “big deal” for patients because it represents a “significant change in functional capacity.” This additional dimension of empagliflozin’s benefit “really impressed me,” Dr. Packer said.
EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Poppas and Dr. O’Connor had no relevant disclosures.
SOURCE: Packer M. ESC 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190.
The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients with heart failure with reduced ejection fraction and no diabetes, with results from a second large, controlled trial showing clear efficacy and safety in this population.
Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) had a statistically significant 25% relative cut in their incidence of cardiovascular death or first heart failure hospitalization, compared with placebo-treated controls when added on top of standard HFrEF treatment, and this benefit was consistent regardless of whether the treated patients also had type 2 diabetes, Milton Packer, MD, reported at the virtual annual congress of the European Society of Cardiology.
This 25% drop in the primary endpoint with empagliflozin treatment in the EMPEROR-Reduced trial exactly matched the cut in incidence of cardiovascular death or heart failure hospitalization produced by treatment with a another SGLT2 inhibitor, dapagliflozin (Farxiga), in the DAPA-HF trial (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).
The performance of these two SGLT2 inhibitors was “incredibly consistent” across the their respective trials run in HFrEF patients with and without type 2 diabetes, and the combined evidence base of the two trials makes for “really compelling evidence” of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment, Dr. Packer said.
Results plant drug class firmly as HFrEF treatment
Dr. Packer stressed in his presentation that optimal treatment of patients with HFrEF now demands use of one of these two SGLT2 inhibitors, as well as sacubitril plus valsartan (Entresto), a beta-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many HFrEF patients who also need treatment for fluid overload. He further advocated for rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives a HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less while acknowledging that optimal up-titration of the beta-blocker would likely take longer.
The order in which a patient starts these drugs shouldn’t matter, and there currently seems to be no evidence that clearly points toward using either dapagliflozin or empagliflozin over the other, Dr. Packer added.
In recognition of the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in HFrEF patients, the American College of Cardiology and American Heart Association are now drafting an “expert decision pathway” to help clinicians as they enter this new prescribing space. This interim guidance should come out before the end of 2020, prior to release of fully revised HFrEF management guidelines in 2021, said Athena Poppas, MD, president of the ACC, in an interview.
“There is clearly need for education” that can help guide physicians who care for HFrEF patients on how to introduce an SGLT2 inhibitor along with the additional, lengthy list of drug classes proven to benefit these patients, noted Dr. Poppas, who is also a professor and chief of cardiology at the Brown University in Providence, R.I. Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in HFrEF patients because recent history has shown substantial pushback from third-party payers in reimbursing for these relatively expensive drugs, Dr. Poppas noted. She added that this is a problem that may be compounded when patients should ideally get both drug classes.
Physicians who care for heart failure patients have their own history of dragging their feet when adding new drugs to the regimens HFrEF patients receive. The angiotensin converting enzyme inhibitors and beta-blockers took about 17 years each to start reaching a majority of U.S. HFrEF patients, and sacubitril plus valsartan is now used on perhaps a quarter to a third of HFrEF patients despite receiving Food and Drug Administration approval for these patients in mid 2015, noted Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Va.
Despite dapagliflozin receiving FDA approval in May 2020 for treating HFrEF in patients without diabetes, early uptake in U.S. practice has been very slow, with findings from large U.S. patient registries suggesting that perhaps 1% of suitable HFrEF patients currently get the drug, estimated Dr. O’Connor in an interview.
Given how strong the evidence now is for benefit and safety from dapagliflozin and empagliflozin, it may take as little as 5 years to reach greater than 50% penetration of one of these drugs into U.S. HFrEF patient populations, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.
EMPEROR-Reduced outcomes
The road to routine use of these SGLT2 inhibitor drugs should be hastened by empagliflozin’s impressive performance in EMPEROR-Reduced, in which the drug scored highly significant benefits over placebo for the prespecified primary and two major secondary endpoints, one of which was a measure of preserved renal function.
The trial randomized 3,730 patients at 520 sites in 20 countries during 2017-2019 and followed them on treatment for a median of 16 months. All patients had a left ventricular ejection fraction of 40% or less, and roughly three-quarters had New York Heart Association (NYHA) class II function, nearly one-quarter had class III function, and fewer than 1% of patients fell into the class IV category.
The primary endpoint occurred in 19% of the empagliflozin-treated patients and in 25% of those who received placebo. Among the half of patients with diabetes in the trial, the relative risk reduction by empagliflozin compared with placebo was a statistically significant 28%; among those without diabetes, it was a statistically significant 22%. Concurrently with Dr. Packer’s report, the results appeared in an article posted online (N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190).
The study also had two main prespecified secondary endpoints: the incidence of total hospitalizations for heart failure, both first and recurrent, which fell by 30% in the empagliflozin-treated patients, compared with placebo, and the rate of declining renal function during the 16 months of the study as measured by estimated glomerular filtration rate, which dropped by roughly 1 mL/min per 1.73 m2 among the empagliflozin recipients and by about 4 mL/min/ per 1.73 m2 in the placebo patients.
Treatment with empagliflozin also achieved a notable, statistically significant 50% drop in major adverse renal events, consistent with the performance of other drugs in the class.
“Renal protection is a big plus” of empagliflozin in this trial and from the other SGLT2 inhibitors in prior studies, noted Dr. O’Connor.
The EMPEROR-Reduced results also showed an important benefit for HFrEF patients from empagliflozin not previously seen as quickly with any other drug class, noted Dr. Packer. The SGLT2 inhibitor led to statistically a significant slowing in the progression of patients from NYHA class II function to class III, compared with placebo, and it also significantly promoted the recovery of patients from NYHA class III to class II, an effect that became apparent within the first month on treatment and a benefit that is a “big deal” for patients because it represents a “significant change in functional capacity.” This additional dimension of empagliflozin’s benefit “really impressed me,” Dr. Packer said.
EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Poppas and Dr. O’Connor had no relevant disclosures.
SOURCE: Packer M. ESC 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190.
The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients with heart failure with reduced ejection fraction and no diabetes, with results from a second large, controlled trial showing clear efficacy and safety in this population.
Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) had a statistically significant 25% relative cut in their incidence of cardiovascular death or first heart failure hospitalization, compared with placebo-treated controls when added on top of standard HFrEF treatment, and this benefit was consistent regardless of whether the treated patients also had type 2 diabetes, Milton Packer, MD, reported at the virtual annual congress of the European Society of Cardiology.
This 25% drop in the primary endpoint with empagliflozin treatment in the EMPEROR-Reduced trial exactly matched the cut in incidence of cardiovascular death or heart failure hospitalization produced by treatment with a another SGLT2 inhibitor, dapagliflozin (Farxiga), in the DAPA-HF trial (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).
The performance of these two SGLT2 inhibitors was “incredibly consistent” across the their respective trials run in HFrEF patients with and without type 2 diabetes, and the combined evidence base of the two trials makes for “really compelling evidence” of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment, Dr. Packer said.
Results plant drug class firmly as HFrEF treatment
Dr. Packer stressed in his presentation that optimal treatment of patients with HFrEF now demands use of one of these two SGLT2 inhibitors, as well as sacubitril plus valsartan (Entresto), a beta-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many HFrEF patients who also need treatment for fluid overload. He further advocated for rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives a HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less while acknowledging that optimal up-titration of the beta-blocker would likely take longer.
The order in which a patient starts these drugs shouldn’t matter, and there currently seems to be no evidence that clearly points toward using either dapagliflozin or empagliflozin over the other, Dr. Packer added.
In recognition of the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in HFrEF patients, the American College of Cardiology and American Heart Association are now drafting an “expert decision pathway” to help clinicians as they enter this new prescribing space. This interim guidance should come out before the end of 2020, prior to release of fully revised HFrEF management guidelines in 2021, said Athena Poppas, MD, president of the ACC, in an interview.
“There is clearly need for education” that can help guide physicians who care for HFrEF patients on how to introduce an SGLT2 inhibitor along with the additional, lengthy list of drug classes proven to benefit these patients, noted Dr. Poppas, who is also a professor and chief of cardiology at the Brown University in Providence, R.I. Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in HFrEF patients because recent history has shown substantial pushback from third-party payers in reimbursing for these relatively expensive drugs, Dr. Poppas noted. She added that this is a problem that may be compounded when patients should ideally get both drug classes.
Physicians who care for heart failure patients have their own history of dragging their feet when adding new drugs to the regimens HFrEF patients receive. The angiotensin converting enzyme inhibitors and beta-blockers took about 17 years each to start reaching a majority of U.S. HFrEF patients, and sacubitril plus valsartan is now used on perhaps a quarter to a third of HFrEF patients despite receiving Food and Drug Administration approval for these patients in mid 2015, noted Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Va.
Despite dapagliflozin receiving FDA approval in May 2020 for treating HFrEF in patients without diabetes, early uptake in U.S. practice has been very slow, with findings from large U.S. patient registries suggesting that perhaps 1% of suitable HFrEF patients currently get the drug, estimated Dr. O’Connor in an interview.
Given how strong the evidence now is for benefit and safety from dapagliflozin and empagliflozin, it may take as little as 5 years to reach greater than 50% penetration of one of these drugs into U.S. HFrEF patient populations, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.
EMPEROR-Reduced outcomes
The road to routine use of these SGLT2 inhibitor drugs should be hastened by empagliflozin’s impressive performance in EMPEROR-Reduced, in which the drug scored highly significant benefits over placebo for the prespecified primary and two major secondary endpoints, one of which was a measure of preserved renal function.
The trial randomized 3,730 patients at 520 sites in 20 countries during 2017-2019 and followed them on treatment for a median of 16 months. All patients had a left ventricular ejection fraction of 40% or less, and roughly three-quarters had New York Heart Association (NYHA) class II function, nearly one-quarter had class III function, and fewer than 1% of patients fell into the class IV category.
The primary endpoint occurred in 19% of the empagliflozin-treated patients and in 25% of those who received placebo. Among the half of patients with diabetes in the trial, the relative risk reduction by empagliflozin compared with placebo was a statistically significant 28%; among those without diabetes, it was a statistically significant 22%. Concurrently with Dr. Packer’s report, the results appeared in an article posted online (N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190).
The study also had two main prespecified secondary endpoints: the incidence of total hospitalizations for heart failure, both first and recurrent, which fell by 30% in the empagliflozin-treated patients, compared with placebo, and the rate of declining renal function during the 16 months of the study as measured by estimated glomerular filtration rate, which dropped by roughly 1 mL/min per 1.73 m2 among the empagliflozin recipients and by about 4 mL/min/ per 1.73 m2 in the placebo patients.
Treatment with empagliflozin also achieved a notable, statistically significant 50% drop in major adverse renal events, consistent with the performance of other drugs in the class.
“Renal protection is a big plus” of empagliflozin in this trial and from the other SGLT2 inhibitors in prior studies, noted Dr. O’Connor.
The EMPEROR-Reduced results also showed an important benefit for HFrEF patients from empagliflozin not previously seen as quickly with any other drug class, noted Dr. Packer. The SGLT2 inhibitor led to statistically a significant slowing in the progression of patients from NYHA class II function to class III, compared with placebo, and it also significantly promoted the recovery of patients from NYHA class III to class II, an effect that became apparent within the first month on treatment and a benefit that is a “big deal” for patients because it represents a “significant change in functional capacity.” This additional dimension of empagliflozin’s benefit “really impressed me,” Dr. Packer said.
EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Poppas and Dr. O’Connor had no relevant disclosures.
SOURCE: Packer M. ESC 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190.
FROM ESC CONGRESS 2020
Vitamin D pearls
Case: A 56-year-old man with a history of type 2 diabetes, hypertension, hyperlipidemia, and obesity calls clinic to discuss concerns about COVID-19, stating: “I want to do everything I can to reduce my risk of infection.” In addition to physical distancing, mask wearing, hand hygiene, and control of chronic conditions, which of the following supplements would you recommend for this patient?
1. Coenzyme Q10 160 mg twice a day
2. Vitamin D 2,000 IU daily
3. Vitamin E 400 IU daily
4. Vitamin B12 1,000 mcg daily
Of these choices, vitamin D supplementation is likely the best option, based on the limited data that is available.
Risk factors for worse COVID-19 outcome, such as older age, obesity, and more pigmented skin are also risk factors for vitamin D deficiency. This makes the study of vitamin D and COVID-19 both challenging and relevant.
In a recent study of 7,807 people living in Israel, Merzon and colleagues found that low plasma vitamin D level was an independent risk factor for COVID-19 infection. Mean plasma vitamin D level was significantly lower among those who tested positive for COVID-19 (19.00 ng/mL) than negative (20.55 ng/ mL). After controlling for demographic variables and several medical conditions, the adjusted odds ratio of COVID-19 infection in those with lower vitamin D was 1.45 (95% confidence interval, 1.08-1.95; P < .001). However, the odds of hospitalization for COVID-19 was not significantly associated with vitamin D level.1
Prior studies have also looked at vitamin D and respiratory infection. Martineau and colleagues analyzed 25 randomized, controlled trials with a pooled number of 11,321 individuals, including healthy ones and those with comorbidities, and found that oral vitamin D supplementation in daily or weekly doses had a protective effect against acute respiratory infection (adjusted odds ratio, 0.88; 95% CI, 0.81-0.96; P < .001). Patients with vitamin D deficiency (less than 25 nmol/L) experienced the most protective benefit. Vitamin D did not influence respiratory infection outcome.2
These studies suggest an adequate vitamin D level may be protective against infection with COVID-19, but who will benefit from vitamin D supplementation, and in what dose? Per U.S. Preventive Services Task Force guidelines, there is insufficient evidence to recommend screening for vitamin D deficiency in asymptomatic adults. Regarding daily dietary intake, the Institute of Medicine recommends 600 IU for persons aged 1-70, and 800 IU for those aged over 70 years. Salmon (447 IU per 3 oz serving), tuna (154 IU), and fortified milk (116 IU) are among the most vitamin D–rich foods.3 The recommended upper level of intake is 4,000 IU/day.
Too much of a good thing?
Extra vitamin D is stored in adipose tissue. If it builds up over time, storage sites may be overwhelmed, causing a rise in serum D level. While one might expect a subsequent rise in calcium levels, studies have shown this happens inconsistently, and at very high vitamin D levels, over 120 ng/mL.4 Most people would have to take at least 50,000 IU daily for several months to see an effect. The main adverse outcome of vitamin D toxicity is kidney stones, mediated by increased calcium in the blood and urine.
Several animal models have demonstrated hypervitaminosis D–induced aortic and coronary artery calcification. Like with kidney stones, the mechanism appears to be through increased calcium and phosphate levels. Shroff and colleagues studied serum vitamin D levels and vascular disease in children with renal disease on dialysis and found a U-shaped distribution: Children with both low and high vitamin D levels had significantly increased carotid artery intima-media thickness and calcification.5 Given the specialized nature of this population, it’s unclear whether these results can be generalized to most people. More studies are warranted on this topic.
Other benefits
Vitamin D is perhaps most famous for helping to build strong bones. Avenell and colleagues performed a Cochrane meta-analysis of vitamin D supplementation in older adults and found that vitamin D alone did not significantly reduce the risk of hip or other new fracture. Vitamin D plus calcium supplementation did reduce the risk of hip fracture (nine trials, pooled number of individuals was 49,853; relative risk, 0.84; P = .01).6
A lesser-known benefit of vitamin D is muscle protection. A prospective study out of the Jewish Hospital of Cincinnati followed 146 adults who were intolerant to two or more statins because of muscle side effects and found to have a vitamin D level below 32 ng per mL. Subjects were given vitamin D replacement (50,000 units weekly) and followed for 2 years. On statin rechallenge, 88-95% tolerated a statin with vitamin D levels 53-55 ng/mL.7
Pearl
Vitamin D supplementation may protect against COVID-19 infection and has very low chance of harm at daily doses at or below 4,000 IU. Other benefits of taking vitamin D include bone protection and reduction in statin-induced myopathy. The main adverse effect is kidney stones.
Ms. Sharninghausen is a medical student at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Merzon E et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: An Israeli population‐based study. FEBS J. 2020. doi: 10.1111/febs.15495.
2. Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583
3. “How to Get More Vitamin D From Your Food,” Cleveland Clinic. 2019 Oct 23. https://health.clevelandclinic.org/how-to-get-more-vitamin-d-from-your-food/.
4. Galior K et al. Development of vitamin d toxicity from overcorrection of vitamin D Deficiency: A review of case reports. Nutrients. 2018;10(8):953. doi: 10.3390/nu10080953
5. Shroff R et al. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol. 2008;19(6):1239-46. doi: 10.1681/ASN.2007090993.
6. Avenell A et al. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database Syst Rev. 2014 Apr 14;2014(4):CD000227. doi: 10.1002/14651858.CD000227.pub4.
7. Khayznikov M et al. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci. 2015;7(3):86-93. doi:10.4103/1947-2714.153919
Case: A 56-year-old man with a history of type 2 diabetes, hypertension, hyperlipidemia, and obesity calls clinic to discuss concerns about COVID-19, stating: “I want to do everything I can to reduce my risk of infection.” In addition to physical distancing, mask wearing, hand hygiene, and control of chronic conditions, which of the following supplements would you recommend for this patient?
1. Coenzyme Q10 160 mg twice a day
2. Vitamin D 2,000 IU daily
3. Vitamin E 400 IU daily
4. Vitamin B12 1,000 mcg daily
Of these choices, vitamin D supplementation is likely the best option, based on the limited data that is available.
Risk factors for worse COVID-19 outcome, such as older age, obesity, and more pigmented skin are also risk factors for vitamin D deficiency. This makes the study of vitamin D and COVID-19 both challenging and relevant.
In a recent study of 7,807 people living in Israel, Merzon and colleagues found that low plasma vitamin D level was an independent risk factor for COVID-19 infection. Mean plasma vitamin D level was significantly lower among those who tested positive for COVID-19 (19.00 ng/mL) than negative (20.55 ng/ mL). After controlling for demographic variables and several medical conditions, the adjusted odds ratio of COVID-19 infection in those with lower vitamin D was 1.45 (95% confidence interval, 1.08-1.95; P < .001). However, the odds of hospitalization for COVID-19 was not significantly associated with vitamin D level.1
Prior studies have also looked at vitamin D and respiratory infection. Martineau and colleagues analyzed 25 randomized, controlled trials with a pooled number of 11,321 individuals, including healthy ones and those with comorbidities, and found that oral vitamin D supplementation in daily or weekly doses had a protective effect against acute respiratory infection (adjusted odds ratio, 0.88; 95% CI, 0.81-0.96; P < .001). Patients with vitamin D deficiency (less than 25 nmol/L) experienced the most protective benefit. Vitamin D did not influence respiratory infection outcome.2
These studies suggest an adequate vitamin D level may be protective against infection with COVID-19, but who will benefit from vitamin D supplementation, and in what dose? Per U.S. Preventive Services Task Force guidelines, there is insufficient evidence to recommend screening for vitamin D deficiency in asymptomatic adults. Regarding daily dietary intake, the Institute of Medicine recommends 600 IU for persons aged 1-70, and 800 IU for those aged over 70 years. Salmon (447 IU per 3 oz serving), tuna (154 IU), and fortified milk (116 IU) are among the most vitamin D–rich foods.3 The recommended upper level of intake is 4,000 IU/day.
Too much of a good thing?
Extra vitamin D is stored in adipose tissue. If it builds up over time, storage sites may be overwhelmed, causing a rise in serum D level. While one might expect a subsequent rise in calcium levels, studies have shown this happens inconsistently, and at very high vitamin D levels, over 120 ng/mL.4 Most people would have to take at least 50,000 IU daily for several months to see an effect. The main adverse outcome of vitamin D toxicity is kidney stones, mediated by increased calcium in the blood and urine.
Several animal models have demonstrated hypervitaminosis D–induced aortic and coronary artery calcification. Like with kidney stones, the mechanism appears to be through increased calcium and phosphate levels. Shroff and colleagues studied serum vitamin D levels and vascular disease in children with renal disease on dialysis and found a U-shaped distribution: Children with both low and high vitamin D levels had significantly increased carotid artery intima-media thickness and calcification.5 Given the specialized nature of this population, it’s unclear whether these results can be generalized to most people. More studies are warranted on this topic.
Other benefits
Vitamin D is perhaps most famous for helping to build strong bones. Avenell and colleagues performed a Cochrane meta-analysis of vitamin D supplementation in older adults and found that vitamin D alone did not significantly reduce the risk of hip or other new fracture. Vitamin D plus calcium supplementation did reduce the risk of hip fracture (nine trials, pooled number of individuals was 49,853; relative risk, 0.84; P = .01).6
A lesser-known benefit of vitamin D is muscle protection. A prospective study out of the Jewish Hospital of Cincinnati followed 146 adults who were intolerant to two or more statins because of muscle side effects and found to have a vitamin D level below 32 ng per mL. Subjects were given vitamin D replacement (50,000 units weekly) and followed for 2 years. On statin rechallenge, 88-95% tolerated a statin with vitamin D levels 53-55 ng/mL.7
Pearl
Vitamin D supplementation may protect against COVID-19 infection and has very low chance of harm at daily doses at or below 4,000 IU. Other benefits of taking vitamin D include bone protection and reduction in statin-induced myopathy. The main adverse effect is kidney stones.
Ms. Sharninghausen is a medical student at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Merzon E et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: An Israeli population‐based study. FEBS J. 2020. doi: 10.1111/febs.15495.
2. Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583
3. “How to Get More Vitamin D From Your Food,” Cleveland Clinic. 2019 Oct 23. https://health.clevelandclinic.org/how-to-get-more-vitamin-d-from-your-food/.
4. Galior K et al. Development of vitamin d toxicity from overcorrection of vitamin D Deficiency: A review of case reports. Nutrients. 2018;10(8):953. doi: 10.3390/nu10080953
5. Shroff R et al. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol. 2008;19(6):1239-46. doi: 10.1681/ASN.2007090993.
6. Avenell A et al. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database Syst Rev. 2014 Apr 14;2014(4):CD000227. doi: 10.1002/14651858.CD000227.pub4.
7. Khayznikov M et al. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci. 2015;7(3):86-93. doi:10.4103/1947-2714.153919
Case: A 56-year-old man with a history of type 2 diabetes, hypertension, hyperlipidemia, and obesity calls clinic to discuss concerns about COVID-19, stating: “I want to do everything I can to reduce my risk of infection.” In addition to physical distancing, mask wearing, hand hygiene, and control of chronic conditions, which of the following supplements would you recommend for this patient?
1. Coenzyme Q10 160 mg twice a day
2. Vitamin D 2,000 IU daily
3. Vitamin E 400 IU daily
4. Vitamin B12 1,000 mcg daily
Of these choices, vitamin D supplementation is likely the best option, based on the limited data that is available.
Risk factors for worse COVID-19 outcome, such as older age, obesity, and more pigmented skin are also risk factors for vitamin D deficiency. This makes the study of vitamin D and COVID-19 both challenging and relevant.
In a recent study of 7,807 people living in Israel, Merzon and colleagues found that low plasma vitamin D level was an independent risk factor for COVID-19 infection. Mean plasma vitamin D level was significantly lower among those who tested positive for COVID-19 (19.00 ng/mL) than negative (20.55 ng/ mL). After controlling for demographic variables and several medical conditions, the adjusted odds ratio of COVID-19 infection in those with lower vitamin D was 1.45 (95% confidence interval, 1.08-1.95; P < .001). However, the odds of hospitalization for COVID-19 was not significantly associated with vitamin D level.1
Prior studies have also looked at vitamin D and respiratory infection. Martineau and colleagues analyzed 25 randomized, controlled trials with a pooled number of 11,321 individuals, including healthy ones and those with comorbidities, and found that oral vitamin D supplementation in daily or weekly doses had a protective effect against acute respiratory infection (adjusted odds ratio, 0.88; 95% CI, 0.81-0.96; P < .001). Patients with vitamin D deficiency (less than 25 nmol/L) experienced the most protective benefit. Vitamin D did not influence respiratory infection outcome.2
These studies suggest an adequate vitamin D level may be protective against infection with COVID-19, but who will benefit from vitamin D supplementation, and in what dose? Per U.S. Preventive Services Task Force guidelines, there is insufficient evidence to recommend screening for vitamin D deficiency in asymptomatic adults. Regarding daily dietary intake, the Institute of Medicine recommends 600 IU for persons aged 1-70, and 800 IU for those aged over 70 years. Salmon (447 IU per 3 oz serving), tuna (154 IU), and fortified milk (116 IU) are among the most vitamin D–rich foods.3 The recommended upper level of intake is 4,000 IU/day.
Too much of a good thing?
Extra vitamin D is stored in adipose tissue. If it builds up over time, storage sites may be overwhelmed, causing a rise in serum D level. While one might expect a subsequent rise in calcium levels, studies have shown this happens inconsistently, and at very high vitamin D levels, over 120 ng/mL.4 Most people would have to take at least 50,000 IU daily for several months to see an effect. The main adverse outcome of vitamin D toxicity is kidney stones, mediated by increased calcium in the blood and urine.
Several animal models have demonstrated hypervitaminosis D–induced aortic and coronary artery calcification. Like with kidney stones, the mechanism appears to be through increased calcium and phosphate levels. Shroff and colleagues studied serum vitamin D levels and vascular disease in children with renal disease on dialysis and found a U-shaped distribution: Children with both low and high vitamin D levels had significantly increased carotid artery intima-media thickness and calcification.5 Given the specialized nature of this population, it’s unclear whether these results can be generalized to most people. More studies are warranted on this topic.
Other benefits
Vitamin D is perhaps most famous for helping to build strong bones. Avenell and colleagues performed a Cochrane meta-analysis of vitamin D supplementation in older adults and found that vitamin D alone did not significantly reduce the risk of hip or other new fracture. Vitamin D plus calcium supplementation did reduce the risk of hip fracture (nine trials, pooled number of individuals was 49,853; relative risk, 0.84; P = .01).6
A lesser-known benefit of vitamin D is muscle protection. A prospective study out of the Jewish Hospital of Cincinnati followed 146 adults who were intolerant to two or more statins because of muscle side effects and found to have a vitamin D level below 32 ng per mL. Subjects were given vitamin D replacement (50,000 units weekly) and followed for 2 years. On statin rechallenge, 88-95% tolerated a statin with vitamin D levels 53-55 ng/mL.7
Pearl
Vitamin D supplementation may protect against COVID-19 infection and has very low chance of harm at daily doses at or below 4,000 IU. Other benefits of taking vitamin D include bone protection and reduction in statin-induced myopathy. The main adverse effect is kidney stones.
Ms. Sharninghausen is a medical student at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Merzon E et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: An Israeli population‐based study. FEBS J. 2020. doi: 10.1111/febs.15495.
2. Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583
3. “How to Get More Vitamin D From Your Food,” Cleveland Clinic. 2019 Oct 23. https://health.clevelandclinic.org/how-to-get-more-vitamin-d-from-your-food/.
4. Galior K et al. Development of vitamin d toxicity from overcorrection of vitamin D Deficiency: A review of case reports. Nutrients. 2018;10(8):953. doi: 10.3390/nu10080953
5. Shroff R et al. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol. 2008;19(6):1239-46. doi: 10.1681/ASN.2007090993.
6. Avenell A et al. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database Syst Rev. 2014 Apr 14;2014(4):CD000227. doi: 10.1002/14651858.CD000227.pub4.
7. Khayznikov M et al. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci. 2015;7(3):86-93. doi:10.4103/1947-2714.153919
FDA pulls amputation boxed warning off canagliflozin label
The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.
As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.
The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.
In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.
In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.
“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.
The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”
The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”
The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.
Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.
As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.
The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.
In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.
In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.
“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.
The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”
The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”
The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.
Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.
As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.
The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.
In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.
In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.
“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.
The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”
The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”
The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.
Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
A version of this article originally appeared on Medscape.com.
SGLT2 inhibitors with metformin look safe for bone
The combination of sodium-glucose transporter-2 (SGLT-2) inhibitors and metformin is not associated with an increase in fracture risk among patients with type 2 diabetes (T2D), according to a new meta-analysis of 25 randomized, controlled trials.
Researchers at The Second Clinical College of Dalian Medical University in Jiangsu, China, compared fracture risk associated with the metformin/SLGT2 combination to metformin alone as well as other T2D therapeutics, and found no differences in risk. The study was published online Aug. 11 in Osteoporosis International.
T2D is associated with an increased risk of fracture, though causative mechanisms remain uncertain. Some lines of evidence suggest multiple factors may contribute to fractures, including hyperglycemia, oxidative stress, toxic effects of advanced glycosylation end-products, altered insulin levels, and treatment-induced hypoglycemia, as well as an association between T2D and increased risk of falls.
Antidiabetes drugs can have positive or negative effects on bone. thiazolidinediones, insulin, and sulfonylureas may increase risk of fractures, while dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-2 (GLP-2) receptor agonists may be protective. Metformin may also reduce fracture risk.
SGLT-2 inhibitors interrupt glucose reabsorption in the kidney, leading to improved glycemic control. Other benefits include improved renal and cardiovascular outcomes, weight loss, and reduced blood pressure, liver fat, and serum uric acid levels.
These properties have made SGLT-2 inhibitors combined with metformin an important therapy for patients at high risk of atherosclerotic disease, or who have heart failure or chronic kidney disease.
But SGLT-2 inhibition increases osmotic diuresis, and this could alter the mineral balance within bone. Some studies also showed that SGLT-2 inhibitors led to changes in bone turnover markers, bone mineral density, and bone microarchitecture. Observational studies of the SGLT-2 inhibitor canagliflozin found associations with a higher rate of fracture risk in patients taking the drug.
Such studies carry the risk of confounding factors, so the researchers took advantage of the fact that many recent clinical trials have examined the impact of SGLT-2 inhibitors on T2D. They pooled data from 25 clinical trials with a total of 19,500 participants, 9,662 of whom received SGLT-2 inhibitors plus metformin; 9,838 received other active comparators.
The fracture rate was 0.91% in the SGLT-2 inhibitors/metformin group, and 0.80% among controls (odds ratio, 0.97; 95% CI, 0.71-1.32), with no heterogeneity. Metformin alone was not associated with a change in fracture rate (OR, 0.95; 95% CI, 0.44-2.08), nor were other forms of diabetes control (OR, 0.95; 95% CI, 0.69-1.31).
There were some differences in fracture risk among SGLT-2 inhibitors when studied individually, though none differed significantly from controls. The highest risk was associated with the canagliflozin/metformin (OR, 2.19; 95% CI, 0.66-7.27), followed by dapagliflozin/metformin (OR, 0.91; 95% CI, 0.50-1.64), empagliflozin/metformin (OR, 0.94; 95% CI, 0.59-1.50), and ertugliflozin/metformin (OR, 0.76; 95% CI, 0.38-1.54).
There were no differences with respect to hip or lumbar spine fractures, or other fractures. The researchers found no differences in bone mineral density or bone turnover markers.
The meta-analysis is limited by the relatively short average follow-up in the included studies, which was 61 weeks. Bone damage may occur over longer time periods. Bone fractures were also not a prespecified adverse event in most included studies.
The studies also did not provide detailed information on the types of fractures experienced, such as whether they were result of a fall, or the location of the fracture, or bone health parameters. Although the results support a belief that SGLT-2 inhibitors do not adversely affect bone health, “given limited information on bone health outcomes, further work is needed to validate this conclusion,” the authors wrote.
The authors did not disclose any funding and had no relevant conflicts of interest.
SOURCE: B-B Qian et al. Osteoporosis Int. 2020 Aug 11. doi: 10.1007/s00198-020-05590-y.
The combination of sodium-glucose transporter-2 (SGLT-2) inhibitors and metformin is not associated with an increase in fracture risk among patients with type 2 diabetes (T2D), according to a new meta-analysis of 25 randomized, controlled trials.
Researchers at The Second Clinical College of Dalian Medical University in Jiangsu, China, compared fracture risk associated with the metformin/SLGT2 combination to metformin alone as well as other T2D therapeutics, and found no differences in risk. The study was published online Aug. 11 in Osteoporosis International.
T2D is associated with an increased risk of fracture, though causative mechanisms remain uncertain. Some lines of evidence suggest multiple factors may contribute to fractures, including hyperglycemia, oxidative stress, toxic effects of advanced glycosylation end-products, altered insulin levels, and treatment-induced hypoglycemia, as well as an association between T2D and increased risk of falls.
Antidiabetes drugs can have positive or negative effects on bone. thiazolidinediones, insulin, and sulfonylureas may increase risk of fractures, while dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-2 (GLP-2) receptor agonists may be protective. Metformin may also reduce fracture risk.
SGLT-2 inhibitors interrupt glucose reabsorption in the kidney, leading to improved glycemic control. Other benefits include improved renal and cardiovascular outcomes, weight loss, and reduced blood pressure, liver fat, and serum uric acid levels.
These properties have made SGLT-2 inhibitors combined with metformin an important therapy for patients at high risk of atherosclerotic disease, or who have heart failure or chronic kidney disease.
But SGLT-2 inhibition increases osmotic diuresis, and this could alter the mineral balance within bone. Some studies also showed that SGLT-2 inhibitors led to changes in bone turnover markers, bone mineral density, and bone microarchitecture. Observational studies of the SGLT-2 inhibitor canagliflozin found associations with a higher rate of fracture risk in patients taking the drug.
Such studies carry the risk of confounding factors, so the researchers took advantage of the fact that many recent clinical trials have examined the impact of SGLT-2 inhibitors on T2D. They pooled data from 25 clinical trials with a total of 19,500 participants, 9,662 of whom received SGLT-2 inhibitors plus metformin; 9,838 received other active comparators.
The fracture rate was 0.91% in the SGLT-2 inhibitors/metformin group, and 0.80% among controls (odds ratio, 0.97; 95% CI, 0.71-1.32), with no heterogeneity. Metformin alone was not associated with a change in fracture rate (OR, 0.95; 95% CI, 0.44-2.08), nor were other forms of diabetes control (OR, 0.95; 95% CI, 0.69-1.31).
There were some differences in fracture risk among SGLT-2 inhibitors when studied individually, though none differed significantly from controls. The highest risk was associated with the canagliflozin/metformin (OR, 2.19; 95% CI, 0.66-7.27), followed by dapagliflozin/metformin (OR, 0.91; 95% CI, 0.50-1.64), empagliflozin/metformin (OR, 0.94; 95% CI, 0.59-1.50), and ertugliflozin/metformin (OR, 0.76; 95% CI, 0.38-1.54).
There were no differences with respect to hip or lumbar spine fractures, or other fractures. The researchers found no differences in bone mineral density or bone turnover markers.
The meta-analysis is limited by the relatively short average follow-up in the included studies, which was 61 weeks. Bone damage may occur over longer time periods. Bone fractures were also not a prespecified adverse event in most included studies.
The studies also did not provide detailed information on the types of fractures experienced, such as whether they were result of a fall, or the location of the fracture, or bone health parameters. Although the results support a belief that SGLT-2 inhibitors do not adversely affect bone health, “given limited information on bone health outcomes, further work is needed to validate this conclusion,” the authors wrote.
The authors did not disclose any funding and had no relevant conflicts of interest.
SOURCE: B-B Qian et al. Osteoporosis Int. 2020 Aug 11. doi: 10.1007/s00198-020-05590-y.
The combination of sodium-glucose transporter-2 (SGLT-2) inhibitors and metformin is not associated with an increase in fracture risk among patients with type 2 diabetes (T2D), according to a new meta-analysis of 25 randomized, controlled trials.
Researchers at The Second Clinical College of Dalian Medical University in Jiangsu, China, compared fracture risk associated with the metformin/SLGT2 combination to metformin alone as well as other T2D therapeutics, and found no differences in risk. The study was published online Aug. 11 in Osteoporosis International.
T2D is associated with an increased risk of fracture, though causative mechanisms remain uncertain. Some lines of evidence suggest multiple factors may contribute to fractures, including hyperglycemia, oxidative stress, toxic effects of advanced glycosylation end-products, altered insulin levels, and treatment-induced hypoglycemia, as well as an association between T2D and increased risk of falls.
Antidiabetes drugs can have positive or negative effects on bone. thiazolidinediones, insulin, and sulfonylureas may increase risk of fractures, while dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-2 (GLP-2) receptor agonists may be protective. Metformin may also reduce fracture risk.
SGLT-2 inhibitors interrupt glucose reabsorption in the kidney, leading to improved glycemic control. Other benefits include improved renal and cardiovascular outcomes, weight loss, and reduced blood pressure, liver fat, and serum uric acid levels.
These properties have made SGLT-2 inhibitors combined with metformin an important therapy for patients at high risk of atherosclerotic disease, or who have heart failure or chronic kidney disease.
But SGLT-2 inhibition increases osmotic diuresis, and this could alter the mineral balance within bone. Some studies also showed that SGLT-2 inhibitors led to changes in bone turnover markers, bone mineral density, and bone microarchitecture. Observational studies of the SGLT-2 inhibitor canagliflozin found associations with a higher rate of fracture risk in patients taking the drug.
Such studies carry the risk of confounding factors, so the researchers took advantage of the fact that many recent clinical trials have examined the impact of SGLT-2 inhibitors on T2D. They pooled data from 25 clinical trials with a total of 19,500 participants, 9,662 of whom received SGLT-2 inhibitors plus metformin; 9,838 received other active comparators.
The fracture rate was 0.91% in the SGLT-2 inhibitors/metformin group, and 0.80% among controls (odds ratio, 0.97; 95% CI, 0.71-1.32), with no heterogeneity. Metformin alone was not associated with a change in fracture rate (OR, 0.95; 95% CI, 0.44-2.08), nor were other forms of diabetes control (OR, 0.95; 95% CI, 0.69-1.31).
There were some differences in fracture risk among SGLT-2 inhibitors when studied individually, though none differed significantly from controls. The highest risk was associated with the canagliflozin/metformin (OR, 2.19; 95% CI, 0.66-7.27), followed by dapagliflozin/metformin (OR, 0.91; 95% CI, 0.50-1.64), empagliflozin/metformin (OR, 0.94; 95% CI, 0.59-1.50), and ertugliflozin/metformin (OR, 0.76; 95% CI, 0.38-1.54).
There were no differences with respect to hip or lumbar spine fractures, or other fractures. The researchers found no differences in bone mineral density or bone turnover markers.
The meta-analysis is limited by the relatively short average follow-up in the included studies, which was 61 weeks. Bone damage may occur over longer time periods. Bone fractures were also not a prespecified adverse event in most included studies.
The studies also did not provide detailed information on the types of fractures experienced, such as whether they were result of a fall, or the location of the fracture, or bone health parameters. Although the results support a belief that SGLT-2 inhibitors do not adversely affect bone health, “given limited information on bone health outcomes, further work is needed to validate this conclusion,” the authors wrote.
The authors did not disclose any funding and had no relevant conflicts of interest.
SOURCE: B-B Qian et al. Osteoporosis Int. 2020 Aug 11. doi: 10.1007/s00198-020-05590-y.
FROM OSTEOPOROSIS INTERNATIONAL
Diabetes plus weight loss equals increased risk of pancreatic cancer
A new study has linked recent-onset diabetes and subsequent weight loss to an increased risk of pancreatic cancer, indicating a distinct group of individuals to screen early for this deadly disease.
“The likelihood of a pancreatic cancer diagnosis was even further elevated among individuals with older age, healthy weight before weight loss, and unintentional weight loss,” wrote Chen Yuan, ScD, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. The study was published in JAMA Oncology.
To determine whether an association exists between diabetes plus weight change and pancreatic cancer, the researchers analyzed decades of medical history data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). The study population from the NHS included 112,818 women with a mean age of 59 years; the population from the HPFS included 46,207 men with a mean age of 65 years. Since enrollment – the baseline was 1978 for the NHS and 1988 for the HPFS – participants have provided follow-up information via biennial questionnaires.
Recent diabetes onset, weight loss boost cancer risk
From those combined groups, 1,116 incident cases of pancreatic cancer (0.7%) were identified. Compared with patients with no diabetes, patients with recent-onset diabetes had triple the risk of pancreatic cancer (age-adjusted hazard ratio, 2.97; 95% confidence interval, 2.31-3.82) and patients with longstanding diabetes had more than double the risk (HR, 2.16; 95% CI, 1.78-2.60). Patients with longer disease duration also had more than twice the risk of pancreatic cancer, with HRs of 2.25 for those with diabetes for 4-10 years (95% CI, 1.74-2.92) and 2.07 for more than 10 years (95% CI, 1.61-2.66).
Compared with patients who hadn’t lost any weight, patients who reported a 1- to 4-pound weight loss (HR, 1.25; 95% CI, 1.03-1.52), a 5- to 8-pound weight loss (HR, 1.33; 95% CI, 1.06-1.66), and a more than 8-pound weight loss (HR, 1.92; 95% CI, 1.58-2.32) had higher risks of pancreatic cancer. Patients with recent-onset diabetes and a 1- to 8-pound weight loss (91 incident cases per 100,000 person-years; 95% CI, 55-151) or a weight loss of more than 8 pounds (164 incident cases per 100,000 person years; 95% CI, 114-238) had a much higher incidence of pancreatic cancer, compared with patients with neither (16 incident cases per 100,000 person-years; 95% CI, 14-17).
After stratified analyses of patients with both recent-onset diabetes and weight loss, rates of pancreatic cancer were also notably high in those 70 years or older (234 cases per 100,000 person years), those with a body mass index of less than 25 kg/m2 before weight loss (400 cases per 100,000 person years), and those with a low likelihood of intentional weight loss (334 cases per 100,000 person years).
“I like the study because it reminds us of the importance of not thinking everyone that presents with type 2 diabetes necessarily has garden-variety diabetes,” Paul Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “I have always been concerned when a new-onset diabetic individual presents with no family history of diabetes or prediabetes, especially if they’re neither overweight nor obese. I have sometimes screened those individuals for pancreatic abnormalities.”
A call for screening
“This study highlights the consideration for further screening to those with weight loss at the time of diabetes diagnosis, which is very sensible given how unusual weight loss is as a presenting symptom at the time of diagnosis of typical type 2 diabetes,” Dr. Jellinger added. “The combination of weight loss and no family history of diabetes at the time of diagnosis should be an even stronger signal for pancreatic cancer screening and potential detection at a much earlier stage.”
The authors acknowledged their study’s limitations, including some patients with pancreatic cancer not returning their questionnaires and the timing of the questionnaires meaning that patients could’ve developed diabetes after returning it. In addition, they recognized that the participants were “predominantly White health professionals” and recommended a study of “additional patient populations” in the future.
The authors noted numerous potential conflicts of interest, including receiving grants and personal fees from various initiatives, organizations, and pharmaceutical companies.
SOURCE: Yuan C et al. JAMA Oncol. 2020 Aug 13. doi: 10.1001/jamaoncol.2020.2948.
A new study has linked recent-onset diabetes and subsequent weight loss to an increased risk of pancreatic cancer, indicating a distinct group of individuals to screen early for this deadly disease.
“The likelihood of a pancreatic cancer diagnosis was even further elevated among individuals with older age, healthy weight before weight loss, and unintentional weight loss,” wrote Chen Yuan, ScD, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. The study was published in JAMA Oncology.
To determine whether an association exists between diabetes plus weight change and pancreatic cancer, the researchers analyzed decades of medical history data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). The study population from the NHS included 112,818 women with a mean age of 59 years; the population from the HPFS included 46,207 men with a mean age of 65 years. Since enrollment – the baseline was 1978 for the NHS and 1988 for the HPFS – participants have provided follow-up information via biennial questionnaires.
Recent diabetes onset, weight loss boost cancer risk
From those combined groups, 1,116 incident cases of pancreatic cancer (0.7%) were identified. Compared with patients with no diabetes, patients with recent-onset diabetes had triple the risk of pancreatic cancer (age-adjusted hazard ratio, 2.97; 95% confidence interval, 2.31-3.82) and patients with longstanding diabetes had more than double the risk (HR, 2.16; 95% CI, 1.78-2.60). Patients with longer disease duration also had more than twice the risk of pancreatic cancer, with HRs of 2.25 for those with diabetes for 4-10 years (95% CI, 1.74-2.92) and 2.07 for more than 10 years (95% CI, 1.61-2.66).
Compared with patients who hadn’t lost any weight, patients who reported a 1- to 4-pound weight loss (HR, 1.25; 95% CI, 1.03-1.52), a 5- to 8-pound weight loss (HR, 1.33; 95% CI, 1.06-1.66), and a more than 8-pound weight loss (HR, 1.92; 95% CI, 1.58-2.32) had higher risks of pancreatic cancer. Patients with recent-onset diabetes and a 1- to 8-pound weight loss (91 incident cases per 100,000 person-years; 95% CI, 55-151) or a weight loss of more than 8 pounds (164 incident cases per 100,000 person years; 95% CI, 114-238) had a much higher incidence of pancreatic cancer, compared with patients with neither (16 incident cases per 100,000 person-years; 95% CI, 14-17).
After stratified analyses of patients with both recent-onset diabetes and weight loss, rates of pancreatic cancer were also notably high in those 70 years or older (234 cases per 100,000 person years), those with a body mass index of less than 25 kg/m2 before weight loss (400 cases per 100,000 person years), and those with a low likelihood of intentional weight loss (334 cases per 100,000 person years).
“I like the study because it reminds us of the importance of not thinking everyone that presents with type 2 diabetes necessarily has garden-variety diabetes,” Paul Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “I have always been concerned when a new-onset diabetic individual presents with no family history of diabetes or prediabetes, especially if they’re neither overweight nor obese. I have sometimes screened those individuals for pancreatic abnormalities.”
A call for screening
“This study highlights the consideration for further screening to those with weight loss at the time of diabetes diagnosis, which is very sensible given how unusual weight loss is as a presenting symptom at the time of diagnosis of typical type 2 diabetes,” Dr. Jellinger added. “The combination of weight loss and no family history of diabetes at the time of diagnosis should be an even stronger signal for pancreatic cancer screening and potential detection at a much earlier stage.”
The authors acknowledged their study’s limitations, including some patients with pancreatic cancer not returning their questionnaires and the timing of the questionnaires meaning that patients could’ve developed diabetes after returning it. In addition, they recognized that the participants were “predominantly White health professionals” and recommended a study of “additional patient populations” in the future.
The authors noted numerous potential conflicts of interest, including receiving grants and personal fees from various initiatives, organizations, and pharmaceutical companies.
SOURCE: Yuan C et al. JAMA Oncol. 2020 Aug 13. doi: 10.1001/jamaoncol.2020.2948.
A new study has linked recent-onset diabetes and subsequent weight loss to an increased risk of pancreatic cancer, indicating a distinct group of individuals to screen early for this deadly disease.
“The likelihood of a pancreatic cancer diagnosis was even further elevated among individuals with older age, healthy weight before weight loss, and unintentional weight loss,” wrote Chen Yuan, ScD, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. The study was published in JAMA Oncology.
To determine whether an association exists between diabetes plus weight change and pancreatic cancer, the researchers analyzed decades of medical history data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). The study population from the NHS included 112,818 women with a mean age of 59 years; the population from the HPFS included 46,207 men with a mean age of 65 years. Since enrollment – the baseline was 1978 for the NHS and 1988 for the HPFS – participants have provided follow-up information via biennial questionnaires.
Recent diabetes onset, weight loss boost cancer risk
From those combined groups, 1,116 incident cases of pancreatic cancer (0.7%) were identified. Compared with patients with no diabetes, patients with recent-onset diabetes had triple the risk of pancreatic cancer (age-adjusted hazard ratio, 2.97; 95% confidence interval, 2.31-3.82) and patients with longstanding diabetes had more than double the risk (HR, 2.16; 95% CI, 1.78-2.60). Patients with longer disease duration also had more than twice the risk of pancreatic cancer, with HRs of 2.25 for those with diabetes for 4-10 years (95% CI, 1.74-2.92) and 2.07 for more than 10 years (95% CI, 1.61-2.66).
Compared with patients who hadn’t lost any weight, patients who reported a 1- to 4-pound weight loss (HR, 1.25; 95% CI, 1.03-1.52), a 5- to 8-pound weight loss (HR, 1.33; 95% CI, 1.06-1.66), and a more than 8-pound weight loss (HR, 1.92; 95% CI, 1.58-2.32) had higher risks of pancreatic cancer. Patients with recent-onset diabetes and a 1- to 8-pound weight loss (91 incident cases per 100,000 person-years; 95% CI, 55-151) or a weight loss of more than 8 pounds (164 incident cases per 100,000 person years; 95% CI, 114-238) had a much higher incidence of pancreatic cancer, compared with patients with neither (16 incident cases per 100,000 person-years; 95% CI, 14-17).
After stratified analyses of patients with both recent-onset diabetes and weight loss, rates of pancreatic cancer were also notably high in those 70 years or older (234 cases per 100,000 person years), those with a body mass index of less than 25 kg/m2 before weight loss (400 cases per 100,000 person years), and those with a low likelihood of intentional weight loss (334 cases per 100,000 person years).
“I like the study because it reminds us of the importance of not thinking everyone that presents with type 2 diabetes necessarily has garden-variety diabetes,” Paul Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “I have always been concerned when a new-onset diabetic individual presents with no family history of diabetes or prediabetes, especially if they’re neither overweight nor obese. I have sometimes screened those individuals for pancreatic abnormalities.”
A call for screening
“This study highlights the consideration for further screening to those with weight loss at the time of diabetes diagnosis, which is very sensible given how unusual weight loss is as a presenting symptom at the time of diagnosis of typical type 2 diabetes,” Dr. Jellinger added. “The combination of weight loss and no family history of diabetes at the time of diagnosis should be an even stronger signal for pancreatic cancer screening and potential detection at a much earlier stage.”
The authors acknowledged their study’s limitations, including some patients with pancreatic cancer not returning their questionnaires and the timing of the questionnaires meaning that patients could’ve developed diabetes after returning it. In addition, they recognized that the participants were “predominantly White health professionals” and recommended a study of “additional patient populations” in the future.
The authors noted numerous potential conflicts of interest, including receiving grants and personal fees from various initiatives, organizations, and pharmaceutical companies.
SOURCE: Yuan C et al. JAMA Oncol. 2020 Aug 13. doi: 10.1001/jamaoncol.2020.2948.
FROM JAMA ONCOLOGY
Does metformin reduce risk for death in COVID-19?
Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.
The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.
The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.
Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.
Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.
“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.
“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.
Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”
She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”
Alabama authors say confounding effects ‘unlikely’
In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.
Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).
Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.
Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).
“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.
The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).
“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.
After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.
For metformin, the odds ratio was 0.33 (P = .0210).
But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”
If metformin does reduce COVID-19 deaths, multiple mechanisms likely
In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.
He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.
In totality, four studies suggest 25% death reduction with metformin
Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).
The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).
The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.
In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).
Two smaller observational studies produced similar trends toward survival benefit with metformin.
Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”
He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”
Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”
Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”
Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
*A previous version reversed these two outcomes in error.
Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.
The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.
The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.
Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.
Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.
“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.
“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.
Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”
She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”
Alabama authors say confounding effects ‘unlikely’
In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.
Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).
Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.
Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).
“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.
The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).
“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.
After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.
For metformin, the odds ratio was 0.33 (P = .0210).
But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”
If metformin does reduce COVID-19 deaths, multiple mechanisms likely
In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.
He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.
In totality, four studies suggest 25% death reduction with metformin
Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).
The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).
The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.
In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).
Two smaller observational studies produced similar trends toward survival benefit with metformin.
Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”
He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”
Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”
Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”
Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
*A previous version reversed these two outcomes in error.
Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.
The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.
The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.
Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.
Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.
“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.
“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.
Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”
She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”
Alabama authors say confounding effects ‘unlikely’
In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.
Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).
Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.
Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).
“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.
The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).
“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.
After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.
For metformin, the odds ratio was 0.33 (P = .0210).
But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”
If metformin does reduce COVID-19 deaths, multiple mechanisms likely
In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.
He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.
In totality, four studies suggest 25% death reduction with metformin
Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).
The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).
The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.
In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).
Two smaller observational studies produced similar trends toward survival benefit with metformin.
Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”
He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”
Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”
Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”
Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
*A previous version reversed these two outcomes in error.
RA patients show decreased risk for new-onset type 2 diabetes
Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.
This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”
Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.
After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)
During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.
The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”
The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”
The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).
The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.
“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.
The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.
SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.
Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.
This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”
Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.
After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)
During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.
The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”
The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”
The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).
The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.
“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.
The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.
SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.
Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.
This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”
Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.
After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)
During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.
The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”
The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”
The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).
The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.
“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.
The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.
SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.
FROM ARTHRITIS CARE & RESEARCH
Screening criteria for diabetes in youth won’t capture all at high risk
and therefore “may miss high-risk youth who should be targeted for diabetes prevention,” according to the investigators of a cross-sectional analysis of youth in the 1999-2016 National Health and Nutrition Examination Survey (NHANES) database.
Regardless of whether or not youth meet screening eligibility, they say, hemoglobin A1c appears to be a “specific and useful test” for detecting high-risk youth.
Those with prediabetic levels of A1c or fasting plasma glucose (FPG) – A1c especially – had a high burden of other cardiometabolic risk factors that could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood, wrote Amelia S. Wallace and coinvestigators at the Johns Hopkins Bloomberg School of Public Health, Baltimore. The report is in Pediatrics.Their epidemiologic study had two aims: To assess the performance of the American Diabetes Association guidelines for screening in youth, and to evaluate how well various clinical definitions of diabetes and prediabetes identify U.S. youth at high cardiometabolic risk.
The 2018 ADA guidelines recommend screening for type 2 diabetes and prediabetes in all asymptomatic youth ages 10 years and older who are overweight or obese and who have at least one risk factor for diabetes: nonwhite race, family history of type 2 diabetes, maternal gestational diabetes, or signs of insulin resistance or conditions associated with insulin resistance (Diabetes Care. 2018:41[suppl 1:S13-S37]).
Approximately one-quarter of U.S. youth were found to be eligible for screening under the current ADA criteria, but there were few cases of confirmed diabetes (A1c greater than or equal to 6.5% and fasting plasma glucose greater than or equal to 126 mg/dL) that had gone undiagnosed (less than 0.5%), said Ms. Wallace and her associates.
Considering all hyperglycemia (undiagnosed diabetes or prediabetes) in the NHANES youth population, the sensitivity and specificity of the ADA criteria for detecting A1c-defined hyperglycemia (greater than or equal to 5.7%) were 56% and 76%, respectively, and the sensitivity and specificity for detecting FBG-defined hyperglycemia (greater than or equal to 100 mg/dL) were 36% and 77%.
The prevalence of any hyperglycemia was higher in youth who met ADA screening criteria than in those who didn’t, but there were also “a substantial number of youth with hyperglycemia in the non–screening eligible population,” they wrote. “In fact, the absolute number of youth with elevated FPG was larger in the non–screening eligible population, and the majority (88.5%) of these youth were of normal weight.”
Across all youth (irrespective of screening eligibility), both FPG and A1c-defined hyperglycemia effectively identified children and adolescents who had a high burden of cardiometabolic risk (obesity, metabolic syndrome, and hypercholesterolemia). Using a confirmatory definition of elevations in both FPG and A1c “provided the highest discrimination for cardiometabolic risk,” Ms. Wallace and her associates said.
But in comparing the single tests, risk factor associations with hyperglycemia were consistently stronger with A1c-defined hyperglycemia (odds ratios of 2.6-4.1) than FBG-defined hyperglycemia (ORs of 1.5-3.0). A1c-defined hyperglycemia “identifies a smaller, but higher-risk, population than FPG-defined hyperglycemia,” they said.
In an accompanying commentary, Tamara S. Hannon, MD, MS, of the division of pediatric endocrinology and diabetology at Indiana University in Indianapolis, said that more effective algorithms to determine who should have laboratory testing “could be useful.” Still, “for youth with obesity and multiple risk factors for developing type 2 diabetes, the principal challenge is how to effectively prevent or delay this disease for them and future generations.”
Pediatricians, she said, should screen for prediabetes and type 2 diabetes “according to professional recommendations with simple clinical tests, such as A1c. Screening and education about prediabetes alone can lead to better rates of follow-up for obesity,” she noted (Pediatrics. August 2020. doi: 10.1542/peds.2020-010272).
Sheela N. Magge, MD, MSCE, who directs the division of pediatric endocrinology and diabetes at John Hopkins University, Baltimore, and was asked to comment on the study, similarly said that the findings should not discourage use of the ADA guidelines.
While the guidelines may not have optimal sensitivity and specificity, “neither HbA1c nor fasting glucose are perfect screening tools for prediabetes and likely give us different mechanistic information,” she said. (The ADA guidelines also allow the use of a 2-hour oral glucose tolerance test, but this is not often used by pediatricians, she noted.)
The measurements are “only tools used to identify children who have prediabetes and are therefore at increased risk for type 2 diabetes,” said Dr. Magge, the Lawson Wilkins Endowed Chair of Pediatric Endocrinology at the university. “These children then need to be managed and followed to try to prevent worsening glycemia.”
Both she and Dr. Hannon stressed that youth with type 2 diabetes have more rapidly progressive disease compared with adults.
Microvascular complications are seen even at diagnosis, Dr. Magge said, and “youth may face serious complications such as cardiovascular disease decades earlier than previous generations.”
Dr. Hannon also noted in her commentary that oral diabetes medications often fail in youth with type 2 diabetes, leading to insulin therapy early on.
The prevalence of youth-onset type 2 diabetes has increased because of rising rates of pediatric overweight and obesity, Dr. Magge emphasized. In her experience, the diabetes risk factors that guide the ADA’s screening approach “are so common in overweight and obese youth that they all have at least one.”
The NHANES data did not contain information on all the variables that make up the current diabetes screening criteria in youth; there was no explicit information on history of maternal gestational diabetes and family history of type 2 diabetes, for instance, or the presence of acanthosis nigricans or polycystic ovarian syndrome – conditions associated with insulin resistance. The investigators said it’s likely, therefore, that the study underestimated the number of U.S. youth who would be eligible for diabetes screening.
And, as Dr. Magge said, “it is difficult to determine which risk factors [in the ADA guidelines] were less predictive.”
The NHANES analysis covered 14,119 youth in the 1999-2016 NHANES surveys, which consisted of interviews and standardized physical exams, including laboratory tests, in home and at a mobile examination center. Analyses involving any fasting lab tests were limited to a random subsample of participants aged 12-19 years without diagnosed diabetes who were asked to fast the night before; 6,225 youth properly followed instructions and were included in this subsample.
The surveys are conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The study authors and the editorial author indicated that they have no relevant financial disclosures or conflicts of interest. Dr. Magge also said she has no relevant disclosures.
SOURCE: Wallace AS et al. Pediatrics. August 2020. doi: 10.1542/peds.2020-0265.
and therefore “may miss high-risk youth who should be targeted for diabetes prevention,” according to the investigators of a cross-sectional analysis of youth in the 1999-2016 National Health and Nutrition Examination Survey (NHANES) database.
Regardless of whether or not youth meet screening eligibility, they say, hemoglobin A1c appears to be a “specific and useful test” for detecting high-risk youth.
Those with prediabetic levels of A1c or fasting plasma glucose (FPG) – A1c especially – had a high burden of other cardiometabolic risk factors that could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood, wrote Amelia S. Wallace and coinvestigators at the Johns Hopkins Bloomberg School of Public Health, Baltimore. The report is in Pediatrics.Their epidemiologic study had two aims: To assess the performance of the American Diabetes Association guidelines for screening in youth, and to evaluate how well various clinical definitions of diabetes and prediabetes identify U.S. youth at high cardiometabolic risk.
The 2018 ADA guidelines recommend screening for type 2 diabetes and prediabetes in all asymptomatic youth ages 10 years and older who are overweight or obese and who have at least one risk factor for diabetes: nonwhite race, family history of type 2 diabetes, maternal gestational diabetes, or signs of insulin resistance or conditions associated with insulin resistance (Diabetes Care. 2018:41[suppl 1:S13-S37]).
Approximately one-quarter of U.S. youth were found to be eligible for screening under the current ADA criteria, but there were few cases of confirmed diabetes (A1c greater than or equal to 6.5% and fasting plasma glucose greater than or equal to 126 mg/dL) that had gone undiagnosed (less than 0.5%), said Ms. Wallace and her associates.
Considering all hyperglycemia (undiagnosed diabetes or prediabetes) in the NHANES youth population, the sensitivity and specificity of the ADA criteria for detecting A1c-defined hyperglycemia (greater than or equal to 5.7%) were 56% and 76%, respectively, and the sensitivity and specificity for detecting FBG-defined hyperglycemia (greater than or equal to 100 mg/dL) were 36% and 77%.
The prevalence of any hyperglycemia was higher in youth who met ADA screening criteria than in those who didn’t, but there were also “a substantial number of youth with hyperglycemia in the non–screening eligible population,” they wrote. “In fact, the absolute number of youth with elevated FPG was larger in the non–screening eligible population, and the majority (88.5%) of these youth were of normal weight.”
Across all youth (irrespective of screening eligibility), both FPG and A1c-defined hyperglycemia effectively identified children and adolescents who had a high burden of cardiometabolic risk (obesity, metabolic syndrome, and hypercholesterolemia). Using a confirmatory definition of elevations in both FPG and A1c “provided the highest discrimination for cardiometabolic risk,” Ms. Wallace and her associates said.
But in comparing the single tests, risk factor associations with hyperglycemia were consistently stronger with A1c-defined hyperglycemia (odds ratios of 2.6-4.1) than FBG-defined hyperglycemia (ORs of 1.5-3.0). A1c-defined hyperglycemia “identifies a smaller, but higher-risk, population than FPG-defined hyperglycemia,” they said.
In an accompanying commentary, Tamara S. Hannon, MD, MS, of the division of pediatric endocrinology and diabetology at Indiana University in Indianapolis, said that more effective algorithms to determine who should have laboratory testing “could be useful.” Still, “for youth with obesity and multiple risk factors for developing type 2 diabetes, the principal challenge is how to effectively prevent or delay this disease for them and future generations.”
Pediatricians, she said, should screen for prediabetes and type 2 diabetes “according to professional recommendations with simple clinical tests, such as A1c. Screening and education about prediabetes alone can lead to better rates of follow-up for obesity,” she noted (Pediatrics. August 2020. doi: 10.1542/peds.2020-010272).
Sheela N. Magge, MD, MSCE, who directs the division of pediatric endocrinology and diabetes at John Hopkins University, Baltimore, and was asked to comment on the study, similarly said that the findings should not discourage use of the ADA guidelines.
While the guidelines may not have optimal sensitivity and specificity, “neither HbA1c nor fasting glucose are perfect screening tools for prediabetes and likely give us different mechanistic information,” she said. (The ADA guidelines also allow the use of a 2-hour oral glucose tolerance test, but this is not often used by pediatricians, she noted.)
The measurements are “only tools used to identify children who have prediabetes and are therefore at increased risk for type 2 diabetes,” said Dr. Magge, the Lawson Wilkins Endowed Chair of Pediatric Endocrinology at the university. “These children then need to be managed and followed to try to prevent worsening glycemia.”
Both she and Dr. Hannon stressed that youth with type 2 diabetes have more rapidly progressive disease compared with adults.
Microvascular complications are seen even at diagnosis, Dr. Magge said, and “youth may face serious complications such as cardiovascular disease decades earlier than previous generations.”
Dr. Hannon also noted in her commentary that oral diabetes medications often fail in youth with type 2 diabetes, leading to insulin therapy early on.
The prevalence of youth-onset type 2 diabetes has increased because of rising rates of pediatric overweight and obesity, Dr. Magge emphasized. In her experience, the diabetes risk factors that guide the ADA’s screening approach “are so common in overweight and obese youth that they all have at least one.”
The NHANES data did not contain information on all the variables that make up the current diabetes screening criteria in youth; there was no explicit information on history of maternal gestational diabetes and family history of type 2 diabetes, for instance, or the presence of acanthosis nigricans or polycystic ovarian syndrome – conditions associated with insulin resistance. The investigators said it’s likely, therefore, that the study underestimated the number of U.S. youth who would be eligible for diabetes screening.
And, as Dr. Magge said, “it is difficult to determine which risk factors [in the ADA guidelines] were less predictive.”
The NHANES analysis covered 14,119 youth in the 1999-2016 NHANES surveys, which consisted of interviews and standardized physical exams, including laboratory tests, in home and at a mobile examination center. Analyses involving any fasting lab tests were limited to a random subsample of participants aged 12-19 years without diagnosed diabetes who were asked to fast the night before; 6,225 youth properly followed instructions and were included in this subsample.
The surveys are conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The study authors and the editorial author indicated that they have no relevant financial disclosures or conflicts of interest. Dr. Magge also said she has no relevant disclosures.
SOURCE: Wallace AS et al. Pediatrics. August 2020. doi: 10.1542/peds.2020-0265.
and therefore “may miss high-risk youth who should be targeted for diabetes prevention,” according to the investigators of a cross-sectional analysis of youth in the 1999-2016 National Health and Nutrition Examination Survey (NHANES) database.
Regardless of whether or not youth meet screening eligibility, they say, hemoglobin A1c appears to be a “specific and useful test” for detecting high-risk youth.
Those with prediabetic levels of A1c or fasting plasma glucose (FPG) – A1c especially – had a high burden of other cardiometabolic risk factors that could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood, wrote Amelia S. Wallace and coinvestigators at the Johns Hopkins Bloomberg School of Public Health, Baltimore. The report is in Pediatrics.Their epidemiologic study had two aims: To assess the performance of the American Diabetes Association guidelines for screening in youth, and to evaluate how well various clinical definitions of diabetes and prediabetes identify U.S. youth at high cardiometabolic risk.
The 2018 ADA guidelines recommend screening for type 2 diabetes and prediabetes in all asymptomatic youth ages 10 years and older who are overweight or obese and who have at least one risk factor for diabetes: nonwhite race, family history of type 2 diabetes, maternal gestational diabetes, or signs of insulin resistance or conditions associated with insulin resistance (Diabetes Care. 2018:41[suppl 1:S13-S37]).
Approximately one-quarter of U.S. youth were found to be eligible for screening under the current ADA criteria, but there were few cases of confirmed diabetes (A1c greater than or equal to 6.5% and fasting plasma glucose greater than or equal to 126 mg/dL) that had gone undiagnosed (less than 0.5%), said Ms. Wallace and her associates.
Considering all hyperglycemia (undiagnosed diabetes or prediabetes) in the NHANES youth population, the sensitivity and specificity of the ADA criteria for detecting A1c-defined hyperglycemia (greater than or equal to 5.7%) were 56% and 76%, respectively, and the sensitivity and specificity for detecting FBG-defined hyperglycemia (greater than or equal to 100 mg/dL) were 36% and 77%.
The prevalence of any hyperglycemia was higher in youth who met ADA screening criteria than in those who didn’t, but there were also “a substantial number of youth with hyperglycemia in the non–screening eligible population,” they wrote. “In fact, the absolute number of youth with elevated FPG was larger in the non–screening eligible population, and the majority (88.5%) of these youth were of normal weight.”
Across all youth (irrespective of screening eligibility), both FPG and A1c-defined hyperglycemia effectively identified children and adolescents who had a high burden of cardiometabolic risk (obesity, metabolic syndrome, and hypercholesterolemia). Using a confirmatory definition of elevations in both FPG and A1c “provided the highest discrimination for cardiometabolic risk,” Ms. Wallace and her associates said.
But in comparing the single tests, risk factor associations with hyperglycemia were consistently stronger with A1c-defined hyperglycemia (odds ratios of 2.6-4.1) than FBG-defined hyperglycemia (ORs of 1.5-3.0). A1c-defined hyperglycemia “identifies a smaller, but higher-risk, population than FPG-defined hyperglycemia,” they said.
In an accompanying commentary, Tamara S. Hannon, MD, MS, of the division of pediatric endocrinology and diabetology at Indiana University in Indianapolis, said that more effective algorithms to determine who should have laboratory testing “could be useful.” Still, “for youth with obesity and multiple risk factors for developing type 2 diabetes, the principal challenge is how to effectively prevent or delay this disease for them and future generations.”
Pediatricians, she said, should screen for prediabetes and type 2 diabetes “according to professional recommendations with simple clinical tests, such as A1c. Screening and education about prediabetes alone can lead to better rates of follow-up for obesity,” she noted (Pediatrics. August 2020. doi: 10.1542/peds.2020-010272).
Sheela N. Magge, MD, MSCE, who directs the division of pediatric endocrinology and diabetes at John Hopkins University, Baltimore, and was asked to comment on the study, similarly said that the findings should not discourage use of the ADA guidelines.
While the guidelines may not have optimal sensitivity and specificity, “neither HbA1c nor fasting glucose are perfect screening tools for prediabetes and likely give us different mechanistic information,” she said. (The ADA guidelines also allow the use of a 2-hour oral glucose tolerance test, but this is not often used by pediatricians, she noted.)
The measurements are “only tools used to identify children who have prediabetes and are therefore at increased risk for type 2 diabetes,” said Dr. Magge, the Lawson Wilkins Endowed Chair of Pediatric Endocrinology at the university. “These children then need to be managed and followed to try to prevent worsening glycemia.”
Both she and Dr. Hannon stressed that youth with type 2 diabetes have more rapidly progressive disease compared with adults.
Microvascular complications are seen even at diagnosis, Dr. Magge said, and “youth may face serious complications such as cardiovascular disease decades earlier than previous generations.”
Dr. Hannon also noted in her commentary that oral diabetes medications often fail in youth with type 2 diabetes, leading to insulin therapy early on.
The prevalence of youth-onset type 2 diabetes has increased because of rising rates of pediatric overweight and obesity, Dr. Magge emphasized. In her experience, the diabetes risk factors that guide the ADA’s screening approach “are so common in overweight and obese youth that they all have at least one.”
The NHANES data did not contain information on all the variables that make up the current diabetes screening criteria in youth; there was no explicit information on history of maternal gestational diabetes and family history of type 2 diabetes, for instance, or the presence of acanthosis nigricans or polycystic ovarian syndrome – conditions associated with insulin resistance. The investigators said it’s likely, therefore, that the study underestimated the number of U.S. youth who would be eligible for diabetes screening.
And, as Dr. Magge said, “it is difficult to determine which risk factors [in the ADA guidelines] were less predictive.”
The NHANES analysis covered 14,119 youth in the 1999-2016 NHANES surveys, which consisted of interviews and standardized physical exams, including laboratory tests, in home and at a mobile examination center. Analyses involving any fasting lab tests were limited to a random subsample of participants aged 12-19 years without diagnosed diabetes who were asked to fast the night before; 6,225 youth properly followed instructions and were included in this subsample.
The surveys are conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The study authors and the editorial author indicated that they have no relevant financial disclosures or conflicts of interest. Dr. Magge also said she has no relevant disclosures.
SOURCE: Wallace AS et al. Pediatrics. August 2020. doi: 10.1542/peds.2020-0265.
FROM PEDIATRICS
Guidance covers glycemia in dexamethasone-treated COVID-19 patients
New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.
Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”
RECOVERY trial spurs response
The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.
The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.
The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.
They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.
The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.
Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.
Guidance useful for U.S. physicians
Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”
However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.
He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.
But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”
Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.
Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”
RECOVERY trial spurs response
The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.
The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.
The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.
They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.
The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.
Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.
Guidance useful for U.S. physicians
Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”
However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.
He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.
But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”
Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.
Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”
RECOVERY trial spurs response
The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.
The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.
The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.
They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.
The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.
Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.
Guidance useful for U.S. physicians
Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”
However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.
He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.
But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”
Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
Diabetic amputations soared amid Italian pandemic lockdown
Amid a mandatory national lockdown, the rates of amputations skyrocketed at a hospital far from the hardest-hit region as many patients developed gangrene.
The findings offer critical lessons for the United States, said wound care specialist William H. Tettelbach, MD, of Western Peaks Specialty Hospital near Salt Lake City. “It’s become more obvious that outpatient wound care is a critical care need for the community because of the risk of ignoring these chronic wounds and letting them remain open. We cannot let these services be closed down like some were when the pandemic started.”
The study, led by Paola Caruso, MD, of the University of Campania Luigi Vanvitelli in Naples, appeared in Diabetes Care.
The researchers launched the study to understand how patients with diabetes and DFU fared during the height of the pandemic in Italy, where tens of thousands of people died, mainly in the northern region of the country. They focused on patients in the southern region who were admitted to the division of endocrinology and metabolic diseases at the Teaching Hospital at the University of Campania Luigi Vanvitelli.
The study compared 25 patients who were admitted from March 9 to May 18, 2020, with 38 patients who were admitted from a longer period between January and May 2019. The demographics of the groups are similar, with average ages in the early 60s and more men than women (21:4, respectively, in 2020 and 23:15, respectively, in 2019.)
The results reveal high numbers of emergent and serious cases in 2020. Compared with 2019, fewer were outpatients (16% vs. 45%, P = .028) and more were emergency patients (76% vs. 26%, P < .001).
Clinically, gangrene was much more common in the 2020 group, compared with the 2019 group (64% vs. 29%, P = .009), as was amputation (60% vs. 18%, P = .001).
The researchers determined that amputation was more than three times more likely in the 2020 versus the 2019 group (relative risk, 3.26; 95% confidence interval, 1.55-6.84) even though the 2019 period was longer. After adjustment for gender, the heightened risk in 2020 was 2.50 (95% CI, 1.18-5.29).
There was no statistically significant increase in the risk of revascularization.
“The COVID-19 lockdown may have had a detrimental impact on amputation risk because of the sudden interruption of DFU care and lower-limb preservation pathways, resulting in delayed diagnosis and treatment,” the researchers wrote. “DFU is often characterized by progressive clinical course, which can rapidly lead patients to critical worsening of their ulcers.”
They added that “the higher risk of amputation observed during COVID-19 lockdown confirms the need for proper and timely management of DFU patients to prevent dramatic outcomes responsible for a reduction of quality of life and increased morbidity and mortality.”
The study authors didn’t discuss why more patients seemed to have stayed home and not gotten proper care. It’s not clear if they were scared to get treatment or couldn’t obtain it because of the national shutdown.
Both have been factors affecting diabetic foot care in the United States during the pandemic, said Dr. Tettelbach. He called the study “timely and pertinent,” and said it highlights how wound care is “a critical need” that must remain available even when other medical services such as elective surgeries are shut down.
Infection-control protocols such as allowing patients to wait for appointments in their cars instead of waiting rooms will alleviate the fears of certain patients about seeking in-person care during the pandemic, he said. But some patients will be afraid to come in no matter what, he said, and home health may be the best solution for their care.
Several of the study authors reported various disclosures. Dr. Tettelbach reported no relevant disclosures.
SOURCE: Caruso P et al. Diabetes Care. 2020 Jul 23. doi:10.2337/dc20-1347.
Amid a mandatory national lockdown, the rates of amputations skyrocketed at a hospital far from the hardest-hit region as many patients developed gangrene.
The findings offer critical lessons for the United States, said wound care specialist William H. Tettelbach, MD, of Western Peaks Specialty Hospital near Salt Lake City. “It’s become more obvious that outpatient wound care is a critical care need for the community because of the risk of ignoring these chronic wounds and letting them remain open. We cannot let these services be closed down like some were when the pandemic started.”
The study, led by Paola Caruso, MD, of the University of Campania Luigi Vanvitelli in Naples, appeared in Diabetes Care.
The researchers launched the study to understand how patients with diabetes and DFU fared during the height of the pandemic in Italy, where tens of thousands of people died, mainly in the northern region of the country. They focused on patients in the southern region who were admitted to the division of endocrinology and metabolic diseases at the Teaching Hospital at the University of Campania Luigi Vanvitelli.
The study compared 25 patients who were admitted from March 9 to May 18, 2020, with 38 patients who were admitted from a longer period between January and May 2019. The demographics of the groups are similar, with average ages in the early 60s and more men than women (21:4, respectively, in 2020 and 23:15, respectively, in 2019.)
The results reveal high numbers of emergent and serious cases in 2020. Compared with 2019, fewer were outpatients (16% vs. 45%, P = .028) and more were emergency patients (76% vs. 26%, P < .001).
Clinically, gangrene was much more common in the 2020 group, compared with the 2019 group (64% vs. 29%, P = .009), as was amputation (60% vs. 18%, P = .001).
The researchers determined that amputation was more than three times more likely in the 2020 versus the 2019 group (relative risk, 3.26; 95% confidence interval, 1.55-6.84) even though the 2019 period was longer. After adjustment for gender, the heightened risk in 2020 was 2.50 (95% CI, 1.18-5.29).
There was no statistically significant increase in the risk of revascularization.
“The COVID-19 lockdown may have had a detrimental impact on amputation risk because of the sudden interruption of DFU care and lower-limb preservation pathways, resulting in delayed diagnosis and treatment,” the researchers wrote. “DFU is often characterized by progressive clinical course, which can rapidly lead patients to critical worsening of their ulcers.”
They added that “the higher risk of amputation observed during COVID-19 lockdown confirms the need for proper and timely management of DFU patients to prevent dramatic outcomes responsible for a reduction of quality of life and increased morbidity and mortality.”
The study authors didn’t discuss why more patients seemed to have stayed home and not gotten proper care. It’s not clear if they were scared to get treatment or couldn’t obtain it because of the national shutdown.
Both have been factors affecting diabetic foot care in the United States during the pandemic, said Dr. Tettelbach. He called the study “timely and pertinent,” and said it highlights how wound care is “a critical need” that must remain available even when other medical services such as elective surgeries are shut down.
Infection-control protocols such as allowing patients to wait for appointments in their cars instead of waiting rooms will alleviate the fears of certain patients about seeking in-person care during the pandemic, he said. But some patients will be afraid to come in no matter what, he said, and home health may be the best solution for their care.
Several of the study authors reported various disclosures. Dr. Tettelbach reported no relevant disclosures.
SOURCE: Caruso P et al. Diabetes Care. 2020 Jul 23. doi:10.2337/dc20-1347.
Amid a mandatory national lockdown, the rates of amputations skyrocketed at a hospital far from the hardest-hit region as many patients developed gangrene.
The findings offer critical lessons for the United States, said wound care specialist William H. Tettelbach, MD, of Western Peaks Specialty Hospital near Salt Lake City. “It’s become more obvious that outpatient wound care is a critical care need for the community because of the risk of ignoring these chronic wounds and letting them remain open. We cannot let these services be closed down like some were when the pandemic started.”
The study, led by Paola Caruso, MD, of the University of Campania Luigi Vanvitelli in Naples, appeared in Diabetes Care.
The researchers launched the study to understand how patients with diabetes and DFU fared during the height of the pandemic in Italy, where tens of thousands of people died, mainly in the northern region of the country. They focused on patients in the southern region who were admitted to the division of endocrinology and metabolic diseases at the Teaching Hospital at the University of Campania Luigi Vanvitelli.
The study compared 25 patients who were admitted from March 9 to May 18, 2020, with 38 patients who were admitted from a longer period between January and May 2019. The demographics of the groups are similar, with average ages in the early 60s and more men than women (21:4, respectively, in 2020 and 23:15, respectively, in 2019.)
The results reveal high numbers of emergent and serious cases in 2020. Compared with 2019, fewer were outpatients (16% vs. 45%, P = .028) and more were emergency patients (76% vs. 26%, P < .001).
Clinically, gangrene was much more common in the 2020 group, compared with the 2019 group (64% vs. 29%, P = .009), as was amputation (60% vs. 18%, P = .001).
The researchers determined that amputation was more than three times more likely in the 2020 versus the 2019 group (relative risk, 3.26; 95% confidence interval, 1.55-6.84) even though the 2019 period was longer. After adjustment for gender, the heightened risk in 2020 was 2.50 (95% CI, 1.18-5.29).
There was no statistically significant increase in the risk of revascularization.
“The COVID-19 lockdown may have had a detrimental impact on amputation risk because of the sudden interruption of DFU care and lower-limb preservation pathways, resulting in delayed diagnosis and treatment,” the researchers wrote. “DFU is often characterized by progressive clinical course, which can rapidly lead patients to critical worsening of their ulcers.”
They added that “the higher risk of amputation observed during COVID-19 lockdown confirms the need for proper and timely management of DFU patients to prevent dramatic outcomes responsible for a reduction of quality of life and increased morbidity and mortality.”
The study authors didn’t discuss why more patients seemed to have stayed home and not gotten proper care. It’s not clear if they were scared to get treatment or couldn’t obtain it because of the national shutdown.
Both have been factors affecting diabetic foot care in the United States during the pandemic, said Dr. Tettelbach. He called the study “timely and pertinent,” and said it highlights how wound care is “a critical need” that must remain available even when other medical services such as elective surgeries are shut down.
Infection-control protocols such as allowing patients to wait for appointments in their cars instead of waiting rooms will alleviate the fears of certain patients about seeking in-person care during the pandemic, he said. But some patients will be afraid to come in no matter what, he said, and home health may be the best solution for their care.
Several of the study authors reported various disclosures. Dr. Tettelbach reported no relevant disclosures.
SOURCE: Caruso P et al. Diabetes Care. 2020 Jul 23. doi:10.2337/dc20-1347.
FROM DIABETES CARE