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How to reverse type 2 diabetes with a crash diet: the DiRECT approach
SAN FRANCISCO – , according to United Kingdom investigators.
The odds of remission – meaning a hemoglobin A1c below 6.5% on repeat testing, off all medications – were directly related to the amount of weight patients lost; 60% of subjects who lost 22-33 pounds were free of type 2 disease at 2 years, versus 29% who lost 11-21 pounds, and 5% who lost less than 11 pounds.
“If people lose” around 30 pounds “and keep it off for 2 years, there’s a two-thirds chance of them escaping type 2 [diabetes]. People want to understand their options, and this is an option. This is very good news for people with diabetes,” said senior investigator Roy Taylor, MD, a professor of medicine and metabolism at the University of Newcastle, Newcastle upon Tyne, England, who presented the findings of the Diabetes Remission Clinical Trial (DiRECT) at the annual scientific sessions of the American Diabetes Association (Lancet Diabetes Endocrinol. 2019 May;7(5):344-355).
A subgroup analysis he also presented found that beta cell function rebounds rapidly after weight loss and is pretty much normal at 2 years, so long as people keep the weight off.
The study is rooted in previous work by Dr. Taylor and his colleagues that found that very low-calorie diets normalized fasting plasma glucose in just 7 days in patients with type 2 diabetes due to a rapid fall in liver fat content and subsequent restoration of insulin sensitivity. That and other findings suggested that fast weight loss – instead of the traditional gradual approach – might help.
He and his team randomized 149 volunteers from primary care practices in the United Kingdom to standard care, and 149 others to rapid weight loss; more than a quarter of the patients who were asked agreed to participate.
Patients had diabetes for less than 6 years and were not insulin dependent. The baseline mean body mass index was 35 kg/m2, mean age 54 years, mean hemoglobin A1c 7.6%, and mean duration of disease 3 years; 176 subjects were men.
Diabetes drugs, anti-hypertensives, and diuretics were stopped in the weight loss group; the program consisted of three Optifast meal replacement shakes or soups per day – Optifast is one of many commercially available options – for a daily intake of 825-853 kcal. There was no other food, and alcohol was not permitted. The weight loss goal was 33 pounds or more over 3-5 months; almost 90% of the intervention group made it. The protocol did not include exercise.
Next came a 2-8 week stepped reintroduction to normal food, followed by counseling and other supportive care out to 2 years, plus some extra packets of Optifast, just in case.
“People [had] panic attacks when they [went] back into the kitchen, but that’s marvelous: we [had] a blank slate on which to write new dietary habits, building up knowledge of portion size and what to eat.” Dr. Taylor said.
At 1 year, 68 (46%) of the intervention participants were in remission off all drugs, and 36 (24%) had maintained at least a 33-pound weight loss. At 2 years, 53 (36%) were in remission, and 17 (11%) had maintained. Percent remission was linked to the extent of sustained weight loss.
Strokes, heart attacks, and other serious adverse outcomes were less common in the diet group, versus standard care, at both 1 and 2 years.
Among those who went into remission, the rapid initial response to a glucose bolus came back to near normal soon after food reintroduction, and “was sufficient to get nondiabetic blood glucose control,” with a mean hemoglobin A1c of 6% at 2 years. “We [also] saw, quite remarkably, was a slow steady return to almost completely normal” maximum beta cell capacity over the first 12 months, Dr. Taylor said.
The most likely explanation is that beta cells are overwhelmed and shut down in a milieu of too much fat and glucose, but are able to reconstitute their specialist function and come back online once it’s addressed, he added.
The study was funded by Diabetes UK. Dr. Taylor reported financial relationships with Self, Wilmington Healthcare, Lilly Diabetes, and Novartis AG.
SOURCE: Zhyzhneuskaya SV et al., ADA 2019 abstract 66-OR
Alvin Powers, MD, is director of the diabetes center and a professor of medicine at Vanderbilt University, Nashville. He moderated the presentation and had no relevant disclosures.
Alvin Powers, MD, is director of the diabetes center and a professor of medicine at Vanderbilt University, Nashville. He moderated the presentation and had no relevant disclosures.
Alvin Powers, MD, is director of the diabetes center and a professor of medicine at Vanderbilt University, Nashville. He moderated the presentation and had no relevant disclosures.
SAN FRANCISCO – , according to United Kingdom investigators.
The odds of remission – meaning a hemoglobin A1c below 6.5% on repeat testing, off all medications – were directly related to the amount of weight patients lost; 60% of subjects who lost 22-33 pounds were free of type 2 disease at 2 years, versus 29% who lost 11-21 pounds, and 5% who lost less than 11 pounds.
“If people lose” around 30 pounds “and keep it off for 2 years, there’s a two-thirds chance of them escaping type 2 [diabetes]. People want to understand their options, and this is an option. This is very good news for people with diabetes,” said senior investigator Roy Taylor, MD, a professor of medicine and metabolism at the University of Newcastle, Newcastle upon Tyne, England, who presented the findings of the Diabetes Remission Clinical Trial (DiRECT) at the annual scientific sessions of the American Diabetes Association (Lancet Diabetes Endocrinol. 2019 May;7(5):344-355).
A subgroup analysis he also presented found that beta cell function rebounds rapidly after weight loss and is pretty much normal at 2 years, so long as people keep the weight off.
The study is rooted in previous work by Dr. Taylor and his colleagues that found that very low-calorie diets normalized fasting plasma glucose in just 7 days in patients with type 2 diabetes due to a rapid fall in liver fat content and subsequent restoration of insulin sensitivity. That and other findings suggested that fast weight loss – instead of the traditional gradual approach – might help.
He and his team randomized 149 volunteers from primary care practices in the United Kingdom to standard care, and 149 others to rapid weight loss; more than a quarter of the patients who were asked agreed to participate.
Patients had diabetes for less than 6 years and were not insulin dependent. The baseline mean body mass index was 35 kg/m2, mean age 54 years, mean hemoglobin A1c 7.6%, and mean duration of disease 3 years; 176 subjects were men.
Diabetes drugs, anti-hypertensives, and diuretics were stopped in the weight loss group; the program consisted of three Optifast meal replacement shakes or soups per day – Optifast is one of many commercially available options – for a daily intake of 825-853 kcal. There was no other food, and alcohol was not permitted. The weight loss goal was 33 pounds or more over 3-5 months; almost 90% of the intervention group made it. The protocol did not include exercise.
Next came a 2-8 week stepped reintroduction to normal food, followed by counseling and other supportive care out to 2 years, plus some extra packets of Optifast, just in case.
“People [had] panic attacks when they [went] back into the kitchen, but that’s marvelous: we [had] a blank slate on which to write new dietary habits, building up knowledge of portion size and what to eat.” Dr. Taylor said.
At 1 year, 68 (46%) of the intervention participants were in remission off all drugs, and 36 (24%) had maintained at least a 33-pound weight loss. At 2 years, 53 (36%) were in remission, and 17 (11%) had maintained. Percent remission was linked to the extent of sustained weight loss.
Strokes, heart attacks, and other serious adverse outcomes were less common in the diet group, versus standard care, at both 1 and 2 years.
Among those who went into remission, the rapid initial response to a glucose bolus came back to near normal soon after food reintroduction, and “was sufficient to get nondiabetic blood glucose control,” with a mean hemoglobin A1c of 6% at 2 years. “We [also] saw, quite remarkably, was a slow steady return to almost completely normal” maximum beta cell capacity over the first 12 months, Dr. Taylor said.
The most likely explanation is that beta cells are overwhelmed and shut down in a milieu of too much fat and glucose, but are able to reconstitute their specialist function and come back online once it’s addressed, he added.
The study was funded by Diabetes UK. Dr. Taylor reported financial relationships with Self, Wilmington Healthcare, Lilly Diabetes, and Novartis AG.
SOURCE: Zhyzhneuskaya SV et al., ADA 2019 abstract 66-OR
SAN FRANCISCO – , according to United Kingdom investigators.
The odds of remission – meaning a hemoglobin A1c below 6.5% on repeat testing, off all medications – were directly related to the amount of weight patients lost; 60% of subjects who lost 22-33 pounds were free of type 2 disease at 2 years, versus 29% who lost 11-21 pounds, and 5% who lost less than 11 pounds.
“If people lose” around 30 pounds “and keep it off for 2 years, there’s a two-thirds chance of them escaping type 2 [diabetes]. People want to understand their options, and this is an option. This is very good news for people with diabetes,” said senior investigator Roy Taylor, MD, a professor of medicine and metabolism at the University of Newcastle, Newcastle upon Tyne, England, who presented the findings of the Diabetes Remission Clinical Trial (DiRECT) at the annual scientific sessions of the American Diabetes Association (Lancet Diabetes Endocrinol. 2019 May;7(5):344-355).
A subgroup analysis he also presented found that beta cell function rebounds rapidly after weight loss and is pretty much normal at 2 years, so long as people keep the weight off.
The study is rooted in previous work by Dr. Taylor and his colleagues that found that very low-calorie diets normalized fasting plasma glucose in just 7 days in patients with type 2 diabetes due to a rapid fall in liver fat content and subsequent restoration of insulin sensitivity. That and other findings suggested that fast weight loss – instead of the traditional gradual approach – might help.
He and his team randomized 149 volunteers from primary care practices in the United Kingdom to standard care, and 149 others to rapid weight loss; more than a quarter of the patients who were asked agreed to participate.
Patients had diabetes for less than 6 years and were not insulin dependent. The baseline mean body mass index was 35 kg/m2, mean age 54 years, mean hemoglobin A1c 7.6%, and mean duration of disease 3 years; 176 subjects were men.
Diabetes drugs, anti-hypertensives, and diuretics were stopped in the weight loss group; the program consisted of three Optifast meal replacement shakes or soups per day – Optifast is one of many commercially available options – for a daily intake of 825-853 kcal. There was no other food, and alcohol was not permitted. The weight loss goal was 33 pounds or more over 3-5 months; almost 90% of the intervention group made it. The protocol did not include exercise.
Next came a 2-8 week stepped reintroduction to normal food, followed by counseling and other supportive care out to 2 years, plus some extra packets of Optifast, just in case.
“People [had] panic attacks when they [went] back into the kitchen, but that’s marvelous: we [had] a blank slate on which to write new dietary habits, building up knowledge of portion size and what to eat.” Dr. Taylor said.
At 1 year, 68 (46%) of the intervention participants were in remission off all drugs, and 36 (24%) had maintained at least a 33-pound weight loss. At 2 years, 53 (36%) were in remission, and 17 (11%) had maintained. Percent remission was linked to the extent of sustained weight loss.
Strokes, heart attacks, and other serious adverse outcomes were less common in the diet group, versus standard care, at both 1 and 2 years.
Among those who went into remission, the rapid initial response to a glucose bolus came back to near normal soon after food reintroduction, and “was sufficient to get nondiabetic blood glucose control,” with a mean hemoglobin A1c of 6% at 2 years. “We [also] saw, quite remarkably, was a slow steady return to almost completely normal” maximum beta cell capacity over the first 12 months, Dr. Taylor said.
The most likely explanation is that beta cells are overwhelmed and shut down in a milieu of too much fat and glucose, but are able to reconstitute their specialist function and come back online once it’s addressed, he added.
The study was funded by Diabetes UK. Dr. Taylor reported financial relationships with Self, Wilmington Healthcare, Lilly Diabetes, and Novartis AG.
SOURCE: Zhyzhneuskaya SV et al., ADA 2019 abstract 66-OR
REPORTING FROM ADA 2019
Key clinical point: Type 2 diabetes patients can shed significant weight quickly and eliminate the disease.
Major finding: Seventy-percent of patients with type 2 diabetes who lost more than 33 pounds on a liquid diet over a few months, and kept it off, were free of the disease at 2 years.
Study details: Open-label, randomized trial with 298 patients
Disclosures: The study was funded by Diabetes UK. Dr. Taylor reported financial relationships with Self, Wilmington Healthcare, Lilly Diabetes, and Novartis AG.
Source: Zhyzhneuskaya SV et al., ADA 2019 abstract 66-OR
Breast cancer risk in type 2 diabetes related to adiposity
ORLANDO – findings from meta-analyses suggest.
In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.
However, there was substantial unexplained heterogeneity of results across the individual studies (I2 = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.
“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.
In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.
Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I2 = 0%) among the premenopausal breast cancer study groups and high (I2 = 70%) among the postmenopausal study groups.
The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.
“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”
This study was limited by insufficient data for investigating the sources of heterogeneity, she said.
“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed
In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.
“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”
Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I2 = 23%).
“But we see that the story is not that simple,” he said.
For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.
Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.
“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.
Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
ORLANDO – findings from meta-analyses suggest.
In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.
However, there was substantial unexplained heterogeneity of results across the individual studies (I2 = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.
“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.
In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.
Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I2 = 0%) among the premenopausal breast cancer study groups and high (I2 = 70%) among the postmenopausal study groups.
The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.
“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”
This study was limited by insufficient data for investigating the sources of heterogeneity, she said.
“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed
In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.
“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”
Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I2 = 23%).
“But we see that the story is not that simple,” he said.
For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.
Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.
“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.
Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
ORLANDO – findings from meta-analyses suggest.
In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.
However, there was substantial unexplained heterogeneity of results across the individual studies (I2 = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.
“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.
In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.
Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I2 = 0%) among the premenopausal breast cancer study groups and high (I2 = 70%) among the postmenopausal study groups.
The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.
“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”
This study was limited by insufficient data for investigating the sources of heterogeneity, she said.
“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed
In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.
“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”
Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I2 = 23%).
“But we see that the story is not that simple,” he said.
For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.
Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.
“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.
Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
REPORTING FROM ADA 2018
Key clinical point: Adiposity accounts for the increased risk of breast cancer among women with diabetes.
Major finding: An analysis of 12 studies that adjusted for BMI showed a summary relative risk for breast cancer of 1.09 in diabetic versus nondiabetic women, with moderate study heterogeneity.
Study details: Meta-analyses including 21 and 12 studies, respectively.
Disclosures: Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
Source: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
GBS in T2DM patients: Study highlights pros and cons, need for better patient selection
ORLANDO – , according to a nationwide, matched, observational cohort study in Sweden.
After 9 years of follow-up, all-cause mortality was 49% lower among 5,321 patients with T2DM compared with 5,321 matched control (183 vs. 351 deaths; hazard ratio, 0.51), as has been reported in prior studies, Vasileios Liakopoulos, MD, of the University of Gothenburg (Sweden) reported at the annual scientific sessions of the American Diabetes Association.
Cardiovascular disease (CVD) risk was 34% lower (108 vs. 150 patients; HR, 0.66), fatal CVD risk was 66% lower (21 vs. 64 patients; HR, 0.34), acute myocardial infarction risk was 45% lower (51 vs. 85 events; HR, 0.55) congestive heart failure risk was 51% lower (109 vs. 225 events; HR, 0.49), and cancer risk was 22% lower (153 vs. 188 cases; HR, 0.78) in cases vs. controls, respectively.
“[As for] the diagnoses that related to diabetes, hyperglycemia was lower by 66%, admission to the hospital due to amputation was 49% lower, and we also found something relatively new – that renal disease was lower by 42%,” Dr. Liakopoulos said.
Renal disease occurred in 105 cases vs. 187 controls (HR, 0.58), with the difference between the groups intensifying after the third year of follow-up, he noted.
However, numerous adverse events occurred more often in case patients, he said.
For example, hospitalizations for psychiatric disorders were increased by 33% (317 vs. 268; HR, 1.33), alcohol-related diagnoses were nearly threefold higher (180 vs. 65; HR, 2.90), malnutrition occurred nearly three times more often (128 vs. 46 patients; HR, 2.81), and anemia occurred nearly twice as often (84 vs. 46 cases; HR, 1.92) in cases vs. controls.
Of course, all the surgery-related adverse events occurred more often in the case patients, but interestingly, those events – which included things like gastrointestinal surgery other than gastric bypass, abdominal pain, gallstones/pancreatitis, gastrointestinal ulcers and reflux, and bowel obstruction – did not occur more often in case patients than in gastric bypass patients without diabetes in other studies, he noted.
The findings were based on merged data from the Scandinavian Obesity Surgery Registry, the Swedish National Diabetes Register, and other national databases, and persons with T2DM who had undergone gastric bypass surgery between 2007 and 2013 were matched by propensity score (based on sex, age, body mass index, and calendar time from the beginning of the study) with obese individuals who were not surgically treated for obesity. The risks of postoperative outcomes were assessed using a Cox regression model adjusted for sex, age, body mass index, and socioeconomic status, Dr. Liakopoulos said.
This study, though limited by its observational nature, minor differences in patient characteristics between the cases and controls, and potential residual confounding, confirms the benefits of gastric bypass surgery in obese patients with T2DM but also characterizes an array of both short- and long-term adverse events after bariatric surgery in these patients, he said.
“The beneficial effects of gastric bypass have been presented in terms of weight reduction, improvements in risk factors and cardiovascular disease, and mortality reduction in people with or without diabetes,” he said, noting, however, that only a few reports have addressed long-term incidence of complications after gastric bypass – and type 2 diabetes has only been addressed in small randomized studies or in low proportions in large prospective studies.
“[Based on the findings] we suggest better selection of patients for bariatric surgery, and we think improved long-term postoperative monitoring might further improve the results of such treatment,” he concluded.
Dr. Liakopoulos reported having no disclosures.
SOURCE: Liakopoulos V et al. ADA 2018, Abstract 131-OR.
ORLANDO – , according to a nationwide, matched, observational cohort study in Sweden.
After 9 years of follow-up, all-cause mortality was 49% lower among 5,321 patients with T2DM compared with 5,321 matched control (183 vs. 351 deaths; hazard ratio, 0.51), as has been reported in prior studies, Vasileios Liakopoulos, MD, of the University of Gothenburg (Sweden) reported at the annual scientific sessions of the American Diabetes Association.
Cardiovascular disease (CVD) risk was 34% lower (108 vs. 150 patients; HR, 0.66), fatal CVD risk was 66% lower (21 vs. 64 patients; HR, 0.34), acute myocardial infarction risk was 45% lower (51 vs. 85 events; HR, 0.55) congestive heart failure risk was 51% lower (109 vs. 225 events; HR, 0.49), and cancer risk was 22% lower (153 vs. 188 cases; HR, 0.78) in cases vs. controls, respectively.
“[As for] the diagnoses that related to diabetes, hyperglycemia was lower by 66%, admission to the hospital due to amputation was 49% lower, and we also found something relatively new – that renal disease was lower by 42%,” Dr. Liakopoulos said.
Renal disease occurred in 105 cases vs. 187 controls (HR, 0.58), with the difference between the groups intensifying after the third year of follow-up, he noted.
However, numerous adverse events occurred more often in case patients, he said.
For example, hospitalizations for psychiatric disorders were increased by 33% (317 vs. 268; HR, 1.33), alcohol-related diagnoses were nearly threefold higher (180 vs. 65; HR, 2.90), malnutrition occurred nearly three times more often (128 vs. 46 patients; HR, 2.81), and anemia occurred nearly twice as often (84 vs. 46 cases; HR, 1.92) in cases vs. controls.
Of course, all the surgery-related adverse events occurred more often in the case patients, but interestingly, those events – which included things like gastrointestinal surgery other than gastric bypass, abdominal pain, gallstones/pancreatitis, gastrointestinal ulcers and reflux, and bowel obstruction – did not occur more often in case patients than in gastric bypass patients without diabetes in other studies, he noted.
The findings were based on merged data from the Scandinavian Obesity Surgery Registry, the Swedish National Diabetes Register, and other national databases, and persons with T2DM who had undergone gastric bypass surgery between 2007 and 2013 were matched by propensity score (based on sex, age, body mass index, and calendar time from the beginning of the study) with obese individuals who were not surgically treated for obesity. The risks of postoperative outcomes were assessed using a Cox regression model adjusted for sex, age, body mass index, and socioeconomic status, Dr. Liakopoulos said.
This study, though limited by its observational nature, minor differences in patient characteristics between the cases and controls, and potential residual confounding, confirms the benefits of gastric bypass surgery in obese patients with T2DM but also characterizes an array of both short- and long-term adverse events after bariatric surgery in these patients, he said.
“The beneficial effects of gastric bypass have been presented in terms of weight reduction, improvements in risk factors and cardiovascular disease, and mortality reduction in people with or without diabetes,” he said, noting, however, that only a few reports have addressed long-term incidence of complications after gastric bypass – and type 2 diabetes has only been addressed in small randomized studies or in low proportions in large prospective studies.
“[Based on the findings] we suggest better selection of patients for bariatric surgery, and we think improved long-term postoperative monitoring might further improve the results of such treatment,” he concluded.
Dr. Liakopoulos reported having no disclosures.
SOURCE: Liakopoulos V et al. ADA 2018, Abstract 131-OR.
ORLANDO – , according to a nationwide, matched, observational cohort study in Sweden.
After 9 years of follow-up, all-cause mortality was 49% lower among 5,321 patients with T2DM compared with 5,321 matched control (183 vs. 351 deaths; hazard ratio, 0.51), as has been reported in prior studies, Vasileios Liakopoulos, MD, of the University of Gothenburg (Sweden) reported at the annual scientific sessions of the American Diabetes Association.
Cardiovascular disease (CVD) risk was 34% lower (108 vs. 150 patients; HR, 0.66), fatal CVD risk was 66% lower (21 vs. 64 patients; HR, 0.34), acute myocardial infarction risk was 45% lower (51 vs. 85 events; HR, 0.55) congestive heart failure risk was 51% lower (109 vs. 225 events; HR, 0.49), and cancer risk was 22% lower (153 vs. 188 cases; HR, 0.78) in cases vs. controls, respectively.
“[As for] the diagnoses that related to diabetes, hyperglycemia was lower by 66%, admission to the hospital due to amputation was 49% lower, and we also found something relatively new – that renal disease was lower by 42%,” Dr. Liakopoulos said.
Renal disease occurred in 105 cases vs. 187 controls (HR, 0.58), with the difference between the groups intensifying after the third year of follow-up, he noted.
However, numerous adverse events occurred more often in case patients, he said.
For example, hospitalizations for psychiatric disorders were increased by 33% (317 vs. 268; HR, 1.33), alcohol-related diagnoses were nearly threefold higher (180 vs. 65; HR, 2.90), malnutrition occurred nearly three times more often (128 vs. 46 patients; HR, 2.81), and anemia occurred nearly twice as often (84 vs. 46 cases; HR, 1.92) in cases vs. controls.
Of course, all the surgery-related adverse events occurred more often in the case patients, but interestingly, those events – which included things like gastrointestinal surgery other than gastric bypass, abdominal pain, gallstones/pancreatitis, gastrointestinal ulcers and reflux, and bowel obstruction – did not occur more often in case patients than in gastric bypass patients without diabetes in other studies, he noted.
The findings were based on merged data from the Scandinavian Obesity Surgery Registry, the Swedish National Diabetes Register, and other national databases, and persons with T2DM who had undergone gastric bypass surgery between 2007 and 2013 were matched by propensity score (based on sex, age, body mass index, and calendar time from the beginning of the study) with obese individuals who were not surgically treated for obesity. The risks of postoperative outcomes were assessed using a Cox regression model adjusted for sex, age, body mass index, and socioeconomic status, Dr. Liakopoulos said.
This study, though limited by its observational nature, minor differences in patient characteristics between the cases and controls, and potential residual confounding, confirms the benefits of gastric bypass surgery in obese patients with T2DM but also characterizes an array of both short- and long-term adverse events after bariatric surgery in these patients, he said.
“The beneficial effects of gastric bypass have been presented in terms of weight reduction, improvements in risk factors and cardiovascular disease, and mortality reduction in people with or without diabetes,” he said, noting, however, that only a few reports have addressed long-term incidence of complications after gastric bypass – and type 2 diabetes has only been addressed in small randomized studies or in low proportions in large prospective studies.
“[Based on the findings] we suggest better selection of patients for bariatric surgery, and we think improved long-term postoperative monitoring might further improve the results of such treatment,” he concluded.
Dr. Liakopoulos reported having no disclosures.
SOURCE: Liakopoulos V et al. ADA 2018, Abstract 131-OR.
REPORTING FROM ADA 2018
Key clinical point: Bariatric surgery lowers mortality, CVD, and renal and other risks in obese T2DM patients but also has high complication rates.
Major finding: All-cause mortality, CVD, and renal disease risks were 49%, 34%, and 42% lower, respectively, in cases vs. controls.
Study details: A matched observational cohort study of 5,321 cases and 5,321 controls.
Disclosures: Dr. Liakopoulos reported having no disclosures.
Source: Liakopoulos V et al. ADA 2018, Abstract 131-OR.
Study suggests “alarming” diabetes med discontinuation
ORLANDO – Most patients with type 2 diabetes mellitus stop taking their medication within a year, and nearly one-third stop within the first 3 months, a retrospective analysis of claims data for more than 324,000 patients suggests.
The findings in this population of commercially insured adults are startling and highlight a need for interventions to improve treatment persistence, according to Lisa Latts, MD, deputy chief health officer for IBM Watson Health in Cambridge, Mass.
Dr. Latts and her colleagues reviewed medication claims data for 324,136 patients with at least one diagnosis for type 2 diabetes mellitus and one outpatient pharmacy claim for a type 2 diabetes medication after at least 12 prior months without such a claim.
Of those patients, 58% discontinued treatment within 12 months, 31% discontinued within the first 3 months, and 44% discontinued within 6 months, Dr. Latts reported at the annual scientific sessions of the American Diabetes Association.
“Less than half of those patients who discontinued had a restart within the following year. So what we’re seeing here is a huge percentage of individuals who had a diagnosis of type 2 diabetes, were prescribed a medication, and then did not continue the medication,” she said.
Of those who discontinued within the 12-month follow-up, 27% restarted therapy within 60 days and 39% restarted therapy anytime during the 12-month follow-up (mean treatment gap, 107 days). Of those who discontinued by 3 months, 45% restarted within a year (mean treatment gap, 112 days), and of those who discontinued by 6 months, 44% restarted within a year (mean treatment gap, 119 days).
Patients included in the review, which was a collaborative effort of IBM Watson Health and the ADA, had at least 12 months of continuous enrollment in the Truven Health MarketScan Commercial and Medicare Supplemental Databases between 2013 and 2017, before and after the therapy initiation date.
They had a mean age of 55 years, with 28% aged 45-54 years and 35% aged 55-64 years. About 46% were women, and all had at least one diagnosis for type 2 diabetes mellitus during the study period and at least one outpatient pharmacy claim for a type 2 diabetes medication that was prescribed to be taken for at least 30 days.
“As you would expect, far and away the majority [68%] were given metformin,” Dr. Latts said.
Other prescribed treatments after the initial diagnosis included sulfonylureas (7%), insulin (6%), dipeptidyl peptidase–4 inhibitors (6%), sodium-glucose cotransporter 2 inhibitors (1.5%), and a variety of combination treatments – typically metformin plus sulfonylureas (5%).
This study provides real-world evidence that a majority of patients with type 2 diabetes discontinue their treatment within 1 year – an important finding given that medication persistence is imperative for successful treatment, Dr. Latts said. She noted that prior research has shown treatment discontinuation of prescribed medication within the first year is common for a number of chronic disease treatments and is associated with poor clinical outcomes.
“If you treat diabetes, this is alarming,” she said. “These are people who should be on a diabetes med, their doctor probably thinks they’re on a diabetes med, and they’re not taking it.”
The findings are limited by factors associated with the use of administrative claims data, such as possible coding inaccuracies and missed cases in which patients paid out of pocket for medications through low-cost pharmacy offers, as well as by the 12-month window used for the study. She added that the findings may not be generalizable to uninsured or Medicare patients.
Nevertheless, the findings are concerning and may reflect misunderstandings among patients about the need to refill prescriptions after the initial supply runs out, or may relate to side effects that patients don’t report to their physicians, Sherita Golden, MD, of Johns Hopkins University, Baltimore, said during a question-and-answer period following Dr. Latts’ presentation.
“I do treat patients with diabetes so I am very alarmed,” she said, adding that there is a need to improve communication between patients and physicians about treatment and side effects.
Dr. Latts reported relationships with Medtronic, Novo Nordisk, and Sanofi. Her coauthors from IBM Watson and the ADA all reported having no financial disclosures.
SOURCE: Latts L et al. ADA 2018, Abstract 135-OR.
ORLANDO – Most patients with type 2 diabetes mellitus stop taking their medication within a year, and nearly one-third stop within the first 3 months, a retrospective analysis of claims data for more than 324,000 patients suggests.
The findings in this population of commercially insured adults are startling and highlight a need for interventions to improve treatment persistence, according to Lisa Latts, MD, deputy chief health officer for IBM Watson Health in Cambridge, Mass.
Dr. Latts and her colleagues reviewed medication claims data for 324,136 patients with at least one diagnosis for type 2 diabetes mellitus and one outpatient pharmacy claim for a type 2 diabetes medication after at least 12 prior months without such a claim.
Of those patients, 58% discontinued treatment within 12 months, 31% discontinued within the first 3 months, and 44% discontinued within 6 months, Dr. Latts reported at the annual scientific sessions of the American Diabetes Association.
“Less than half of those patients who discontinued had a restart within the following year. So what we’re seeing here is a huge percentage of individuals who had a diagnosis of type 2 diabetes, were prescribed a medication, and then did not continue the medication,” she said.
Of those who discontinued within the 12-month follow-up, 27% restarted therapy within 60 days and 39% restarted therapy anytime during the 12-month follow-up (mean treatment gap, 107 days). Of those who discontinued by 3 months, 45% restarted within a year (mean treatment gap, 112 days), and of those who discontinued by 6 months, 44% restarted within a year (mean treatment gap, 119 days).
Patients included in the review, which was a collaborative effort of IBM Watson Health and the ADA, had at least 12 months of continuous enrollment in the Truven Health MarketScan Commercial and Medicare Supplemental Databases between 2013 and 2017, before and after the therapy initiation date.
They had a mean age of 55 years, with 28% aged 45-54 years and 35% aged 55-64 years. About 46% were women, and all had at least one diagnosis for type 2 diabetes mellitus during the study period and at least one outpatient pharmacy claim for a type 2 diabetes medication that was prescribed to be taken for at least 30 days.
“As you would expect, far and away the majority [68%] were given metformin,” Dr. Latts said.
Other prescribed treatments after the initial diagnosis included sulfonylureas (7%), insulin (6%), dipeptidyl peptidase–4 inhibitors (6%), sodium-glucose cotransporter 2 inhibitors (1.5%), and a variety of combination treatments – typically metformin plus sulfonylureas (5%).
This study provides real-world evidence that a majority of patients with type 2 diabetes discontinue their treatment within 1 year – an important finding given that medication persistence is imperative for successful treatment, Dr. Latts said. She noted that prior research has shown treatment discontinuation of prescribed medication within the first year is common for a number of chronic disease treatments and is associated with poor clinical outcomes.
“If you treat diabetes, this is alarming,” she said. “These are people who should be on a diabetes med, their doctor probably thinks they’re on a diabetes med, and they’re not taking it.”
The findings are limited by factors associated with the use of administrative claims data, such as possible coding inaccuracies and missed cases in which patients paid out of pocket for medications through low-cost pharmacy offers, as well as by the 12-month window used for the study. She added that the findings may not be generalizable to uninsured or Medicare patients.
Nevertheless, the findings are concerning and may reflect misunderstandings among patients about the need to refill prescriptions after the initial supply runs out, or may relate to side effects that patients don’t report to their physicians, Sherita Golden, MD, of Johns Hopkins University, Baltimore, said during a question-and-answer period following Dr. Latts’ presentation.
“I do treat patients with diabetes so I am very alarmed,” she said, adding that there is a need to improve communication between patients and physicians about treatment and side effects.
Dr. Latts reported relationships with Medtronic, Novo Nordisk, and Sanofi. Her coauthors from IBM Watson and the ADA all reported having no financial disclosures.
SOURCE: Latts L et al. ADA 2018, Abstract 135-OR.
ORLANDO – Most patients with type 2 diabetes mellitus stop taking their medication within a year, and nearly one-third stop within the first 3 months, a retrospective analysis of claims data for more than 324,000 patients suggests.
The findings in this population of commercially insured adults are startling and highlight a need for interventions to improve treatment persistence, according to Lisa Latts, MD, deputy chief health officer for IBM Watson Health in Cambridge, Mass.
Dr. Latts and her colleagues reviewed medication claims data for 324,136 patients with at least one diagnosis for type 2 diabetes mellitus and one outpatient pharmacy claim for a type 2 diabetes medication after at least 12 prior months without such a claim.
Of those patients, 58% discontinued treatment within 12 months, 31% discontinued within the first 3 months, and 44% discontinued within 6 months, Dr. Latts reported at the annual scientific sessions of the American Diabetes Association.
“Less than half of those patients who discontinued had a restart within the following year. So what we’re seeing here is a huge percentage of individuals who had a diagnosis of type 2 diabetes, were prescribed a medication, and then did not continue the medication,” she said.
Of those who discontinued within the 12-month follow-up, 27% restarted therapy within 60 days and 39% restarted therapy anytime during the 12-month follow-up (mean treatment gap, 107 days). Of those who discontinued by 3 months, 45% restarted within a year (mean treatment gap, 112 days), and of those who discontinued by 6 months, 44% restarted within a year (mean treatment gap, 119 days).
Patients included in the review, which was a collaborative effort of IBM Watson Health and the ADA, had at least 12 months of continuous enrollment in the Truven Health MarketScan Commercial and Medicare Supplemental Databases between 2013 and 2017, before and after the therapy initiation date.
They had a mean age of 55 years, with 28% aged 45-54 years and 35% aged 55-64 years. About 46% were women, and all had at least one diagnosis for type 2 diabetes mellitus during the study period and at least one outpatient pharmacy claim for a type 2 diabetes medication that was prescribed to be taken for at least 30 days.
“As you would expect, far and away the majority [68%] were given metformin,” Dr. Latts said.
Other prescribed treatments after the initial diagnosis included sulfonylureas (7%), insulin (6%), dipeptidyl peptidase–4 inhibitors (6%), sodium-glucose cotransporter 2 inhibitors (1.5%), and a variety of combination treatments – typically metformin plus sulfonylureas (5%).
This study provides real-world evidence that a majority of patients with type 2 diabetes discontinue their treatment within 1 year – an important finding given that medication persistence is imperative for successful treatment, Dr. Latts said. She noted that prior research has shown treatment discontinuation of prescribed medication within the first year is common for a number of chronic disease treatments and is associated with poor clinical outcomes.
“If you treat diabetes, this is alarming,” she said. “These are people who should be on a diabetes med, their doctor probably thinks they’re on a diabetes med, and they’re not taking it.”
The findings are limited by factors associated with the use of administrative claims data, such as possible coding inaccuracies and missed cases in which patients paid out of pocket for medications through low-cost pharmacy offers, as well as by the 12-month window used for the study. She added that the findings may not be generalizable to uninsured or Medicare patients.
Nevertheless, the findings are concerning and may reflect misunderstandings among patients about the need to refill prescriptions after the initial supply runs out, or may relate to side effects that patients don’t report to their physicians, Sherita Golden, MD, of Johns Hopkins University, Baltimore, said during a question-and-answer period following Dr. Latts’ presentation.
“I do treat patients with diabetes so I am very alarmed,” she said, adding that there is a need to improve communication between patients and physicians about treatment and side effects.
Dr. Latts reported relationships with Medtronic, Novo Nordisk, and Sanofi. Her coauthors from IBM Watson and the ADA all reported having no financial disclosures.
SOURCE: Latts L et al. ADA 2018, Abstract 135-OR.
REPORTING FROM ADA 2018
Key clinical point:
Major finding: In total, 58% of patients discontinued treatment within 12 months, and just 39% of those patients restarted within 1 year.
Study details: An analysis of claims data for more than 324,000 patients.
Disclosures: Dr. Latts reported relationships with Medtronic, Novo Nordisk, and Sanofi. Her coauthors from IBM Watson and the American Diabetes Association all reported having no financial disclosures.
Source: Latts L et al. ADA 2018, Abstract 135-OR.
The dextrose-sulfonylurea challenge: a screen for monogenetic diabetes?
ORLANDO – When investigators at Washington University, St. Louis, gave 42 patients with type 1 diabetes mellitus a dose of the sulfonylurea glipizide (Glucotrol), a curious thing happened.
C-peptide levels rose in 13 patients (31%), which means they secreted their own insulin.
The finding was unexpected; people with type 1 diabetes mellitus (T1DM) aren’t supposed to be able to produce endogenous insulin because they don’t have beta cells. They shouldn’t have had any response to glipizide, a beta-cell stimulator.
It wasn’t that the 13 subjects were in the honeymoon phase of T1DM, meaning that they still had a few beta cells left. Like the other patients, their glucose levels rose when they were given dextrose, but their C-peptide levels did not. Also, all patients, including the 13 who secreted insulin, had been diagnosed with T1DM for a mean of 6 years and were insulin dependent. They ranged in age up to 33 years, and their hemoglobin A1c was about 8.6%.
In short, the 13 patients didn’t have classic type 1 diabetes. They had something wrong with their beta cells, explained Colin G. Nichols, PhD, a professor of cell biology and physiology at Washington University.
They likely had monogenetic diabetes, a genetic mutation that caused potassium channels in their beta cells to be permanently hyperpolarized. Blocking the channels with a sulfonylurea allowed the cells to depolarize and secrete insulin.
Monogenetic diabetes is a known but underrecognized entity. If it’s not picked up in infancy, most patients are misdiagnosed with classic T1DM and inappropriately treated with insulin. If they finally try a sulfonylurea, “they don’t need insulin injections anymore. This has been a very magical story for this group of patients,” Dr. Nichols said at the annual scientific sessions of the American Diabetes Association.
All they need is a sulfonylurea pill once a day.
Monogenetic patients are missed because there are no easy, widely-available screening tests for the condition. Genetic testing works, but it’s expensive and often not done. Dr. Nichols and his team hope their dextrose-sulfonylurea challenge will solve the problem.
They are currently working to recruit more subjects and perform confirmatory genetic testing. They want to know how much insulin secretion is possible for their glipizide responders and how long their responses last. If funding comes through, they hope to do a screening and treatment trial in patients with T1DM.
The promise is that the dextrose-sulfonylurea challenge will shorten the time to a correct diagnosis and proper treatment, and save people from decades of insulin shots. It might also pick up nongenetic, metabolic causes of beta-cell potassium channel dysfunction that would respond to sulfonylureas. The challenge could even be used to prescreen for genetic testing, to increase its yield and shift the cost-benefit ratio more into the black.
As for the specifics of the study, the 42 patients were given an intravenous dextrose bolus of 0.5 g/kg, followed 20 minutes later by a single dose of glipizide, 0.3 mg/kg. Blood glucose and C-peptide were measured at baseline and at regular intervals during the 4-hour challenge. The challenge was safe; there were no serious side effects.
Among the 13 responders – meaning flat insulin secretion with dextrose but insulin secretion with glipizide – the peak change in C-peptide was around 0.41 ng/mL ± 0.45 an hour or so after the glipizide dose, and was maintained for about an hour from a baseline of about 0.6 ng/mL.
To make sure that the responders didn’t have just a delayed insulin response to dextrose, they were given another dextrose challenge 6 months later, without the glipizide. Again, their C-peptide levels were flat.
The investigators had no disclosures to report, and there was no industry funding.
SOURCE: Nichols CG et al. ADA 2018, Abstract 310-LB.
ORLANDO – When investigators at Washington University, St. Louis, gave 42 patients with type 1 diabetes mellitus a dose of the sulfonylurea glipizide (Glucotrol), a curious thing happened.
C-peptide levels rose in 13 patients (31%), which means they secreted their own insulin.
The finding was unexpected; people with type 1 diabetes mellitus (T1DM) aren’t supposed to be able to produce endogenous insulin because they don’t have beta cells. They shouldn’t have had any response to glipizide, a beta-cell stimulator.
It wasn’t that the 13 subjects were in the honeymoon phase of T1DM, meaning that they still had a few beta cells left. Like the other patients, their glucose levels rose when they were given dextrose, but their C-peptide levels did not. Also, all patients, including the 13 who secreted insulin, had been diagnosed with T1DM for a mean of 6 years and were insulin dependent. They ranged in age up to 33 years, and their hemoglobin A1c was about 8.6%.
In short, the 13 patients didn’t have classic type 1 diabetes. They had something wrong with their beta cells, explained Colin G. Nichols, PhD, a professor of cell biology and physiology at Washington University.
They likely had monogenetic diabetes, a genetic mutation that caused potassium channels in their beta cells to be permanently hyperpolarized. Blocking the channels with a sulfonylurea allowed the cells to depolarize and secrete insulin.
Monogenetic diabetes is a known but underrecognized entity. If it’s not picked up in infancy, most patients are misdiagnosed with classic T1DM and inappropriately treated with insulin. If they finally try a sulfonylurea, “they don’t need insulin injections anymore. This has been a very magical story for this group of patients,” Dr. Nichols said at the annual scientific sessions of the American Diabetes Association.
All they need is a sulfonylurea pill once a day.
Monogenetic patients are missed because there are no easy, widely-available screening tests for the condition. Genetic testing works, but it’s expensive and often not done. Dr. Nichols and his team hope their dextrose-sulfonylurea challenge will solve the problem.
They are currently working to recruit more subjects and perform confirmatory genetic testing. They want to know how much insulin secretion is possible for their glipizide responders and how long their responses last. If funding comes through, they hope to do a screening and treatment trial in patients with T1DM.
The promise is that the dextrose-sulfonylurea challenge will shorten the time to a correct diagnosis and proper treatment, and save people from decades of insulin shots. It might also pick up nongenetic, metabolic causes of beta-cell potassium channel dysfunction that would respond to sulfonylureas. The challenge could even be used to prescreen for genetic testing, to increase its yield and shift the cost-benefit ratio more into the black.
As for the specifics of the study, the 42 patients were given an intravenous dextrose bolus of 0.5 g/kg, followed 20 minutes later by a single dose of glipizide, 0.3 mg/kg. Blood glucose and C-peptide were measured at baseline and at regular intervals during the 4-hour challenge. The challenge was safe; there were no serious side effects.
Among the 13 responders – meaning flat insulin secretion with dextrose but insulin secretion with glipizide – the peak change in C-peptide was around 0.41 ng/mL ± 0.45 an hour or so after the glipizide dose, and was maintained for about an hour from a baseline of about 0.6 ng/mL.
To make sure that the responders didn’t have just a delayed insulin response to dextrose, they were given another dextrose challenge 6 months later, without the glipizide. Again, their C-peptide levels were flat.
The investigators had no disclosures to report, and there was no industry funding.
SOURCE: Nichols CG et al. ADA 2018, Abstract 310-LB.
ORLANDO – When investigators at Washington University, St. Louis, gave 42 patients with type 1 diabetes mellitus a dose of the sulfonylurea glipizide (Glucotrol), a curious thing happened.
C-peptide levels rose in 13 patients (31%), which means they secreted their own insulin.
The finding was unexpected; people with type 1 diabetes mellitus (T1DM) aren’t supposed to be able to produce endogenous insulin because they don’t have beta cells. They shouldn’t have had any response to glipizide, a beta-cell stimulator.
It wasn’t that the 13 subjects were in the honeymoon phase of T1DM, meaning that they still had a few beta cells left. Like the other patients, their glucose levels rose when they were given dextrose, but their C-peptide levels did not. Also, all patients, including the 13 who secreted insulin, had been diagnosed with T1DM for a mean of 6 years and were insulin dependent. They ranged in age up to 33 years, and their hemoglobin A1c was about 8.6%.
In short, the 13 patients didn’t have classic type 1 diabetes. They had something wrong with their beta cells, explained Colin G. Nichols, PhD, a professor of cell biology and physiology at Washington University.
They likely had monogenetic diabetes, a genetic mutation that caused potassium channels in their beta cells to be permanently hyperpolarized. Blocking the channels with a sulfonylurea allowed the cells to depolarize and secrete insulin.
Monogenetic diabetes is a known but underrecognized entity. If it’s not picked up in infancy, most patients are misdiagnosed with classic T1DM and inappropriately treated with insulin. If they finally try a sulfonylurea, “they don’t need insulin injections anymore. This has been a very magical story for this group of patients,” Dr. Nichols said at the annual scientific sessions of the American Diabetes Association.
All they need is a sulfonylurea pill once a day.
Monogenetic patients are missed because there are no easy, widely-available screening tests for the condition. Genetic testing works, but it’s expensive and often not done. Dr. Nichols and his team hope their dextrose-sulfonylurea challenge will solve the problem.
They are currently working to recruit more subjects and perform confirmatory genetic testing. They want to know how much insulin secretion is possible for their glipizide responders and how long their responses last. If funding comes through, they hope to do a screening and treatment trial in patients with T1DM.
The promise is that the dextrose-sulfonylurea challenge will shorten the time to a correct diagnosis and proper treatment, and save people from decades of insulin shots. It might also pick up nongenetic, metabolic causes of beta-cell potassium channel dysfunction that would respond to sulfonylureas. The challenge could even be used to prescreen for genetic testing, to increase its yield and shift the cost-benefit ratio more into the black.
As for the specifics of the study, the 42 patients were given an intravenous dextrose bolus of 0.5 g/kg, followed 20 minutes later by a single dose of glipizide, 0.3 mg/kg. Blood glucose and C-peptide were measured at baseline and at regular intervals during the 4-hour challenge. The challenge was safe; there were no serious side effects.
Among the 13 responders – meaning flat insulin secretion with dextrose but insulin secretion with glipizide – the peak change in C-peptide was around 0.41 ng/mL ± 0.45 an hour or so after the glipizide dose, and was maintained for about an hour from a baseline of about 0.6 ng/mL.
To make sure that the responders didn’t have just a delayed insulin response to dextrose, they were given another dextrose challenge 6 months later, without the glipizide. Again, their C-peptide levels were flat.
The investigators had no disclosures to report, and there was no industry funding.
SOURCE: Nichols CG et al. ADA 2018, Abstract 310-LB.
REPORTING FROM ADA 2018
Key clinical point: Some patients with type 1 diabetes mellitus might need just a daily dose of a sulfonylurea instead of multiple insulin injections; a test to find them is being developed.
Major finding: Nearly one-third of patients with long-standing, insulin-dependent type 1 diabetes secreted their own insulin when given the beta-cell stimulator glipizide.
Study details: An observational study of 42 people with type 1 diabetes mellitus.
Disclosures: The investigators had no disclosures to report, and there was no industry funding.
Source: Nichols CG et al. ADA 2018, Abstract 310-LB.
Plan now for outpatient diabetes tech in the hospital
ORLANDO –
A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.
All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.
In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.
“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.
As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”
To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.
Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.
Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.
CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.
But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.
Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.
ORLANDO –
A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.
All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.
In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.
“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.
As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”
To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.
Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.
Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.
CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.
But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.
Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.
ORLANDO –
A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.
All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.
In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.
“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.
As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”
To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.
Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.
Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.
CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.
But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.
Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.
EXPERT ANALYSIS FROM ADA 2018
Bone biopsy in suspected osteomyelitis: Culture and histology matter
Diabetic foot ulcers and infections can lead to osteomyelitis, a potentially devastating infection in the bone.
How much of a difference can osteomyelitis make to a patient’s prognosis? A 2014 commentary by Benjamin A. Lipsky, MD, a prominent expert in problems associated with diabetic patients’ feet who’s with the University of Washington, Seattle, hints at the potential toll: “Overall, about 20% of patients with a diabetic foot infection (and over 60% of those with severe infections) have underlying osteomyelitis, which dramatically increases the risk of lower-extremity amputation” (Diabetes Care. 2014 Mar;37[3]:593-5).
Diagnosis of osteomyelitis, which relies on a bone biopsy, is clearly important. But there’s a big gap in diagnostic findings depending on whether doctors request culture or histology results, according to a new study released at the 2018 scientific meeting of the American Diabetes Association (Diabetes. 2018 Jul. doi: 10.2337/db18-110-OR).
In an interview, lead author and podiatrist Peter A. Crisologo, DPM, of University of Texas Southwestern Medical Center, Dallas, explained the study findings and offered guidance for requesting bone biopsies in possible cases of osteomyelitis.
Q: What makes diagnosis and treatment of osteomyelitis unique?
A: In the foot, there’s not a lot of soft tissue between the outside world and your bone. If the wounds on the feet go deep enough, they can spread a bacterial infection to the bone. This changes how foot infections are treated.
If you have a skin infection, it requires 11-12 days of antibiotics. Things start ramping up once you start getting into the bone. You’re talking potential surgery and 6 weeks of antibiotics through IV treatments. This is why it’s really important that you get your diagnosis right.
A lot of people say “I’m going to do the safe thing” and treat a bone infection with an extended course of antibiotics.
That’s not necessarily safe. If you’re overdiagnosing – for example, you identify bacteria that’s just a contaminant – you could put a patient through 6 weeks of IV treatment along with the risks of a PICC (peripherally inserted central catheter ) line infection, complications from IV placement, and complications from the antibiotic.
Also, acute kidney injury develops in at least a third of the patients who undergo 6 weeks of antibiotics. That’s not to mention the cost of the visits and the labs you have to draw. But we don’t want to underdiagnose either. If osteomyelitis is underdiagnosed and then not treated, the infection can smolder and continue to progress and worsen.
Q: Your study looks at the bone biopsy. How does it fit into care of osteomyelitis in the diabetic foot?
A: A bone biopsy is the standard for diagnosis under the guidelines of the Infectious Diseases Society of America/International Working Group on the Diabetic Foot (Clin Infect Dis. 2012;54[12]:e132-73 ).
But beyond that, nobody says anything. Everyone has an operational definition of how a bone biopsy is interpreted, and there’s a need for a consensus on how a bone biopsy can be used to diagnose osteomyelitis.
You’ll get different percentages of your patients diagnosed with osteomyelitis. For example, someone may say the biopsy is only positive if the histology is positive, while another says the histology doesn’t matter if the culture is positive.
Q: Your study looks at histology and culture analyses. What do these reveal?
A: A traditional culture helps you identify the bacteria, as well as guide your treatment when it’s tested against antibiotics.
A traditional histology allows the pathologist to look under a microscope for signs of osteomyelitis: Do they see the right inflammatory cells, white cells, lymphocytes, combinations of cells? Does this look like an acute or chronic osteomyelitis?
Q: Why might it be wise to combine culture and histology analyses?
A: If you have bacteria that’s difficult to culture via traditional methods, it may be a bacteria that doesn’t grow well or easily. If you combine culture with histology, pathologists can look and say, “Your culture was negative but we see these other signs, so we feel this is osteomyelitis.”
Q: Your study examined 35 consecutive patients aged at least 21 years who had moderate or severe infections bone infections in the foot linked with type 1 diabetes (n = 4) or type 2 diabetes (n = 31).
The samples were analyzed via culture, histology, and culture/histology examinations. You also performed genetic sequencing (quantitative polymerase chain reaction targeting 16S rRNA). How does this test fit in to bone biopsies in the clinic?
A: That’s a newer method and not a standard of care treatment for the diabetic foot. This analysis looks at DNA that’s present, bypassing the analysis of difficult-to-grow bacteria.
Q: What did you discover?
A: In this study, histology had the lowest incidence of positively detecting osteomyelitis. (45.7%). The level increases when a culture is taken (68.6% vs. histology; P = .02).
Then it goes up when DNA is used because it’s catching everything (82.9%, P = .001 vs. histology and P = .31 vs. culture).
[The study also found that adding histology to culture or to genetic sequencing did not change positive findings.]
Q: Does the study suggest one approach is better than the others?
A: This paper doesn’t provide enough evidence to use one method over another. The main purpose was to raise the concern that diagnosis can change dramatically depending on how the gold standard of bone biopsy is interpreted.
Q: What were the pros and cons of the genetic sequencing approach?
A: When we use this approach, our positive diagnostic rate significantly increases. But there are also downsides. We don’t know whether the bacteria we see is alive or dead. We just know it was there. So are the patients truly positive? That’s a question we can’t answer.
Genetic sequencing also doesn’t tell us about susceptibilities to antibiotics.
Q: What is the take-home message here for physicians who may order bone biopsies?
A: The thing to do is request both traditional culture and traditional histology.
As far as DNA sequencing, that not something I’d recommend as a standard of care.
Q: Can you comment on cost and insurance coverage for these approaches?
A: As far as I know, genetic sequencing is not covered as it is not standard of care in the diabetic foot and is used mainly for research at this time.
Pathology and culture are standard of care when evaluating for osteomyelitis and should be a covered service. However, a patient should call their insurance company first prior to having the procedure done to see whether it is covered.
Q: What’s next for research in this area?
A: From here, the next step is bigger numbers: Increase the study size and look at this again. Also, we may be able to identify susceptibilities by identifying resistance within the DNA.
Dr. Crisologo and two other study authors report no relevant disclosures. One study author reported various disclosures including research support, consulting, and service on speakers' bureaus.
Diabetic foot ulcers and infections can lead to osteomyelitis, a potentially devastating infection in the bone.
How much of a difference can osteomyelitis make to a patient’s prognosis? A 2014 commentary by Benjamin A. Lipsky, MD, a prominent expert in problems associated with diabetic patients’ feet who’s with the University of Washington, Seattle, hints at the potential toll: “Overall, about 20% of patients with a diabetic foot infection (and over 60% of those with severe infections) have underlying osteomyelitis, which dramatically increases the risk of lower-extremity amputation” (Diabetes Care. 2014 Mar;37[3]:593-5).
Diagnosis of osteomyelitis, which relies on a bone biopsy, is clearly important. But there’s a big gap in diagnostic findings depending on whether doctors request culture or histology results, according to a new study released at the 2018 scientific meeting of the American Diabetes Association (Diabetes. 2018 Jul. doi: 10.2337/db18-110-OR).
In an interview, lead author and podiatrist Peter A. Crisologo, DPM, of University of Texas Southwestern Medical Center, Dallas, explained the study findings and offered guidance for requesting bone biopsies in possible cases of osteomyelitis.
Q: What makes diagnosis and treatment of osteomyelitis unique?
A: In the foot, there’s not a lot of soft tissue between the outside world and your bone. If the wounds on the feet go deep enough, they can spread a bacterial infection to the bone. This changes how foot infections are treated.
If you have a skin infection, it requires 11-12 days of antibiotics. Things start ramping up once you start getting into the bone. You’re talking potential surgery and 6 weeks of antibiotics through IV treatments. This is why it’s really important that you get your diagnosis right.
A lot of people say “I’m going to do the safe thing” and treat a bone infection with an extended course of antibiotics.
That’s not necessarily safe. If you’re overdiagnosing – for example, you identify bacteria that’s just a contaminant – you could put a patient through 6 weeks of IV treatment along with the risks of a PICC (peripherally inserted central catheter ) line infection, complications from IV placement, and complications from the antibiotic.
Also, acute kidney injury develops in at least a third of the patients who undergo 6 weeks of antibiotics. That’s not to mention the cost of the visits and the labs you have to draw. But we don’t want to underdiagnose either. If osteomyelitis is underdiagnosed and then not treated, the infection can smolder and continue to progress and worsen.
Q: Your study looks at the bone biopsy. How does it fit into care of osteomyelitis in the diabetic foot?
A: A bone biopsy is the standard for diagnosis under the guidelines of the Infectious Diseases Society of America/International Working Group on the Diabetic Foot (Clin Infect Dis. 2012;54[12]:e132-73 ).
But beyond that, nobody says anything. Everyone has an operational definition of how a bone biopsy is interpreted, and there’s a need for a consensus on how a bone biopsy can be used to diagnose osteomyelitis.
You’ll get different percentages of your patients diagnosed with osteomyelitis. For example, someone may say the biopsy is only positive if the histology is positive, while another says the histology doesn’t matter if the culture is positive.
Q: Your study looks at histology and culture analyses. What do these reveal?
A: A traditional culture helps you identify the bacteria, as well as guide your treatment when it’s tested against antibiotics.
A traditional histology allows the pathologist to look under a microscope for signs of osteomyelitis: Do they see the right inflammatory cells, white cells, lymphocytes, combinations of cells? Does this look like an acute or chronic osteomyelitis?
Q: Why might it be wise to combine culture and histology analyses?
A: If you have bacteria that’s difficult to culture via traditional methods, it may be a bacteria that doesn’t grow well or easily. If you combine culture with histology, pathologists can look and say, “Your culture was negative but we see these other signs, so we feel this is osteomyelitis.”
Q: Your study examined 35 consecutive patients aged at least 21 years who had moderate or severe infections bone infections in the foot linked with type 1 diabetes (n = 4) or type 2 diabetes (n = 31).
The samples were analyzed via culture, histology, and culture/histology examinations. You also performed genetic sequencing (quantitative polymerase chain reaction targeting 16S rRNA). How does this test fit in to bone biopsies in the clinic?
A: That’s a newer method and not a standard of care treatment for the diabetic foot. This analysis looks at DNA that’s present, bypassing the analysis of difficult-to-grow bacteria.
Q: What did you discover?
A: In this study, histology had the lowest incidence of positively detecting osteomyelitis. (45.7%). The level increases when a culture is taken (68.6% vs. histology; P = .02).
Then it goes up when DNA is used because it’s catching everything (82.9%, P = .001 vs. histology and P = .31 vs. culture).
[The study also found that adding histology to culture or to genetic sequencing did not change positive findings.]
Q: Does the study suggest one approach is better than the others?
A: This paper doesn’t provide enough evidence to use one method over another. The main purpose was to raise the concern that diagnosis can change dramatically depending on how the gold standard of bone biopsy is interpreted.
Q: What were the pros and cons of the genetic sequencing approach?
A: When we use this approach, our positive diagnostic rate significantly increases. But there are also downsides. We don’t know whether the bacteria we see is alive or dead. We just know it was there. So are the patients truly positive? That’s a question we can’t answer.
Genetic sequencing also doesn’t tell us about susceptibilities to antibiotics.
Q: What is the take-home message here for physicians who may order bone biopsies?
A: The thing to do is request both traditional culture and traditional histology.
As far as DNA sequencing, that not something I’d recommend as a standard of care.
Q: Can you comment on cost and insurance coverage for these approaches?
A: As far as I know, genetic sequencing is not covered as it is not standard of care in the diabetic foot and is used mainly for research at this time.
Pathology and culture are standard of care when evaluating for osteomyelitis and should be a covered service. However, a patient should call their insurance company first prior to having the procedure done to see whether it is covered.
Q: What’s next for research in this area?
A: From here, the next step is bigger numbers: Increase the study size and look at this again. Also, we may be able to identify susceptibilities by identifying resistance within the DNA.
Dr. Crisologo and two other study authors report no relevant disclosures. One study author reported various disclosures including research support, consulting, and service on speakers' bureaus.
Diabetic foot ulcers and infections can lead to osteomyelitis, a potentially devastating infection in the bone.
How much of a difference can osteomyelitis make to a patient’s prognosis? A 2014 commentary by Benjamin A. Lipsky, MD, a prominent expert in problems associated with diabetic patients’ feet who’s with the University of Washington, Seattle, hints at the potential toll: “Overall, about 20% of patients with a diabetic foot infection (and over 60% of those with severe infections) have underlying osteomyelitis, which dramatically increases the risk of lower-extremity amputation” (Diabetes Care. 2014 Mar;37[3]:593-5).
Diagnosis of osteomyelitis, which relies on a bone biopsy, is clearly important. But there’s a big gap in diagnostic findings depending on whether doctors request culture or histology results, according to a new study released at the 2018 scientific meeting of the American Diabetes Association (Diabetes. 2018 Jul. doi: 10.2337/db18-110-OR).
In an interview, lead author and podiatrist Peter A. Crisologo, DPM, of University of Texas Southwestern Medical Center, Dallas, explained the study findings and offered guidance for requesting bone biopsies in possible cases of osteomyelitis.
Q: What makes diagnosis and treatment of osteomyelitis unique?
A: In the foot, there’s not a lot of soft tissue between the outside world and your bone. If the wounds on the feet go deep enough, they can spread a bacterial infection to the bone. This changes how foot infections are treated.
If you have a skin infection, it requires 11-12 days of antibiotics. Things start ramping up once you start getting into the bone. You’re talking potential surgery and 6 weeks of antibiotics through IV treatments. This is why it’s really important that you get your diagnosis right.
A lot of people say “I’m going to do the safe thing” and treat a bone infection with an extended course of antibiotics.
That’s not necessarily safe. If you’re overdiagnosing – for example, you identify bacteria that’s just a contaminant – you could put a patient through 6 weeks of IV treatment along with the risks of a PICC (peripherally inserted central catheter ) line infection, complications from IV placement, and complications from the antibiotic.
Also, acute kidney injury develops in at least a third of the patients who undergo 6 weeks of antibiotics. That’s not to mention the cost of the visits and the labs you have to draw. But we don’t want to underdiagnose either. If osteomyelitis is underdiagnosed and then not treated, the infection can smolder and continue to progress and worsen.
Q: Your study looks at the bone biopsy. How does it fit into care of osteomyelitis in the diabetic foot?
A: A bone biopsy is the standard for diagnosis under the guidelines of the Infectious Diseases Society of America/International Working Group on the Diabetic Foot (Clin Infect Dis. 2012;54[12]:e132-73 ).
But beyond that, nobody says anything. Everyone has an operational definition of how a bone biopsy is interpreted, and there’s a need for a consensus on how a bone biopsy can be used to diagnose osteomyelitis.
You’ll get different percentages of your patients diagnosed with osteomyelitis. For example, someone may say the biopsy is only positive if the histology is positive, while another says the histology doesn’t matter if the culture is positive.
Q: Your study looks at histology and culture analyses. What do these reveal?
A: A traditional culture helps you identify the bacteria, as well as guide your treatment when it’s tested against antibiotics.
A traditional histology allows the pathologist to look under a microscope for signs of osteomyelitis: Do they see the right inflammatory cells, white cells, lymphocytes, combinations of cells? Does this look like an acute or chronic osteomyelitis?
Q: Why might it be wise to combine culture and histology analyses?
A: If you have bacteria that’s difficult to culture via traditional methods, it may be a bacteria that doesn’t grow well or easily. If you combine culture with histology, pathologists can look and say, “Your culture was negative but we see these other signs, so we feel this is osteomyelitis.”
Q: Your study examined 35 consecutive patients aged at least 21 years who had moderate or severe infections bone infections in the foot linked with type 1 diabetes (n = 4) or type 2 diabetes (n = 31).
The samples were analyzed via culture, histology, and culture/histology examinations. You also performed genetic sequencing (quantitative polymerase chain reaction targeting 16S rRNA). How does this test fit in to bone biopsies in the clinic?
A: That’s a newer method and not a standard of care treatment for the diabetic foot. This analysis looks at DNA that’s present, bypassing the analysis of difficult-to-grow bacteria.
Q: What did you discover?
A: In this study, histology had the lowest incidence of positively detecting osteomyelitis. (45.7%). The level increases when a culture is taken (68.6% vs. histology; P = .02).
Then it goes up when DNA is used because it’s catching everything (82.9%, P = .001 vs. histology and P = .31 vs. culture).
[The study also found that adding histology to culture or to genetic sequencing did not change positive findings.]
Q: Does the study suggest one approach is better than the others?
A: This paper doesn’t provide enough evidence to use one method over another. The main purpose was to raise the concern that diagnosis can change dramatically depending on how the gold standard of bone biopsy is interpreted.
Q: What were the pros and cons of the genetic sequencing approach?
A: When we use this approach, our positive diagnostic rate significantly increases. But there are also downsides. We don’t know whether the bacteria we see is alive or dead. We just know it was there. So are the patients truly positive? That’s a question we can’t answer.
Genetic sequencing also doesn’t tell us about susceptibilities to antibiotics.
Q: What is the take-home message here for physicians who may order bone biopsies?
A: The thing to do is request both traditional culture and traditional histology.
As far as DNA sequencing, that not something I’d recommend as a standard of care.
Q: Can you comment on cost and insurance coverage for these approaches?
A: As far as I know, genetic sequencing is not covered as it is not standard of care in the diabetic foot and is used mainly for research at this time.
Pathology and culture are standard of care when evaluating for osteomyelitis and should be a covered service. However, a patient should call their insurance company first prior to having the procedure done to see whether it is covered.
Q: What’s next for research in this area?
A: From here, the next step is bigger numbers: Increase the study size and look at this again. Also, we may be able to identify susceptibilities by identifying resistance within the DNA.
Dr. Crisologo and two other study authors report no relevant disclosures. One study author reported various disclosures including research support, consulting, and service on speakers' bureaus.
EXPERT ANALYSIS FROM ADA 2018
Restrictions on EMT glucagon administration should be lifted
ORLANDO – In 42 states, emergency medical technicians aren’t allowed to administer glucagon to patients with severe hypoglycemia, and that’s a problem, according to investigators from the Joslin Diabetes Center, Boston.
Paramedics can administer the drug, but they’re only about a quarter of medical first-responders, so in many parts of the country, ambulance crews show up with only EMTs [emergency medical technicians] on board, and patients have to wait for the ED to get glucagon.
The delay increases the risk of coma, brain damage, and death. Just like in stroke, time is key with severe hypoglycemia. “The minutes really add up,” said lead investigator Nicole Wagner, a one-time researcher at Joslin and now a medical student at Thomas Jefferson Medical College, Philadelphia.
“Increasing the availability of glucagon in the prehospital setting will likely result in reduced cost burden and adverse consequences of severe hypoglycemia. All emergency persons should have access to glucagon along with the training to administer it,” she and her team concluded at the 2018 American Diabetes Association scientific sessions meeting.
The situation is puzzling because glucagon has a good safety profile – the main concern is nausea – and families of diabetics, at least at Joslin, are taught all the time how to mix and inject it.
One of the investigators, a former EMT, ran into the problem when he was working in New York, so the team wanted to find out how widespread it is. They called emergency medical services offices in all 50 states and asked about their glucagon protocols. “We were surprised [by what we found]. We didn’t expect it,” Ms. Wagner said.
In some states, EMTs aren’t even allowed to check blood glucose.
In the eight states that allow EMTs to administer glucagon – Alaska, Montana, Minnesota, Wisconsin, Illinois, Kansas, Virginia, and Rhode Island – it seemed that someone at some point got fired up and lobbied for change. In the other states seemed to have fallen through the cracks. “When we pressed the offices a little bit, we” were told about bureaucratic red tape, “and that maybe it’s something that would be considered down the line,” Ms. Wagner said.
The Joslin team wants to get proactive. Joslin is one of the nation’s leading diabetes institutions, and it has worked on advocacy before. EMT glucagon might be its next campaign. “It’s something we feel should be addressed. We could work with the EMT community to push this through,” she said.
Meanwhile, the glucagon autoinjectors and nasal sprays companies are working on might alleviate the problem. Time will tell.
The team also looked at the 89,263 cases in the National Emergency Management Information System from 2013-2015 in which glucagon was administered; it’s likely the number would have been far higher if EMTs were allowed to give the drug.
Ambulances showed up an average of 15.34 minutes after the first call. Meanwhile, there were 3,944 adverse events with glucagon, mostly nausea.
Less than half of the cases were dispatched correctly as “diabetic problems,” so it’s likely that EMTs who couldn’t give glucagon handled the call.
There was no industry funding for the work. Ms. Wagner had no disclosures.
SOURCE: Wagner NE et al. 2018 American Diabetes Association scientific sessions abstract 387-P
ORLANDO – In 42 states, emergency medical technicians aren’t allowed to administer glucagon to patients with severe hypoglycemia, and that’s a problem, according to investigators from the Joslin Diabetes Center, Boston.
Paramedics can administer the drug, but they’re only about a quarter of medical first-responders, so in many parts of the country, ambulance crews show up with only EMTs [emergency medical technicians] on board, and patients have to wait for the ED to get glucagon.
The delay increases the risk of coma, brain damage, and death. Just like in stroke, time is key with severe hypoglycemia. “The minutes really add up,” said lead investigator Nicole Wagner, a one-time researcher at Joslin and now a medical student at Thomas Jefferson Medical College, Philadelphia.
“Increasing the availability of glucagon in the prehospital setting will likely result in reduced cost burden and adverse consequences of severe hypoglycemia. All emergency persons should have access to glucagon along with the training to administer it,” she and her team concluded at the 2018 American Diabetes Association scientific sessions meeting.
The situation is puzzling because glucagon has a good safety profile – the main concern is nausea – and families of diabetics, at least at Joslin, are taught all the time how to mix and inject it.
One of the investigators, a former EMT, ran into the problem when he was working in New York, so the team wanted to find out how widespread it is. They called emergency medical services offices in all 50 states and asked about their glucagon protocols. “We were surprised [by what we found]. We didn’t expect it,” Ms. Wagner said.
In some states, EMTs aren’t even allowed to check blood glucose.
In the eight states that allow EMTs to administer glucagon – Alaska, Montana, Minnesota, Wisconsin, Illinois, Kansas, Virginia, and Rhode Island – it seemed that someone at some point got fired up and lobbied for change. In the other states seemed to have fallen through the cracks. “When we pressed the offices a little bit, we” were told about bureaucratic red tape, “and that maybe it’s something that would be considered down the line,” Ms. Wagner said.
The Joslin team wants to get proactive. Joslin is one of the nation’s leading diabetes institutions, and it has worked on advocacy before. EMT glucagon might be its next campaign. “It’s something we feel should be addressed. We could work with the EMT community to push this through,” she said.
Meanwhile, the glucagon autoinjectors and nasal sprays companies are working on might alleviate the problem. Time will tell.
The team also looked at the 89,263 cases in the National Emergency Management Information System from 2013-2015 in which glucagon was administered; it’s likely the number would have been far higher if EMTs were allowed to give the drug.
Ambulances showed up an average of 15.34 minutes after the first call. Meanwhile, there were 3,944 adverse events with glucagon, mostly nausea.
Less than half of the cases were dispatched correctly as “diabetic problems,” so it’s likely that EMTs who couldn’t give glucagon handled the call.
There was no industry funding for the work. Ms. Wagner had no disclosures.
SOURCE: Wagner NE et al. 2018 American Diabetes Association scientific sessions abstract 387-P
ORLANDO – In 42 states, emergency medical technicians aren’t allowed to administer glucagon to patients with severe hypoglycemia, and that’s a problem, according to investigators from the Joslin Diabetes Center, Boston.
Paramedics can administer the drug, but they’re only about a quarter of medical first-responders, so in many parts of the country, ambulance crews show up with only EMTs [emergency medical technicians] on board, and patients have to wait for the ED to get glucagon.
The delay increases the risk of coma, brain damage, and death. Just like in stroke, time is key with severe hypoglycemia. “The minutes really add up,” said lead investigator Nicole Wagner, a one-time researcher at Joslin and now a medical student at Thomas Jefferson Medical College, Philadelphia.
“Increasing the availability of glucagon in the prehospital setting will likely result in reduced cost burden and adverse consequences of severe hypoglycemia. All emergency persons should have access to glucagon along with the training to administer it,” she and her team concluded at the 2018 American Diabetes Association scientific sessions meeting.
The situation is puzzling because glucagon has a good safety profile – the main concern is nausea – and families of diabetics, at least at Joslin, are taught all the time how to mix and inject it.
One of the investigators, a former EMT, ran into the problem when he was working in New York, so the team wanted to find out how widespread it is. They called emergency medical services offices in all 50 states and asked about their glucagon protocols. “We were surprised [by what we found]. We didn’t expect it,” Ms. Wagner said.
In some states, EMTs aren’t even allowed to check blood glucose.
In the eight states that allow EMTs to administer glucagon – Alaska, Montana, Minnesota, Wisconsin, Illinois, Kansas, Virginia, and Rhode Island – it seemed that someone at some point got fired up and lobbied for change. In the other states seemed to have fallen through the cracks. “When we pressed the offices a little bit, we” were told about bureaucratic red tape, “and that maybe it’s something that would be considered down the line,” Ms. Wagner said.
The Joslin team wants to get proactive. Joslin is one of the nation’s leading diabetes institutions, and it has worked on advocacy before. EMT glucagon might be its next campaign. “It’s something we feel should be addressed. We could work with the EMT community to push this through,” she said.
Meanwhile, the glucagon autoinjectors and nasal sprays companies are working on might alleviate the problem. Time will tell.
The team also looked at the 89,263 cases in the National Emergency Management Information System from 2013-2015 in which glucagon was administered; it’s likely the number would have been far higher if EMTs were allowed to give the drug.
Ambulances showed up an average of 15.34 minutes after the first call. Meanwhile, there were 3,944 adverse events with glucagon, mostly nausea.
Less than half of the cases were dispatched correctly as “diabetic problems,” so it’s likely that EMTs who couldn’t give glucagon handled the call.
There was no industry funding for the work. Ms. Wagner had no disclosures.
SOURCE: Wagner NE et al. 2018 American Diabetes Association scientific sessions abstract 387-P
REPORTING FROM ADA 2018
Key clinical point: States need to allow emergency medical technicians to administer glucagon.
Major finding: Only eight do; elsewhere, delays mean that patients face coma, brain damage, and death.
Study details: Query of emergency medical headquarters in all 50 states
Disclosures: There was no industry funding for the work. The presenter didn’t have any disclosures.
Source: Wagner NE et al. 2018 American Diabetes Association scientific sessions abstract 387-P
ADA/EASD: Draft consensus statement on managing hyperglycemia in T2DM
ORLANDO – according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).
The report, a project of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), is currently under review and will be presented in final form Oct. 5 at the EASD annual meeting in Berlin.
The current draft calls, generally, for the initial use of metformin followed by the addition of antihyperglycemic medications based on patient comorbidities and concerns “as we await answers to the many questions that remain,” John Buse, MD, PhD, cochair of the consensus statement writing group, said during a summary of the draft recommendations at the annual scientific sessions of the ADA.
The first step, however, is to assess key patient characteristics; these can include comorbidities, clinical characteristics, issues such as motivation and depression, and cultural and socio-economic context, Deborah J. Wexler, MD, 1 of 10 writing group members, said during the same presentation.
Patients with ASCVD or heart failure
Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.
“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.
The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.
“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.
However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.
“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.
“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.
That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).
These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).
Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.
If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.
In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.
“Then we suggest that if you are still not at [hemoglobin A1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.
In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.
The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
Lifestyle management and medication
With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.
In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.
In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.
“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.
In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.
The hope is that the final consensus statement will make it easier to navigate them, she said.
Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.
The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m2 or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.
Decision making and injectable therapies
The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).
The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.
This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.
The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
Knowledge gaps
In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”
Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.
These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.
“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
Consensus statement development
The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).
The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.
The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.
The updates were mainly based on research generated over the past 2 years, Dr. Davies said.
The final draft will be submitted for publication to Diabetes Care and Diabetologia.
Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.
ORLANDO – according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).
The report, a project of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), is currently under review and will be presented in final form Oct. 5 at the EASD annual meeting in Berlin.
The current draft calls, generally, for the initial use of metformin followed by the addition of antihyperglycemic medications based on patient comorbidities and concerns “as we await answers to the many questions that remain,” John Buse, MD, PhD, cochair of the consensus statement writing group, said during a summary of the draft recommendations at the annual scientific sessions of the ADA.
The first step, however, is to assess key patient characteristics; these can include comorbidities, clinical characteristics, issues such as motivation and depression, and cultural and socio-economic context, Deborah J. Wexler, MD, 1 of 10 writing group members, said during the same presentation.
Patients with ASCVD or heart failure
Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.
“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.
The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.
“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.
However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.
“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.
“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.
That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).
These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).
Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.
If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.
In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.
“Then we suggest that if you are still not at [hemoglobin A1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.
In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.
The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
Lifestyle management and medication
With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.
In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.
In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.
“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.
In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.
The hope is that the final consensus statement will make it easier to navigate them, she said.
Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.
The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m2 or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.
Decision making and injectable therapies
The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).
The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.
This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.
The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
Knowledge gaps
In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”
Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.
These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.
“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
Consensus statement development
The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).
The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.
The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.
The updates were mainly based on research generated over the past 2 years, Dr. Davies said.
The final draft will be submitted for publication to Diabetes Care and Diabetologia.
Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.
ORLANDO – according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).
The report, a project of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), is currently under review and will be presented in final form Oct. 5 at the EASD annual meeting in Berlin.
The current draft calls, generally, for the initial use of metformin followed by the addition of antihyperglycemic medications based on patient comorbidities and concerns “as we await answers to the many questions that remain,” John Buse, MD, PhD, cochair of the consensus statement writing group, said during a summary of the draft recommendations at the annual scientific sessions of the ADA.
The first step, however, is to assess key patient characteristics; these can include comorbidities, clinical characteristics, issues such as motivation and depression, and cultural and socio-economic context, Deborah J. Wexler, MD, 1 of 10 writing group members, said during the same presentation.
Patients with ASCVD or heart failure
Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.
“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.
The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.
“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.
However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.
“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.
“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.
That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).
These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).
Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.
If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.
In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.
“Then we suggest that if you are still not at [hemoglobin A1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.
In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.
The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
Lifestyle management and medication
With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.
In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.
In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.
“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.
In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.
The hope is that the final consensus statement will make it easier to navigate them, she said.
Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.
The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m2 or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.
Decision making and injectable therapies
The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).
The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.
This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.
The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
Knowledge gaps
In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”
Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.
These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.
“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
Consensus statement development
The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).
The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.
The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.
The updates were mainly based on research generated over the past 2 years, Dr. Davies said.
The final draft will be submitted for publication to Diabetes Care and Diabetologia.
Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.
EXPERT ANALYSIS FROM ADA 2018
The VADT at 15 years: No legacy effect of intensive glucose control in T2DM
ORLANDO – , according to final results from the VADT follow-up study (VADT-F).
Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).
This was despite a rapid and statistically significant separation of hemoglobin A1c (HbA1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.
Approximately 6 months after the start of the VADT, median HbA1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.
“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
10-year outcomes
However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.
The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m2, sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.
At that 10-year follow-up, HbA1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.
“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA1c levels over time ... illustrating the difficulty of controlling HbA1c values to this level in this advanced diabetes population,” Dr. Reaven said.
15-year outcomes
At the final 15-year follow up, with the HbA1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).
Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.
The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.
Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.
There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.
Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.
In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.
Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.
The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.
“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.
That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA1c levels achieved during those intervening 10 years of follow-up.
For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA1c), he said, noting that similar findings have been reported from prior trials.
The VADT design
The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.
Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m2, had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.
A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.
“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.
All patients with a BMI of 27 kg/m2 or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.
Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.
“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.
The VADT-F design
The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.
“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.
The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.
The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.
Clinical perspective and future directions
“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”
Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.
However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA1c less than 7%, albeit “with all sorts of caveats.”
“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.
He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA1c control goals in patients with T2DM.
“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A1c targets should be personalized to maximize benefits while limiting risks.”
Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.
“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.
The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.
ORLANDO – , according to final results from the VADT follow-up study (VADT-F).
Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).
This was despite a rapid and statistically significant separation of hemoglobin A1c (HbA1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.
Approximately 6 months after the start of the VADT, median HbA1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.
“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
10-year outcomes
However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.
The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m2, sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.
At that 10-year follow-up, HbA1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.
“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA1c levels over time ... illustrating the difficulty of controlling HbA1c values to this level in this advanced diabetes population,” Dr. Reaven said.
15-year outcomes
At the final 15-year follow up, with the HbA1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).
Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.
The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.
Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.
There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.
Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.
In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.
Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.
The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.
“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.
That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA1c levels achieved during those intervening 10 years of follow-up.
For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA1c), he said, noting that similar findings have been reported from prior trials.
The VADT design
The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.
Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m2, had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.
A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.
“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.
All patients with a BMI of 27 kg/m2 or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.
Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.
“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.
The VADT-F design
The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.
“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.
The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.
The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.
Clinical perspective and future directions
“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”
Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.
However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA1c less than 7%, albeit “with all sorts of caveats.”
“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.
He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA1c control goals in patients with T2DM.
“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A1c targets should be personalized to maximize benefits while limiting risks.”
Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.
“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.
The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.
ORLANDO – , according to final results from the VADT follow-up study (VADT-F).
Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).
This was despite a rapid and statistically significant separation of hemoglobin A1c (HbA1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.
Approximately 6 months after the start of the VADT, median HbA1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.
“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
10-year outcomes
However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.
The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m2, sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.
At that 10-year follow-up, HbA1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.
“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA1c levels over time ... illustrating the difficulty of controlling HbA1c values to this level in this advanced diabetes population,” Dr. Reaven said.
15-year outcomes
At the final 15-year follow up, with the HbA1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).
Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.
The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.
Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.
There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.
Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.
In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.
Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.
The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.
“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.
That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA1c levels achieved during those intervening 10 years of follow-up.
For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA1c), he said, noting that similar findings have been reported from prior trials.
The VADT design
The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.
Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m2, had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.
A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.
“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.
All patients with a BMI of 27 kg/m2 or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.
Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.
“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.
The VADT-F design
The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.
“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.
The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.
The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.
Clinical perspective and future directions
“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”
Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.
However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA1c less than 7%, albeit “with all sorts of caveats.”
“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.
He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA1c control goals in patients with T2DM.
“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A1c targets should be personalized to maximize benefits while limiting risks.”
Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.
“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.
The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.
EXPERT ANALYSIS FROM ADA 2018