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Impact of carbs vs. fats on CVD risk becoming better understood
LOS ANGELES – When it comes to understanding the impact of diet on cardiovascular disease, mounting evidence suggests that a high carbohydrate diet is associated with a higher risk of mortality, while consumption of fats, including saturated and unsaturated fats, is associated with a lower risk of mortality.
Ronald M. Krauss, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “There are various categories of evidence that we all consider. Randomized clinical trials are the most robust, but, in this field, there are few and, of these, a number have been subject to criticism. Observational cohort studies provide much of the data on which we base our dietary recommendations. This is a problem, because dietary information can be flawed, it’s challenging to adjust for all the covariates in an observational trial, and you can’t determine causation.”
Dr. Krauss, senior scientist and director of atherosclerosis research at Children’s Hospital Oakland (Calif.) Research Institute, emphasized that current dietary recommendations are often not based on food context. Meta-analyses may be used to make dietary recommendations, “but you have to be careful,” he said. “There is quite a bit of subjectivity in the criteria used to select the studies. Finally, there is individual variability in dietary effects. You lose that when you do statistical analysis in large study populations.”
An analysis of prospective observational cohort studies over the past several years showed that there is no significant effect of saturated fat intake on all-cause mortality, cardiovascular disease (CVD), coronary heart disease (CHD), ischemic stroke, or type 2 diabetes mellitus (BMJ. 2015 Aug 12. doi: 10.1136/bmj.h3978). However, it found that trans fats are associated with all-cause mortality, total CHD, and CHD mortality. A more recent meta-analysis of randomized, controlled trials of saturated fat intake and coronary heart disease in the past 5 years yielded similar findings.
“Saturated fat intake per se is not associated with all-cause mortality, CVD, CHD, stroke, or type 2 diabetes,” said Dr. Krauss, who was an author of a recent analysis on dietary fat and cardiometabolic health (BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2139). “The replacement nutrient is important, but there has been controversy as to whether replacing saturated fat with n-6 (omega-6) polyunsaturated fatty acids reduced CHD events, CHD mortality, or total mortality.”
Other research has demonstrated differences in the relationship of saturated fat from meat sources vs. that from dairy sources. An analysis of 5,209 subjects who participated in the Multi-Ethnic Study of Atherosclerosis (MESA) study over 10 years found that a higher intake of dairy saturated fat was associated with lower CVD risk (Am J Clin Nutr. 2012;96[2]:397-404). In contrast, a higher intake of saturated fat from meat was associated with greater CVD risk.
In what Dr. Krauss said is the most extensive prospective cohort study of its kind to date, researchers led by Mahshid Dehghan, PhD, collected self-reported dietary data from 135,335 people aged 35-70 years in 18 countries, and grouped them according to the amount of carbohydrate, fat, and protein they consumed (Lancet. 2017 Aug 29. doi: 10.1016/S0140-6736[17]32252-3). Outcomes for the study, known as PURE, were major CVD and total mortality.
Over a median follow-up of 7.4 years, the researchers documented 5,796 deaths and 4,784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs. lowest quintile [quintile 1] category, hazard ratio 1.28; P = .0001) but not with the risk of CVD or CVD mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs. quintile 1, total fat: HR, 0.77, P less than .0001; saturated fat, HR, 0.86, P = .0088; monounsaturated fat: HR 0.81, P less than .0001; and polyunsaturated fat: HR 0.80, P less than .0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs. quintile 1, HR, 0.79; P = .0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality.
“The fat intake becomes a protective factor, while carbohydrates are the bad guys,” said Dr. Krauss, who also holds faculty positions at the University of California, San Francisco, and the University of California, Berkeley. He acknowledged certain limitations of PURE, including the fact that the random measurement used in the assessment of diet may dilute real associations, that high carbohydrate and low-fat diets may be a proxy for poverty, and that data on vegetable oil use were not included.
Dr. Krauss went on to note that work from other studies has shown that the Apo B/Apo A-1 ratio and its association with small – but not large – LDL particles is a stronger marker than is LDL cholesterol for predicting dietary effects on CVD risk (Lancet. 2004;364[9438]:937-52 and Arterioscler Thromb Vasc Biol. 2014;34[5]:1069-77). “These risk measures can be improved by lowering dietary carbohydrates, and not by lowering saturated fats,” he said.
Dr. Krauss disclosed that he has received grants from the National Institutes of Health and Dairy Management Inc. He is a member of the scientific advisory board for Virta Health and DayTwo and holds a patent related to lipoprotein particle analysis.
LOS ANGELES – When it comes to understanding the impact of diet on cardiovascular disease, mounting evidence suggests that a high carbohydrate diet is associated with a higher risk of mortality, while consumption of fats, including saturated and unsaturated fats, is associated with a lower risk of mortality.
Ronald M. Krauss, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “There are various categories of evidence that we all consider. Randomized clinical trials are the most robust, but, in this field, there are few and, of these, a number have been subject to criticism. Observational cohort studies provide much of the data on which we base our dietary recommendations. This is a problem, because dietary information can be flawed, it’s challenging to adjust for all the covariates in an observational trial, and you can’t determine causation.”
Dr. Krauss, senior scientist and director of atherosclerosis research at Children’s Hospital Oakland (Calif.) Research Institute, emphasized that current dietary recommendations are often not based on food context. Meta-analyses may be used to make dietary recommendations, “but you have to be careful,” he said. “There is quite a bit of subjectivity in the criteria used to select the studies. Finally, there is individual variability in dietary effects. You lose that when you do statistical analysis in large study populations.”
An analysis of prospective observational cohort studies over the past several years showed that there is no significant effect of saturated fat intake on all-cause mortality, cardiovascular disease (CVD), coronary heart disease (CHD), ischemic stroke, or type 2 diabetes mellitus (BMJ. 2015 Aug 12. doi: 10.1136/bmj.h3978). However, it found that trans fats are associated with all-cause mortality, total CHD, and CHD mortality. A more recent meta-analysis of randomized, controlled trials of saturated fat intake and coronary heart disease in the past 5 years yielded similar findings.
“Saturated fat intake per se is not associated with all-cause mortality, CVD, CHD, stroke, or type 2 diabetes,” said Dr. Krauss, who was an author of a recent analysis on dietary fat and cardiometabolic health (BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2139). “The replacement nutrient is important, but there has been controversy as to whether replacing saturated fat with n-6 (omega-6) polyunsaturated fatty acids reduced CHD events, CHD mortality, or total mortality.”
Other research has demonstrated differences in the relationship of saturated fat from meat sources vs. that from dairy sources. An analysis of 5,209 subjects who participated in the Multi-Ethnic Study of Atherosclerosis (MESA) study over 10 years found that a higher intake of dairy saturated fat was associated with lower CVD risk (Am J Clin Nutr. 2012;96[2]:397-404). In contrast, a higher intake of saturated fat from meat was associated with greater CVD risk.
In what Dr. Krauss said is the most extensive prospective cohort study of its kind to date, researchers led by Mahshid Dehghan, PhD, collected self-reported dietary data from 135,335 people aged 35-70 years in 18 countries, and grouped them according to the amount of carbohydrate, fat, and protein they consumed (Lancet. 2017 Aug 29. doi: 10.1016/S0140-6736[17]32252-3). Outcomes for the study, known as PURE, were major CVD and total mortality.
Over a median follow-up of 7.4 years, the researchers documented 5,796 deaths and 4,784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs. lowest quintile [quintile 1] category, hazard ratio 1.28; P = .0001) but not with the risk of CVD or CVD mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs. quintile 1, total fat: HR, 0.77, P less than .0001; saturated fat, HR, 0.86, P = .0088; monounsaturated fat: HR 0.81, P less than .0001; and polyunsaturated fat: HR 0.80, P less than .0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs. quintile 1, HR, 0.79; P = .0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality.
“The fat intake becomes a protective factor, while carbohydrates are the bad guys,” said Dr. Krauss, who also holds faculty positions at the University of California, San Francisco, and the University of California, Berkeley. He acknowledged certain limitations of PURE, including the fact that the random measurement used in the assessment of diet may dilute real associations, that high carbohydrate and low-fat diets may be a proxy for poverty, and that data on vegetable oil use were not included.
Dr. Krauss went on to note that work from other studies has shown that the Apo B/Apo A-1 ratio and its association with small – but not large – LDL particles is a stronger marker than is LDL cholesterol for predicting dietary effects on CVD risk (Lancet. 2004;364[9438]:937-52 and Arterioscler Thromb Vasc Biol. 2014;34[5]:1069-77). “These risk measures can be improved by lowering dietary carbohydrates, and not by lowering saturated fats,” he said.
Dr. Krauss disclosed that he has received grants from the National Institutes of Health and Dairy Management Inc. He is a member of the scientific advisory board for Virta Health and DayTwo and holds a patent related to lipoprotein particle analysis.
LOS ANGELES – When it comes to understanding the impact of diet on cardiovascular disease, mounting evidence suggests that a high carbohydrate diet is associated with a higher risk of mortality, while consumption of fats, including saturated and unsaturated fats, is associated with a lower risk of mortality.
Ronald M. Krauss, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “There are various categories of evidence that we all consider. Randomized clinical trials are the most robust, but, in this field, there are few and, of these, a number have been subject to criticism. Observational cohort studies provide much of the data on which we base our dietary recommendations. This is a problem, because dietary information can be flawed, it’s challenging to adjust for all the covariates in an observational trial, and you can’t determine causation.”
Dr. Krauss, senior scientist and director of atherosclerosis research at Children’s Hospital Oakland (Calif.) Research Institute, emphasized that current dietary recommendations are often not based on food context. Meta-analyses may be used to make dietary recommendations, “but you have to be careful,” he said. “There is quite a bit of subjectivity in the criteria used to select the studies. Finally, there is individual variability in dietary effects. You lose that when you do statistical analysis in large study populations.”
An analysis of prospective observational cohort studies over the past several years showed that there is no significant effect of saturated fat intake on all-cause mortality, cardiovascular disease (CVD), coronary heart disease (CHD), ischemic stroke, or type 2 diabetes mellitus (BMJ. 2015 Aug 12. doi: 10.1136/bmj.h3978). However, it found that trans fats are associated with all-cause mortality, total CHD, and CHD mortality. A more recent meta-analysis of randomized, controlled trials of saturated fat intake and coronary heart disease in the past 5 years yielded similar findings.
“Saturated fat intake per se is not associated with all-cause mortality, CVD, CHD, stroke, or type 2 diabetes,” said Dr. Krauss, who was an author of a recent analysis on dietary fat and cardiometabolic health (BMJ. 2018 Jun 13. doi: 10.1136/bmj.k2139). “The replacement nutrient is important, but there has been controversy as to whether replacing saturated fat with n-6 (omega-6) polyunsaturated fatty acids reduced CHD events, CHD mortality, or total mortality.”
Other research has demonstrated differences in the relationship of saturated fat from meat sources vs. that from dairy sources. An analysis of 5,209 subjects who participated in the Multi-Ethnic Study of Atherosclerosis (MESA) study over 10 years found that a higher intake of dairy saturated fat was associated with lower CVD risk (Am J Clin Nutr. 2012;96[2]:397-404). In contrast, a higher intake of saturated fat from meat was associated with greater CVD risk.
In what Dr. Krauss said is the most extensive prospective cohort study of its kind to date, researchers led by Mahshid Dehghan, PhD, collected self-reported dietary data from 135,335 people aged 35-70 years in 18 countries, and grouped them according to the amount of carbohydrate, fat, and protein they consumed (Lancet. 2017 Aug 29. doi: 10.1016/S0140-6736[17]32252-3). Outcomes for the study, known as PURE, were major CVD and total mortality.
Over a median follow-up of 7.4 years, the researchers documented 5,796 deaths and 4,784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs. lowest quintile [quintile 1] category, hazard ratio 1.28; P = .0001) but not with the risk of CVD or CVD mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs. quintile 1, total fat: HR, 0.77, P less than .0001; saturated fat, HR, 0.86, P = .0088; monounsaturated fat: HR 0.81, P less than .0001; and polyunsaturated fat: HR 0.80, P less than .0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs. quintile 1, HR, 0.79; P = .0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality.
“The fat intake becomes a protective factor, while carbohydrates are the bad guys,” said Dr. Krauss, who also holds faculty positions at the University of California, San Francisco, and the University of California, Berkeley. He acknowledged certain limitations of PURE, including the fact that the random measurement used in the assessment of diet may dilute real associations, that high carbohydrate and low-fat diets may be a proxy for poverty, and that data on vegetable oil use were not included.
Dr. Krauss went on to note that work from other studies has shown that the Apo B/Apo A-1 ratio and its association with small – but not large – LDL particles is a stronger marker than is LDL cholesterol for predicting dietary effects on CVD risk (Lancet. 2004;364[9438]:937-52 and Arterioscler Thromb Vasc Biol. 2014;34[5]:1069-77). “These risk measures can be improved by lowering dietary carbohydrates, and not by lowering saturated fats,” he said.
Dr. Krauss disclosed that he has received grants from the National Institutes of Health and Dairy Management Inc. He is a member of the scientific advisory board for Virta Health and DayTwo and holds a patent related to lipoprotein particle analysis.
EXPERT ANALYSIS FROM WCIRDC 2018
Tic disorders are associated with obesity and diabetes
The movement disorders are associated with cardiometabolic problems “even after taking into account a number of covariates and shared familial confounders and excluding relevant psychiatric comorbidities,” the researchers wrote. “The results highlight the importance of carefully monitoring cardiometabolic health in patients with Tourette syndrome or chronic tic disorder across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder (ADHD).”
Gustaf Brander, a researcher in the department of clinical neuroscience at Karolinska Institutet in Stockholm, and his colleagues conducted a longitudinal population-based cohort study of individuals living in Sweden between Jan. 1, 1973, and Dec. 31, 2013. The researchers assessed outcomes for patients with previously validated diagnoses of Tourette syndrome or chronic tic disorder in the Swedish National Patient Register. Main outcomes included obesity, dyslipidemia, hypertension, T2DM, and cardiovascular diseases, including ischemic heart diseases, arrhythmia, cerebrovascular diseases, transient ischemic attack, and arteriosclerosis. In addition, the researchers identified families with full siblings discordant for Tourette syndrome or chronic tic disorder.
Of the more than 14 million individuals in the cohort, 7,804 (76.4% male; median age at first diagnosis, 13.3 years) had a diagnosis of Tourette syndrome or chronic tic disorder in specialist care. Furthermore, the cohort included 5,141 families with full siblings who were discordant for these disorders.
Individuals with Tourette syndrome or chronic tic disorder had a higher risk for any metabolic or cardiovascular disorder, compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99) and sibling controls (aHR, 1.37). Specifically, individuals with Tourette syndrome or chronic tic disorder had higher risks for obesity (aHR, 2.76), T2DM(aHR, 1.67), and circulatory system diseases (aHR, 1.76).
The increased risk of any cardiometabolic disorder was significantly greater for males than it was for females (aHRs, 2.13 vs. 1.79), as was the risk of obesity (aHRs, 3.24 vs. 1.97).
The increased risk for cardiometabolic disorders in this patient population was evident by age 8 years. Exclusion of those patients with comorbid ADHD reduced but did not eliminate the risk (aHR, 1.52). The exclusion of other comorbidities did not significantly affect the results. Among patients with Tourette syndrome or chronic tic disorder, those who had received antipsychotic treatment for more than 1 year were significantly less likely to have metabolic and cardiovascular disorders, compared with patients not taking antipsychotic medication. This association may be related to “greater medical vigilance” and “should not be taken as evidence that antipsychotics are free from cardiometabolic adverse effects,” the authors noted.
The study was supported by a research grant from Tourettes Action. In addition, authors reported support from the Swedish Research Council and a Karolinska Institutet PhD stipend. Two authors disclosed personal fees from publishers, and one author disclosed grants and other funding from Shire.
SOURCE: Brander G et al. JAMA Neurol. 2019 Jan 14. doi: 10.1001/jamaneurol.2018.4279.
The movement disorders are associated with cardiometabolic problems “even after taking into account a number of covariates and shared familial confounders and excluding relevant psychiatric comorbidities,” the researchers wrote. “The results highlight the importance of carefully monitoring cardiometabolic health in patients with Tourette syndrome or chronic tic disorder across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder (ADHD).”
Gustaf Brander, a researcher in the department of clinical neuroscience at Karolinska Institutet in Stockholm, and his colleagues conducted a longitudinal population-based cohort study of individuals living in Sweden between Jan. 1, 1973, and Dec. 31, 2013. The researchers assessed outcomes for patients with previously validated diagnoses of Tourette syndrome or chronic tic disorder in the Swedish National Patient Register. Main outcomes included obesity, dyslipidemia, hypertension, T2DM, and cardiovascular diseases, including ischemic heart diseases, arrhythmia, cerebrovascular diseases, transient ischemic attack, and arteriosclerosis. In addition, the researchers identified families with full siblings discordant for Tourette syndrome or chronic tic disorder.
Of the more than 14 million individuals in the cohort, 7,804 (76.4% male; median age at first diagnosis, 13.3 years) had a diagnosis of Tourette syndrome or chronic tic disorder in specialist care. Furthermore, the cohort included 5,141 families with full siblings who were discordant for these disorders.
Individuals with Tourette syndrome or chronic tic disorder had a higher risk for any metabolic or cardiovascular disorder, compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99) and sibling controls (aHR, 1.37). Specifically, individuals with Tourette syndrome or chronic tic disorder had higher risks for obesity (aHR, 2.76), T2DM(aHR, 1.67), and circulatory system diseases (aHR, 1.76).
The increased risk of any cardiometabolic disorder was significantly greater for males than it was for females (aHRs, 2.13 vs. 1.79), as was the risk of obesity (aHRs, 3.24 vs. 1.97).
The increased risk for cardiometabolic disorders in this patient population was evident by age 8 years. Exclusion of those patients with comorbid ADHD reduced but did not eliminate the risk (aHR, 1.52). The exclusion of other comorbidities did not significantly affect the results. Among patients with Tourette syndrome or chronic tic disorder, those who had received antipsychotic treatment for more than 1 year were significantly less likely to have metabolic and cardiovascular disorders, compared with patients not taking antipsychotic medication. This association may be related to “greater medical vigilance” and “should not be taken as evidence that antipsychotics are free from cardiometabolic adverse effects,” the authors noted.
The study was supported by a research grant from Tourettes Action. In addition, authors reported support from the Swedish Research Council and a Karolinska Institutet PhD stipend. Two authors disclosed personal fees from publishers, and one author disclosed grants and other funding from Shire.
SOURCE: Brander G et al. JAMA Neurol. 2019 Jan 14. doi: 10.1001/jamaneurol.2018.4279.
The movement disorders are associated with cardiometabolic problems “even after taking into account a number of covariates and shared familial confounders and excluding relevant psychiatric comorbidities,” the researchers wrote. “The results highlight the importance of carefully monitoring cardiometabolic health in patients with Tourette syndrome or chronic tic disorder across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder (ADHD).”
Gustaf Brander, a researcher in the department of clinical neuroscience at Karolinska Institutet in Stockholm, and his colleagues conducted a longitudinal population-based cohort study of individuals living in Sweden between Jan. 1, 1973, and Dec. 31, 2013. The researchers assessed outcomes for patients with previously validated diagnoses of Tourette syndrome or chronic tic disorder in the Swedish National Patient Register. Main outcomes included obesity, dyslipidemia, hypertension, T2DM, and cardiovascular diseases, including ischemic heart diseases, arrhythmia, cerebrovascular diseases, transient ischemic attack, and arteriosclerosis. In addition, the researchers identified families with full siblings discordant for Tourette syndrome or chronic tic disorder.
Of the more than 14 million individuals in the cohort, 7,804 (76.4% male; median age at first diagnosis, 13.3 years) had a diagnosis of Tourette syndrome or chronic tic disorder in specialist care. Furthermore, the cohort included 5,141 families with full siblings who were discordant for these disorders.
Individuals with Tourette syndrome or chronic tic disorder had a higher risk for any metabolic or cardiovascular disorder, compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99) and sibling controls (aHR, 1.37). Specifically, individuals with Tourette syndrome or chronic tic disorder had higher risks for obesity (aHR, 2.76), T2DM(aHR, 1.67), and circulatory system diseases (aHR, 1.76).
The increased risk of any cardiometabolic disorder was significantly greater for males than it was for females (aHRs, 2.13 vs. 1.79), as was the risk of obesity (aHRs, 3.24 vs. 1.97).
The increased risk for cardiometabolic disorders in this patient population was evident by age 8 years. Exclusion of those patients with comorbid ADHD reduced but did not eliminate the risk (aHR, 1.52). The exclusion of other comorbidities did not significantly affect the results. Among patients with Tourette syndrome or chronic tic disorder, those who had received antipsychotic treatment for more than 1 year were significantly less likely to have metabolic and cardiovascular disorders, compared with patients not taking antipsychotic medication. This association may be related to “greater medical vigilance” and “should not be taken as evidence that antipsychotics are free from cardiometabolic adverse effects,” the authors noted.
The study was supported by a research grant from Tourettes Action. In addition, authors reported support from the Swedish Research Council and a Karolinska Institutet PhD stipend. Two authors disclosed personal fees from publishers, and one author disclosed grants and other funding from Shire.
SOURCE: Brander G et al. JAMA Neurol. 2019 Jan 14. doi: 10.1001/jamaneurol.2018.4279.
FROM JAMA NEUROLOGY
Key clinical point: Monitor cardiometabolic health in patients with Tourette syndrome or chronic tic disorder.
Major finding: Patients with Tourette syndrome or chronic tic disorder have a higher risk of metabolic or cardiovascular disorders, compared with the general population (adjusted hazard ratio, 1.99) and sibling controls (adjusted hazard ratio, 1.37).
Study details: A Swedish longitudinal, population-based cohort study of 7,804 individuals with Tourette syndrome or chronic tic disorder.
Disclosures: The study was supported by a research grant from Tourettes Action. Authors reported support from the Swedish Research Council and a Karolinska Institutet PhD stipend. Two authors disclosed personal fees from publishers, and one author disclosed grants and other funding from Shire.
Source: Brander G et al. JAMA Neurol. 2019 Jan 14. doi: 10.1001/jamaneurol.2018.4279.
SGLT-2 inhibitors promising for heart failure prevention, not treatment
LOS ANGELES –
They also may play a role in the treatment of patients with known heart failure (HF), but further studies are required to prove definite treatment benefit.
“These trials enrolled a minority of patients with known heart failure, and, in those subgroups, the drugs seems to reduce the risk for hospitalization, opening the possibility of treatment benefit,” Javed Butler, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But there were not enough patients to conclude this. If you are treating diabetes with these agents in patients with heart failure, more power to you. But don’t think you are treating heart failure per se until the results of the dedicated heart failure trials come out.”
Good glycemic control has not been shown to affect heart failure outcomes per se, said Dr. Butler, professor and chairman of the department of medicine at the University of Mississippi Medical Center, Jackson.
“People seem to mix the concepts of prevention and treatment together,” he said. “We have now very good evidence across all trials with SGLT-2 inhibitors for prevention of heart failure. But for treatment, we need more data despite favorable early signals.
“Also, these trials include most patients with ischemic heart disease, but we don’t have data on nonischemic etiology for the development of heart failure from these trials,” Dr. Butler added.
The best available data from clinical trials suggest that patients with American College of Cardiology Foundation/American Heart Association heart failure classification stages A and B benefit the most from aggressive treatment to prevent HF.
“Either they have diseases like high blood pressure or diabetes, but their hearts are normal, or, perhaps, their hearts are abnormal, and they develop left ventricular hypertrophy or atrial fibrillation,” he said. “However, if someone is stage C – manifest heart failure – or stage D – advanced heart failure – we need further data on novel therapies to improve their outcomes.”
Dr. Butler emphasized that not all heart failure is associated with atherosclerotic vascular disease. In fact, the Health, Aging, and Body Composition Study showed that the incidence of heart failure increased progressively across age groups, both for those with and without a preceding vascular event (P = .03 and P less than .001, respectively; Eur J Heart Fail. 2014 May;16[5]:526-34). “There’s a whole other world of nonischemic heart failure that we also need to worry about,” he said. “There is a lot of microvascular endothelial dysfunction.”
The combination of heart failure and diabetes is especially lethal. “If you put them together, you’re looking at about a 10-fold higher risk of mortality, which is a horrible prognosis,” Dr. Butler said. “That means that we need to think about prevention and treatment separately.”
Data from the SAVOR-TIMI 53, EXAMINE, and TECOS trials show there is no protective effect of dipeptidyl peptidase–4 inhibitors when it comes to hospitalization for heart failure.
“The other classes of drugs either increase the risk, or we don’t have very good data,” Dr. Butler said. “So far, across the spectrum of therapies for diabetes, the effect on heart failure is neutral and perhaps confers some risk.”
SGLT-2 inhibitors convey a different story.
In the EMPA-REG OUTCOME Trial, one inclusion criterion was established cardiovascular disease (CVD) in the form of a prior MI, coronary artery disease, stroke, unstable angina, or occlusive peripheral artery disease, but not heart failure alone (N Engl J Med. 2015 Nov 26; 373[22]:2117-28). “This was not a heart failure study, so we don’t know what their New York Heart Association class was, or the details of their baseline HF treatment in the minority of patients who were enrolled who had a history of HF,” Dr. Butler cautioned.
However, the trial found that empagliflozin conferred an overall cardiovascular death risk reduction of 38%, compared with placebo. When the researchers assessed the impact of treatment on all modes of cardiovascular death, they found that death from heart failure benefited the most (hazard ratio, 0.32; P = .0008), while sudden death benefited as well. Empagliflozin also had a significant impact on reduced hospitalization for heart failure, compared with placebo (HR, 0.65).
“This is a large enough cohort that you should feel comfortable that this drug is preventing heart failure in those with HF at baseline,” said Dr. Butler, who was not involved with the study. “We can have a debate about whether this is a treatment for heart failure or not, but for prevention of heart failure, I feel comfortable that these drugs do that.”
A subsequent study of canagliflozin and cardiovascular and renal events in type 2 diabetes showed the same result (N Engl J Med. 2017 Aug 17; 377[7]:644-57). It reduced hospitalization for heart failure by 33% (HR, 0.67).
Then came the CVD-REAL study, which found low rates of hospitalization for heart failure and all-cause death in new users of SGLT-2 inhibitors. More recently, DECLARE-TIMI 58 yielded similar results.
“One of the criticisms of these findings is that heart failure characteristics were not well phenotyped in these studies,” Dr. Butler said. “I say it really does not matter. Heart failure hospitalizations are associated with a poor prognosis irrespective of whether the hospitalization occurred in patients without heart failure or in a patient with previously diagnosed heart failure, or whether the patient has reduced or preserved ejection fraction.
“Framingham and other classic studies show us that 5-year mortality for heart failure is about 50%,” he noted. “If you can prevent a disease that has a 5-year mortality of 50%, doesn’t that sound like a really good deal?”
A contemporary appraisal of the heart failure epidemic in Olmstead County, Minn., during 2000-2010 found that the mortality was 20.2% at 1 year after diagnosis, and 52.6% at 5 years after diagnosis. The data include new-onset HF in both inpatient and outpatient settings.
Specifically, new-onset HF hospitalization was associated with a 1-year post discharge mortality of 21.1% (JAMA Intern Med. 2015;175[6]:996-1004). “We cannot ignore prevention of heart failure,” Dr. Butler said. “Also, for treatment, once you get hospitalized for heart failure, the fundamental natural history of the disease changes. There is a 30% cumulative incremental death risk between the second and third hospitalizations.”
Dr. Butler concluded his presentation by noting that five randomized, controlled trials evaluating SGLT-2 inhibitors in HF have been launched, and should help elucidate any effects the drugs may have in treating the condition. They include EMPEROR-Preserved (NCT03057951), EMPEROR-Reduced (NCT03057977), Dapa-HF (NCT03036124), and SOLOIST-WHF (NCT03521934) and DELIVER (NCT03619213).
Dr. Butler disclosed that he has received research support from the National Institutes of Health, the European Union, and the Patient-Centered Outcomes Research Institute. He has also been a consultant for numerous pharmaceutical companies, including Boehringer Ingelheim, Janssen, and AstraZeneca, which sponsored the EMPA-REG, CANVAS, and DECLARE TIMI 58 trials.
LOS ANGELES –
They also may play a role in the treatment of patients with known heart failure (HF), but further studies are required to prove definite treatment benefit.
“These trials enrolled a minority of patients with known heart failure, and, in those subgroups, the drugs seems to reduce the risk for hospitalization, opening the possibility of treatment benefit,” Javed Butler, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But there were not enough patients to conclude this. If you are treating diabetes with these agents in patients with heart failure, more power to you. But don’t think you are treating heart failure per se until the results of the dedicated heart failure trials come out.”
Good glycemic control has not been shown to affect heart failure outcomes per se, said Dr. Butler, professor and chairman of the department of medicine at the University of Mississippi Medical Center, Jackson.
“People seem to mix the concepts of prevention and treatment together,” he said. “We have now very good evidence across all trials with SGLT-2 inhibitors for prevention of heart failure. But for treatment, we need more data despite favorable early signals.
“Also, these trials include most patients with ischemic heart disease, but we don’t have data on nonischemic etiology for the development of heart failure from these trials,” Dr. Butler added.
The best available data from clinical trials suggest that patients with American College of Cardiology Foundation/American Heart Association heart failure classification stages A and B benefit the most from aggressive treatment to prevent HF.
“Either they have diseases like high blood pressure or diabetes, but their hearts are normal, or, perhaps, their hearts are abnormal, and they develop left ventricular hypertrophy or atrial fibrillation,” he said. “However, if someone is stage C – manifest heart failure – or stage D – advanced heart failure – we need further data on novel therapies to improve their outcomes.”
Dr. Butler emphasized that not all heart failure is associated with atherosclerotic vascular disease. In fact, the Health, Aging, and Body Composition Study showed that the incidence of heart failure increased progressively across age groups, both for those with and without a preceding vascular event (P = .03 and P less than .001, respectively; Eur J Heart Fail. 2014 May;16[5]:526-34). “There’s a whole other world of nonischemic heart failure that we also need to worry about,” he said. “There is a lot of microvascular endothelial dysfunction.”
The combination of heart failure and diabetes is especially lethal. “If you put them together, you’re looking at about a 10-fold higher risk of mortality, which is a horrible prognosis,” Dr. Butler said. “That means that we need to think about prevention and treatment separately.”
Data from the SAVOR-TIMI 53, EXAMINE, and TECOS trials show there is no protective effect of dipeptidyl peptidase–4 inhibitors when it comes to hospitalization for heart failure.
“The other classes of drugs either increase the risk, or we don’t have very good data,” Dr. Butler said. “So far, across the spectrum of therapies for diabetes, the effect on heart failure is neutral and perhaps confers some risk.”
SGLT-2 inhibitors convey a different story.
In the EMPA-REG OUTCOME Trial, one inclusion criterion was established cardiovascular disease (CVD) in the form of a prior MI, coronary artery disease, stroke, unstable angina, or occlusive peripheral artery disease, but not heart failure alone (N Engl J Med. 2015 Nov 26; 373[22]:2117-28). “This was not a heart failure study, so we don’t know what their New York Heart Association class was, or the details of their baseline HF treatment in the minority of patients who were enrolled who had a history of HF,” Dr. Butler cautioned.
However, the trial found that empagliflozin conferred an overall cardiovascular death risk reduction of 38%, compared with placebo. When the researchers assessed the impact of treatment on all modes of cardiovascular death, they found that death from heart failure benefited the most (hazard ratio, 0.32; P = .0008), while sudden death benefited as well. Empagliflozin also had a significant impact on reduced hospitalization for heart failure, compared with placebo (HR, 0.65).
“This is a large enough cohort that you should feel comfortable that this drug is preventing heart failure in those with HF at baseline,” said Dr. Butler, who was not involved with the study. “We can have a debate about whether this is a treatment for heart failure or not, but for prevention of heart failure, I feel comfortable that these drugs do that.”
A subsequent study of canagliflozin and cardiovascular and renal events in type 2 diabetes showed the same result (N Engl J Med. 2017 Aug 17; 377[7]:644-57). It reduced hospitalization for heart failure by 33% (HR, 0.67).
Then came the CVD-REAL study, which found low rates of hospitalization for heart failure and all-cause death in new users of SGLT-2 inhibitors. More recently, DECLARE-TIMI 58 yielded similar results.
“One of the criticisms of these findings is that heart failure characteristics were not well phenotyped in these studies,” Dr. Butler said. “I say it really does not matter. Heart failure hospitalizations are associated with a poor prognosis irrespective of whether the hospitalization occurred in patients without heart failure or in a patient with previously diagnosed heart failure, or whether the patient has reduced or preserved ejection fraction.
“Framingham and other classic studies show us that 5-year mortality for heart failure is about 50%,” he noted. “If you can prevent a disease that has a 5-year mortality of 50%, doesn’t that sound like a really good deal?”
A contemporary appraisal of the heart failure epidemic in Olmstead County, Minn., during 2000-2010 found that the mortality was 20.2% at 1 year after diagnosis, and 52.6% at 5 years after diagnosis. The data include new-onset HF in both inpatient and outpatient settings.
Specifically, new-onset HF hospitalization was associated with a 1-year post discharge mortality of 21.1% (JAMA Intern Med. 2015;175[6]:996-1004). “We cannot ignore prevention of heart failure,” Dr. Butler said. “Also, for treatment, once you get hospitalized for heart failure, the fundamental natural history of the disease changes. There is a 30% cumulative incremental death risk between the second and third hospitalizations.”
Dr. Butler concluded his presentation by noting that five randomized, controlled trials evaluating SGLT-2 inhibitors in HF have been launched, and should help elucidate any effects the drugs may have in treating the condition. They include EMPEROR-Preserved (NCT03057951), EMPEROR-Reduced (NCT03057977), Dapa-HF (NCT03036124), and SOLOIST-WHF (NCT03521934) and DELIVER (NCT03619213).
Dr. Butler disclosed that he has received research support from the National Institutes of Health, the European Union, and the Patient-Centered Outcomes Research Institute. He has also been a consultant for numerous pharmaceutical companies, including Boehringer Ingelheim, Janssen, and AstraZeneca, which sponsored the EMPA-REG, CANVAS, and DECLARE TIMI 58 trials.
LOS ANGELES –
They also may play a role in the treatment of patients with known heart failure (HF), but further studies are required to prove definite treatment benefit.
“These trials enrolled a minority of patients with known heart failure, and, in those subgroups, the drugs seems to reduce the risk for hospitalization, opening the possibility of treatment benefit,” Javed Butler, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But there were not enough patients to conclude this. If you are treating diabetes with these agents in patients with heart failure, more power to you. But don’t think you are treating heart failure per se until the results of the dedicated heart failure trials come out.”
Good glycemic control has not been shown to affect heart failure outcomes per se, said Dr. Butler, professor and chairman of the department of medicine at the University of Mississippi Medical Center, Jackson.
“People seem to mix the concepts of prevention and treatment together,” he said. “We have now very good evidence across all trials with SGLT-2 inhibitors for prevention of heart failure. But for treatment, we need more data despite favorable early signals.
“Also, these trials include most patients with ischemic heart disease, but we don’t have data on nonischemic etiology for the development of heart failure from these trials,” Dr. Butler added.
The best available data from clinical trials suggest that patients with American College of Cardiology Foundation/American Heart Association heart failure classification stages A and B benefit the most from aggressive treatment to prevent HF.
“Either they have diseases like high blood pressure or diabetes, but their hearts are normal, or, perhaps, their hearts are abnormal, and they develop left ventricular hypertrophy or atrial fibrillation,” he said. “However, if someone is stage C – manifest heart failure – or stage D – advanced heart failure – we need further data on novel therapies to improve their outcomes.”
Dr. Butler emphasized that not all heart failure is associated with atherosclerotic vascular disease. In fact, the Health, Aging, and Body Composition Study showed that the incidence of heart failure increased progressively across age groups, both for those with and without a preceding vascular event (P = .03 and P less than .001, respectively; Eur J Heart Fail. 2014 May;16[5]:526-34). “There’s a whole other world of nonischemic heart failure that we also need to worry about,” he said. “There is a lot of microvascular endothelial dysfunction.”
The combination of heart failure and diabetes is especially lethal. “If you put them together, you’re looking at about a 10-fold higher risk of mortality, which is a horrible prognosis,” Dr. Butler said. “That means that we need to think about prevention and treatment separately.”
Data from the SAVOR-TIMI 53, EXAMINE, and TECOS trials show there is no protective effect of dipeptidyl peptidase–4 inhibitors when it comes to hospitalization for heart failure.
“The other classes of drugs either increase the risk, or we don’t have very good data,” Dr. Butler said. “So far, across the spectrum of therapies for diabetes, the effect on heart failure is neutral and perhaps confers some risk.”
SGLT-2 inhibitors convey a different story.
In the EMPA-REG OUTCOME Trial, one inclusion criterion was established cardiovascular disease (CVD) in the form of a prior MI, coronary artery disease, stroke, unstable angina, or occlusive peripheral artery disease, but not heart failure alone (N Engl J Med. 2015 Nov 26; 373[22]:2117-28). “This was not a heart failure study, so we don’t know what their New York Heart Association class was, or the details of their baseline HF treatment in the minority of patients who were enrolled who had a history of HF,” Dr. Butler cautioned.
However, the trial found that empagliflozin conferred an overall cardiovascular death risk reduction of 38%, compared with placebo. When the researchers assessed the impact of treatment on all modes of cardiovascular death, they found that death from heart failure benefited the most (hazard ratio, 0.32; P = .0008), while sudden death benefited as well. Empagliflozin also had a significant impact on reduced hospitalization for heart failure, compared with placebo (HR, 0.65).
“This is a large enough cohort that you should feel comfortable that this drug is preventing heart failure in those with HF at baseline,” said Dr. Butler, who was not involved with the study. “We can have a debate about whether this is a treatment for heart failure or not, but for prevention of heart failure, I feel comfortable that these drugs do that.”
A subsequent study of canagliflozin and cardiovascular and renal events in type 2 diabetes showed the same result (N Engl J Med. 2017 Aug 17; 377[7]:644-57). It reduced hospitalization for heart failure by 33% (HR, 0.67).
Then came the CVD-REAL study, which found low rates of hospitalization for heart failure and all-cause death in new users of SGLT-2 inhibitors. More recently, DECLARE-TIMI 58 yielded similar results.
“One of the criticisms of these findings is that heart failure characteristics were not well phenotyped in these studies,” Dr. Butler said. “I say it really does not matter. Heart failure hospitalizations are associated with a poor prognosis irrespective of whether the hospitalization occurred in patients without heart failure or in a patient with previously diagnosed heart failure, or whether the patient has reduced or preserved ejection fraction.
“Framingham and other classic studies show us that 5-year mortality for heart failure is about 50%,” he noted. “If you can prevent a disease that has a 5-year mortality of 50%, doesn’t that sound like a really good deal?”
A contemporary appraisal of the heart failure epidemic in Olmstead County, Minn., during 2000-2010 found that the mortality was 20.2% at 1 year after diagnosis, and 52.6% at 5 years after diagnosis. The data include new-onset HF in both inpatient and outpatient settings.
Specifically, new-onset HF hospitalization was associated with a 1-year post discharge mortality of 21.1% (JAMA Intern Med. 2015;175[6]:996-1004). “We cannot ignore prevention of heart failure,” Dr. Butler said. “Also, for treatment, once you get hospitalized for heart failure, the fundamental natural history of the disease changes. There is a 30% cumulative incremental death risk between the second and third hospitalizations.”
Dr. Butler concluded his presentation by noting that five randomized, controlled trials evaluating SGLT-2 inhibitors in HF have been launched, and should help elucidate any effects the drugs may have in treating the condition. They include EMPEROR-Preserved (NCT03057951), EMPEROR-Reduced (NCT03057977), Dapa-HF (NCT03036124), and SOLOIST-WHF (NCT03521934) and DELIVER (NCT03619213).
Dr. Butler disclosed that he has received research support from the National Institutes of Health, the European Union, and the Patient-Centered Outcomes Research Institute. He has also been a consultant for numerous pharmaceutical companies, including Boehringer Ingelheim, Janssen, and AstraZeneca, which sponsored the EMPA-REG, CANVAS, and DECLARE TIMI 58 trials.
EXPERT ANALYSIS FROM WCIRDC 2018
Does reduced degradation of insulin by the liver cause type 2 diabetes?
LOS ANGELES –
That’s a hypothesis that Richard N. Bergman, PhD, and his colleagues are testing in his lab at the Sports Spectacular Diabetes and Obesity Wellness and Research Center at Cedars-Sinai Medical Center, Los Angeles.
“More than 50% of insulin secreted into the portal vein is degraded by the liver and never enters the systemic circulation,” Dr. Bergman said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “We have found that if you make an animal insulin resistant with a high fat diet, they degrade less of the insulin. Why is that? They deliver a higher fraction of the insulin into the systemic circulation. One of the answers is that the liver is a gateway for insulin delivery to the systemic circulation.” In fact, when he and his colleagues tested a population of normal dogs, they found wide variability in the ability of the liver to take up and degrade insulin (Diabetes. 2018 67[8]:1495-503).
“It ranged from 20% to 70%; I didn’t believe these data,” said Dr. Bergman, who is also chair in diabetes research at Cedars-Sinai. “We had to redo the study and the same thing was true. There’s a wide variation in what fraction of insulin that enters the liver is degraded. That led to the idea that this could be true in humans.”
To follow up on this concept, he and his colleagues used data from 100 African immigrants without diabetes to develop a model to estimate hepatic versus extrahepatic insulin clearance in humans (Diabetes. 2016;65[6]:1556-64). “This population was chosen because previous studies have suggested that individuals of African descent have reduced hepatic insulin clearance compared with Western subjects,” the authors wrote in the article. “Similarly, FSIGT [frequently sampled intravenous glucose tolerance test] data from two groups showed that African American women had much higher plasma insulin concentrations than European American women during periods of elevated endogenous secretion but not after intravenous insulin infusion, also suggesting reduced hepatic, but not extrahepatic, insulin clearance in African American subjects. Thus, this population was of special interest for applying a model that could quantify both hepatic and extrahepatic insulin clearance.”
The model was able to reproduce accurately the full plasma insulin profiles observed during the FSIGT and identify clear differences in parameter values among individuals. “The ability of the liver to degrade insulin is very variable across a normal human population,” Dr. Bergman said. “That means this may be a controlled variable.”
In a separate analysis of 23 African American and 23 European American women, Dr. Bergman, Francesca Piccinini, PhD, Barbara A. Gower, PhD, and colleagues found that hepatic but not extrahepatic insulin clearance is lower in the African American women, compared with their European American counterparts (Diabetes. 2017;66[10]:2564-70). Data from a cohort of children found the same thing (Diabetes Obes & Metab. 2018 Jul 18. doi: 10.1111/dom.13471).
“What does this mean that different ethnic groups have different clearance of insulin?” he asked. “It means that African Americans deliver a higher fraction of secreted insulin into the systemic circulation. We know that African Americans tend to be hyperinsulinemic. That isn’t necessarily due to oversecretion of insulin; it’s likely due primarily to reduced degradation of insulin. The question then is, can the reduced insulin clearance play a causal role in the pathogenesis of type 2 diabetes?”
He hypothesized that, in normal individuals, half of insulin secreted by the pancreas is exported into the systemic circulation and half is degraded. “We propose that in people at risk for diabetes, insulin is secreted by the pancreas but much less of it is degraded,” Dr. Bergman continued. “Insulin gets into the systemic circulation, so then you can get hyperinsulinemia, and insulin resistance. The resistance stresses the beta cells of the pancreas. Thus, the idea is that differences in clearance of insulin by the liver in some individuals may be pathogenic in the cause of diabetes.”
Dr. Bergman reported that he has done consulting/collaboration with Janssen, January, Novo Nordisk, and Zafgen. He has also received research grants from Astra Zeneca, Janssen, and the National Institutes of Health.
LOS ANGELES –
That’s a hypothesis that Richard N. Bergman, PhD, and his colleagues are testing in his lab at the Sports Spectacular Diabetes and Obesity Wellness and Research Center at Cedars-Sinai Medical Center, Los Angeles.
“More than 50% of insulin secreted into the portal vein is degraded by the liver and never enters the systemic circulation,” Dr. Bergman said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “We have found that if you make an animal insulin resistant with a high fat diet, they degrade less of the insulin. Why is that? They deliver a higher fraction of the insulin into the systemic circulation. One of the answers is that the liver is a gateway for insulin delivery to the systemic circulation.” In fact, when he and his colleagues tested a population of normal dogs, they found wide variability in the ability of the liver to take up and degrade insulin (Diabetes. 2018 67[8]:1495-503).
“It ranged from 20% to 70%; I didn’t believe these data,” said Dr. Bergman, who is also chair in diabetes research at Cedars-Sinai. “We had to redo the study and the same thing was true. There’s a wide variation in what fraction of insulin that enters the liver is degraded. That led to the idea that this could be true in humans.”
To follow up on this concept, he and his colleagues used data from 100 African immigrants without diabetes to develop a model to estimate hepatic versus extrahepatic insulin clearance in humans (Diabetes. 2016;65[6]:1556-64). “This population was chosen because previous studies have suggested that individuals of African descent have reduced hepatic insulin clearance compared with Western subjects,” the authors wrote in the article. “Similarly, FSIGT [frequently sampled intravenous glucose tolerance test] data from two groups showed that African American women had much higher plasma insulin concentrations than European American women during periods of elevated endogenous secretion but not after intravenous insulin infusion, also suggesting reduced hepatic, but not extrahepatic, insulin clearance in African American subjects. Thus, this population was of special interest for applying a model that could quantify both hepatic and extrahepatic insulin clearance.”
The model was able to reproduce accurately the full plasma insulin profiles observed during the FSIGT and identify clear differences in parameter values among individuals. “The ability of the liver to degrade insulin is very variable across a normal human population,” Dr. Bergman said. “That means this may be a controlled variable.”
In a separate analysis of 23 African American and 23 European American women, Dr. Bergman, Francesca Piccinini, PhD, Barbara A. Gower, PhD, and colleagues found that hepatic but not extrahepatic insulin clearance is lower in the African American women, compared with their European American counterparts (Diabetes. 2017;66[10]:2564-70). Data from a cohort of children found the same thing (Diabetes Obes & Metab. 2018 Jul 18. doi: 10.1111/dom.13471).
“What does this mean that different ethnic groups have different clearance of insulin?” he asked. “It means that African Americans deliver a higher fraction of secreted insulin into the systemic circulation. We know that African Americans tend to be hyperinsulinemic. That isn’t necessarily due to oversecretion of insulin; it’s likely due primarily to reduced degradation of insulin. The question then is, can the reduced insulin clearance play a causal role in the pathogenesis of type 2 diabetes?”
He hypothesized that, in normal individuals, half of insulin secreted by the pancreas is exported into the systemic circulation and half is degraded. “We propose that in people at risk for diabetes, insulin is secreted by the pancreas but much less of it is degraded,” Dr. Bergman continued. “Insulin gets into the systemic circulation, so then you can get hyperinsulinemia, and insulin resistance. The resistance stresses the beta cells of the pancreas. Thus, the idea is that differences in clearance of insulin by the liver in some individuals may be pathogenic in the cause of diabetes.”
Dr. Bergman reported that he has done consulting/collaboration with Janssen, January, Novo Nordisk, and Zafgen. He has also received research grants from Astra Zeneca, Janssen, and the National Institutes of Health.
LOS ANGELES –
That’s a hypothesis that Richard N. Bergman, PhD, and his colleagues are testing in his lab at the Sports Spectacular Diabetes and Obesity Wellness and Research Center at Cedars-Sinai Medical Center, Los Angeles.
“More than 50% of insulin secreted into the portal vein is degraded by the liver and never enters the systemic circulation,” Dr. Bergman said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “We have found that if you make an animal insulin resistant with a high fat diet, they degrade less of the insulin. Why is that? They deliver a higher fraction of the insulin into the systemic circulation. One of the answers is that the liver is a gateway for insulin delivery to the systemic circulation.” In fact, when he and his colleagues tested a population of normal dogs, they found wide variability in the ability of the liver to take up and degrade insulin (Diabetes. 2018 67[8]:1495-503).
“It ranged from 20% to 70%; I didn’t believe these data,” said Dr. Bergman, who is also chair in diabetes research at Cedars-Sinai. “We had to redo the study and the same thing was true. There’s a wide variation in what fraction of insulin that enters the liver is degraded. That led to the idea that this could be true in humans.”
To follow up on this concept, he and his colleagues used data from 100 African immigrants without diabetes to develop a model to estimate hepatic versus extrahepatic insulin clearance in humans (Diabetes. 2016;65[6]:1556-64). “This population was chosen because previous studies have suggested that individuals of African descent have reduced hepatic insulin clearance compared with Western subjects,” the authors wrote in the article. “Similarly, FSIGT [frequently sampled intravenous glucose tolerance test] data from two groups showed that African American women had much higher plasma insulin concentrations than European American women during periods of elevated endogenous secretion but not after intravenous insulin infusion, also suggesting reduced hepatic, but not extrahepatic, insulin clearance in African American subjects. Thus, this population was of special interest for applying a model that could quantify both hepatic and extrahepatic insulin clearance.”
The model was able to reproduce accurately the full plasma insulin profiles observed during the FSIGT and identify clear differences in parameter values among individuals. “The ability of the liver to degrade insulin is very variable across a normal human population,” Dr. Bergman said. “That means this may be a controlled variable.”
In a separate analysis of 23 African American and 23 European American women, Dr. Bergman, Francesca Piccinini, PhD, Barbara A. Gower, PhD, and colleagues found that hepatic but not extrahepatic insulin clearance is lower in the African American women, compared with their European American counterparts (Diabetes. 2017;66[10]:2564-70). Data from a cohort of children found the same thing (Diabetes Obes & Metab. 2018 Jul 18. doi: 10.1111/dom.13471).
“What does this mean that different ethnic groups have different clearance of insulin?” he asked. “It means that African Americans deliver a higher fraction of secreted insulin into the systemic circulation. We know that African Americans tend to be hyperinsulinemic. That isn’t necessarily due to oversecretion of insulin; it’s likely due primarily to reduced degradation of insulin. The question then is, can the reduced insulin clearance play a causal role in the pathogenesis of type 2 diabetes?”
He hypothesized that, in normal individuals, half of insulin secreted by the pancreas is exported into the systemic circulation and half is degraded. “We propose that in people at risk for diabetes, insulin is secreted by the pancreas but much less of it is degraded,” Dr. Bergman continued. “Insulin gets into the systemic circulation, so then you can get hyperinsulinemia, and insulin resistance. The resistance stresses the beta cells of the pancreas. Thus, the idea is that differences in clearance of insulin by the liver in some individuals may be pathogenic in the cause of diabetes.”
Dr. Bergman reported that he has done consulting/collaboration with Janssen, January, Novo Nordisk, and Zafgen. He has also received research grants from Astra Zeneca, Janssen, and the National Institutes of Health.
EXPERT ANALYSIS FROM WCIRDC 2018
Torrent Pharmaceuticals expands losartan recall
Torrent Pharmaceuticals is expanding its recall of losartan potassium tablets from 2 lots to 12 lots, according to a Safety Alert from the Food and Drug Administration.
The recall was based on the discovery of N-nitrosodiethylamine (NDEA) above recommended levels in seven 100-mg lots of losartan, four 50-mg lots, and one 25-mg lot. NDEA is a naturally occurring substance that has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Torrent Pharmaceuticals has not reported any adverse events related to the recall.
Losartan currently is indicated to treat hypertension, hypertensive patients with left ventricular hypertrophy, and nephropathy in type 2 diabetic patients. Patients who are taking losartan should continue to do so, as stopping treatment without an alternative could represent a greater health risk.
“Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication,” the FDA said in the press release.
Find the full press release on the FDA website.
Torrent Pharmaceuticals is expanding its recall of losartan potassium tablets from 2 lots to 12 lots, according to a Safety Alert from the Food and Drug Administration.
The recall was based on the discovery of N-nitrosodiethylamine (NDEA) above recommended levels in seven 100-mg lots of losartan, four 50-mg lots, and one 25-mg lot. NDEA is a naturally occurring substance that has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Torrent Pharmaceuticals has not reported any adverse events related to the recall.
Losartan currently is indicated to treat hypertension, hypertensive patients with left ventricular hypertrophy, and nephropathy in type 2 diabetic patients. Patients who are taking losartan should continue to do so, as stopping treatment without an alternative could represent a greater health risk.
“Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication,” the FDA said in the press release.
Find the full press release on the FDA website.
Torrent Pharmaceuticals is expanding its recall of losartan potassium tablets from 2 lots to 12 lots, according to a Safety Alert from the Food and Drug Administration.
The recall was based on the discovery of N-nitrosodiethylamine (NDEA) above recommended levels in seven 100-mg lots of losartan, four 50-mg lots, and one 25-mg lot. NDEA is a naturally occurring substance that has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Torrent Pharmaceuticals has not reported any adverse events related to the recall.
Losartan currently is indicated to treat hypertension, hypertensive patients with left ventricular hypertrophy, and nephropathy in type 2 diabetic patients. Patients who are taking losartan should continue to do so, as stopping treatment without an alternative could represent a greater health risk.
“Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication,” the FDA said in the press release.
Find the full press release on the FDA website.
Postprandial glucose responses to identical meals vary from person to person
LOS ANGELES – .
“The reason we got interested in nutrition in general is for its important role in health and disease, but also because, reading the literature on nutrition in general, it seemed that the science was relatively poor,” Eran Segal, PhD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As a testament, you can see how frequently dietary recommendations for the public are changed. For example, 30 years ago, the cover of Time magazine said that eating cholesterol in the diet is very bad for you. Fifteen years later, Time magazine said that some cholesterol is actually good for you. There are other questions, like should you be eating dairy products? I think it shows that we have a poor understanding of what healthy nutrition is for human individuals. That’s why we wanted to start a study which would collect the right amount and the right kind of data to try to answer the question of what is a healthy diet for human individuals.”
In what is believed to be the first study of its kind, Dr. Segal, professor of computer science and applied mathematics at the Weizmann Institute of Science in Rehovot, Israel, and his associates recruited 1,000 individuals and asked them to wear a continuous glucose monitor (CGM) for 1 week (Cell 2015;163[5]:1079-94). For the study, known as The Personalized Nutrition Project, participants were asked to log everything they ate into a mobile app the researchers developed. “They would select a meal from a database of 10,000 foods,” Dr. Segal explained. “Each meal has full nutritional value so at the end of the study, we had about 50,000 meals that we had measurements of postprandial glucose response to, coupled with full nutritional values.” They also collected a comprehensive profile of individuals, which included body measurements, blood tests, medical background, food frequency questionnaires, and a measurement of the microbiome by both 16S rRNA sequencing and shotgun metagenomics.
For the first part of the study, researchers supplied a breakfast to all participants: either bread, bread with butter, glucose, or fructose, in each case 50 g of available carbohydrates. “The participants were asked to consume these the morning after the night fast,” Dr. Segal said. “This allowed us to compare how the same individual responds to eating the exact same food versus how different individuals respond to eating the same food.” The researchers found that, when the same person ate the same meal on 2 different days, the glucose response was highly reproducible. In contrast, different people had widely different postmeal glucose responses to identical meals. “Some individuals responded most highly to glucose; others responded most highly to bread,” Dr. Segal said. “There was about 10% of individuals who responded to bread and butter, compared to the other test foods. These results mean that any universal diet is going to have limited efficacy in its ability to balance blood glucose levels, because some foods will spike glucose levels in one person but not in another person. It also means that the concepts we’ve been using like the glycemic index are also going to have limited efficacy.”
Next, the researchers aimed to determine what factors influence the variability in people’s responses to the same food. “We found many different correlations between the various blood markers and physical measurements that we obtained, but what was most novel was the variability in postmeal glucose response across people associated with microbiota composition and function,” Dr. Segal said. From this, he and his colleagues developed a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota. Using this algorithm, the prediction accuracy of personalized glucose responses achieved an r value of 0.68, which explains about 50% of the variability. For the final component of the study, the researchers randomized 26 participants to one of five dietary arms and followed for 1 week by continuous glucose monitoring. They were able to demonstrate that personally tailored diets lower the postprandial glucose response.
As a follow-up to this work, Dr. Segal and his associates enrolled 200 people with an hemoglobin A1c between 5.7% and 6.5% into the Personalized Nutrition Project for Prediabetes (PNP3) study, which investigates whether personalized diet intervention will improve postprandial blood glucose levels and other metabolic health factors in individuals with prediabetes, compared with the standard Mediterranean-style low-fat diet (NCT03222791). Participants were randomized to 6 months of standard of care following Dietary Guidelines for Americans 2015-2020, Eighth Edition, or to an algorithm diet. Primary outcomes are reduction in average glucose levels and evaluation of the total daily time of plasma glucose levels were below 140 mg/dL. Participants wore the continuous glucose monitor for the entire 6 months of intervention. “I don’t think this was ever done before,” he said. “We’re also looking at secondary metabolic endpoints and exploratory endpoints such as changes in the microbiome. We’re asking people to log everything they eat for the entire 6 months of intervention. It gives us a lot of power in terms assessing compliance. It’s an immense amount of data.”
Evaluation of the data are not yet complete, but interim results are promising. For example, he discussed results from one study participant on the algorithm diet. “Across 1 month, this person was able to entirely reduce the peaks in glucose levels and dramatic reductions in the time above 140 mg/dL in the 6-month treatment period,” said Dr. Segal, who is one of the study’s principal investigators. He disclosed that he is a paid consultant to DayTwo.
LOS ANGELES – .
“The reason we got interested in nutrition in general is for its important role in health and disease, but also because, reading the literature on nutrition in general, it seemed that the science was relatively poor,” Eran Segal, PhD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As a testament, you can see how frequently dietary recommendations for the public are changed. For example, 30 years ago, the cover of Time magazine said that eating cholesterol in the diet is very bad for you. Fifteen years later, Time magazine said that some cholesterol is actually good for you. There are other questions, like should you be eating dairy products? I think it shows that we have a poor understanding of what healthy nutrition is for human individuals. That’s why we wanted to start a study which would collect the right amount and the right kind of data to try to answer the question of what is a healthy diet for human individuals.”
In what is believed to be the first study of its kind, Dr. Segal, professor of computer science and applied mathematics at the Weizmann Institute of Science in Rehovot, Israel, and his associates recruited 1,000 individuals and asked them to wear a continuous glucose monitor (CGM) for 1 week (Cell 2015;163[5]:1079-94). For the study, known as The Personalized Nutrition Project, participants were asked to log everything they ate into a mobile app the researchers developed. “They would select a meal from a database of 10,000 foods,” Dr. Segal explained. “Each meal has full nutritional value so at the end of the study, we had about 50,000 meals that we had measurements of postprandial glucose response to, coupled with full nutritional values.” They also collected a comprehensive profile of individuals, which included body measurements, blood tests, medical background, food frequency questionnaires, and a measurement of the microbiome by both 16S rRNA sequencing and shotgun metagenomics.
For the first part of the study, researchers supplied a breakfast to all participants: either bread, bread with butter, glucose, or fructose, in each case 50 g of available carbohydrates. “The participants were asked to consume these the morning after the night fast,” Dr. Segal said. “This allowed us to compare how the same individual responds to eating the exact same food versus how different individuals respond to eating the same food.” The researchers found that, when the same person ate the same meal on 2 different days, the glucose response was highly reproducible. In contrast, different people had widely different postmeal glucose responses to identical meals. “Some individuals responded most highly to glucose; others responded most highly to bread,” Dr. Segal said. “There was about 10% of individuals who responded to bread and butter, compared to the other test foods. These results mean that any universal diet is going to have limited efficacy in its ability to balance blood glucose levels, because some foods will spike glucose levels in one person but not in another person. It also means that the concepts we’ve been using like the glycemic index are also going to have limited efficacy.”
Next, the researchers aimed to determine what factors influence the variability in people’s responses to the same food. “We found many different correlations between the various blood markers and physical measurements that we obtained, but what was most novel was the variability in postmeal glucose response across people associated with microbiota composition and function,” Dr. Segal said. From this, he and his colleagues developed a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota. Using this algorithm, the prediction accuracy of personalized glucose responses achieved an r value of 0.68, which explains about 50% of the variability. For the final component of the study, the researchers randomized 26 participants to one of five dietary arms and followed for 1 week by continuous glucose monitoring. They were able to demonstrate that personally tailored diets lower the postprandial glucose response.
As a follow-up to this work, Dr. Segal and his associates enrolled 200 people with an hemoglobin A1c between 5.7% and 6.5% into the Personalized Nutrition Project for Prediabetes (PNP3) study, which investigates whether personalized diet intervention will improve postprandial blood glucose levels and other metabolic health factors in individuals with prediabetes, compared with the standard Mediterranean-style low-fat diet (NCT03222791). Participants were randomized to 6 months of standard of care following Dietary Guidelines for Americans 2015-2020, Eighth Edition, or to an algorithm diet. Primary outcomes are reduction in average glucose levels and evaluation of the total daily time of plasma glucose levels were below 140 mg/dL. Participants wore the continuous glucose monitor for the entire 6 months of intervention. “I don’t think this was ever done before,” he said. “We’re also looking at secondary metabolic endpoints and exploratory endpoints such as changes in the microbiome. We’re asking people to log everything they eat for the entire 6 months of intervention. It gives us a lot of power in terms assessing compliance. It’s an immense amount of data.”
Evaluation of the data are not yet complete, but interim results are promising. For example, he discussed results from one study participant on the algorithm diet. “Across 1 month, this person was able to entirely reduce the peaks in glucose levels and dramatic reductions in the time above 140 mg/dL in the 6-month treatment period,” said Dr. Segal, who is one of the study’s principal investigators. He disclosed that he is a paid consultant to DayTwo.
LOS ANGELES – .
“The reason we got interested in nutrition in general is for its important role in health and disease, but also because, reading the literature on nutrition in general, it seemed that the science was relatively poor,” Eran Segal, PhD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As a testament, you can see how frequently dietary recommendations for the public are changed. For example, 30 years ago, the cover of Time magazine said that eating cholesterol in the diet is very bad for you. Fifteen years later, Time magazine said that some cholesterol is actually good for you. There are other questions, like should you be eating dairy products? I think it shows that we have a poor understanding of what healthy nutrition is for human individuals. That’s why we wanted to start a study which would collect the right amount and the right kind of data to try to answer the question of what is a healthy diet for human individuals.”
In what is believed to be the first study of its kind, Dr. Segal, professor of computer science and applied mathematics at the Weizmann Institute of Science in Rehovot, Israel, and his associates recruited 1,000 individuals and asked them to wear a continuous glucose monitor (CGM) for 1 week (Cell 2015;163[5]:1079-94). For the study, known as The Personalized Nutrition Project, participants were asked to log everything they ate into a mobile app the researchers developed. “They would select a meal from a database of 10,000 foods,” Dr. Segal explained. “Each meal has full nutritional value so at the end of the study, we had about 50,000 meals that we had measurements of postprandial glucose response to, coupled with full nutritional values.” They also collected a comprehensive profile of individuals, which included body measurements, blood tests, medical background, food frequency questionnaires, and a measurement of the microbiome by both 16S rRNA sequencing and shotgun metagenomics.
For the first part of the study, researchers supplied a breakfast to all participants: either bread, bread with butter, glucose, or fructose, in each case 50 g of available carbohydrates. “The participants were asked to consume these the morning after the night fast,” Dr. Segal said. “This allowed us to compare how the same individual responds to eating the exact same food versus how different individuals respond to eating the same food.” The researchers found that, when the same person ate the same meal on 2 different days, the glucose response was highly reproducible. In contrast, different people had widely different postmeal glucose responses to identical meals. “Some individuals responded most highly to glucose; others responded most highly to bread,” Dr. Segal said. “There was about 10% of individuals who responded to bread and butter, compared to the other test foods. These results mean that any universal diet is going to have limited efficacy in its ability to balance blood glucose levels, because some foods will spike glucose levels in one person but not in another person. It also means that the concepts we’ve been using like the glycemic index are also going to have limited efficacy.”
Next, the researchers aimed to determine what factors influence the variability in people’s responses to the same food. “We found many different correlations between the various blood markers and physical measurements that we obtained, but what was most novel was the variability in postmeal glucose response across people associated with microbiota composition and function,” Dr. Segal said. From this, he and his colleagues developed a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota. Using this algorithm, the prediction accuracy of personalized glucose responses achieved an r value of 0.68, which explains about 50% of the variability. For the final component of the study, the researchers randomized 26 participants to one of five dietary arms and followed for 1 week by continuous glucose monitoring. They were able to demonstrate that personally tailored diets lower the postprandial glucose response.
As a follow-up to this work, Dr. Segal and his associates enrolled 200 people with an hemoglobin A1c between 5.7% and 6.5% into the Personalized Nutrition Project for Prediabetes (PNP3) study, which investigates whether personalized diet intervention will improve postprandial blood glucose levels and other metabolic health factors in individuals with prediabetes, compared with the standard Mediterranean-style low-fat diet (NCT03222791). Participants were randomized to 6 months of standard of care following Dietary Guidelines for Americans 2015-2020, Eighth Edition, or to an algorithm diet. Primary outcomes are reduction in average glucose levels and evaluation of the total daily time of plasma glucose levels were below 140 mg/dL. Participants wore the continuous glucose monitor for the entire 6 months of intervention. “I don’t think this was ever done before,” he said. “We’re also looking at secondary metabolic endpoints and exploratory endpoints such as changes in the microbiome. We’re asking people to log everything they eat for the entire 6 months of intervention. It gives us a lot of power in terms assessing compliance. It’s an immense amount of data.”
Evaluation of the data are not yet complete, but interim results are promising. For example, he discussed results from one study participant on the algorithm diet. “Across 1 month, this person was able to entirely reduce the peaks in glucose levels and dramatic reductions in the time above 140 mg/dL in the 6-month treatment period,” said Dr. Segal, who is one of the study’s principal investigators. He disclosed that he is a paid consultant to DayTwo.
EXPERT ANALYSIS FROM WCIRDC 2018
Researchers exploring ways to mitigate aging’s impact on diabetes
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2018
Osteomyelitis amputation risk linked to comorbidity burden
BOSTON – The higher the comorbidity burden, the greater the likelihood that osteomyelitis will lead to amputation within 2 years, according to a review of 1,186 adult osteomyelitis patients at the University of Michigan, Ann Arbor.
The limb amputation incidence was 7.2% over 2 years in patients with no comorbidities, 21.4% among patients with heart failure, 36.1% in patients with diabetes, and 36.7% among those with peripheral vascular disease (PVD).
The 2-year incidence marched steadily upward with combined comorbidities to 47.4% in patients with diabetes and heart failure; 64.5% in patients with diabetes and PVD; and 75.0% in patients with diabetes, heart failure, and PVD.
“What this means is that looking at diabetes versus no diabetes alone is not sufficient to gauge the risk of amputation. We have to look at the patient’s comorbidity profile as a whole; greater comorbidity burden and different combinations of comorbidities [increase] amputation incidence, but there’s considerable risk [7.2%] even among otherwise healthy patients,” said lead investigator Toby Keeney-Bonthrone, a medical student at the university.
The ultimate goal of the work is to develop an osteomyelitis amputation risk calculator for physicians and patients to improve decision making, validated by nationwide data. “The question is if some patients would benefit from [an earlier,] more prophylactic amputation. Would it be better to just take off the limb and be done with it, and would that decrease overall morbidity?” he said at the annual clinical congress of the American College of Surgeons.
“We often find ourselves reacting to osteomyelitis as it progresses. I think patients deserve a better deal than that. They deserve for us to think one or two steps ahead,” Mr. Keeney-Bonthrone said.
The immediate goal of the study was to fill the data gap on long-term osteomyelitis outcomes, something that hasn’t been addressed much in the literature. The team reviewed adult patients from 2004 to 2015 who were followed for at least 2 years after diagnosis; 610 had diabetes, a known risk factor for osteomyelitis and amputation, and 576 did not.
Comorbidities were considerably more common in the diabetes group, including PVD and heart failure, but also chronic obstructive pulmonary disease, previous heart attack, prior amputation, and especially renal disease. The 2-year amputation incidence was also higher in the diabetes group (43.1% vs. 12.3%), as was 2-year mortality (22.3% vs. 15.5%).
Odds ratios for lower limb amputation climbed in a stepwise fashion on multivariate analysis, from almost a 100% increase in men and in black patients to a 158% increase among patients with past amputations; a 206% increase with PVD; a 256% increase in patients with type 2 diabetes, and a 349% increase among patients with type 1 diabetes. The investigators were puzzled that the amputation risk was higher among type 1 patients than in those with type 2, because comorbidity burdens are generally higher in type 2 diabetes.
No data was provided on treatment differences between the groups, including antibiotic use.
The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
SOURCE: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
BOSTON – The higher the comorbidity burden, the greater the likelihood that osteomyelitis will lead to amputation within 2 years, according to a review of 1,186 adult osteomyelitis patients at the University of Michigan, Ann Arbor.
The limb amputation incidence was 7.2% over 2 years in patients with no comorbidities, 21.4% among patients with heart failure, 36.1% in patients with diabetes, and 36.7% among those with peripheral vascular disease (PVD).
The 2-year incidence marched steadily upward with combined comorbidities to 47.4% in patients with diabetes and heart failure; 64.5% in patients with diabetes and PVD; and 75.0% in patients with diabetes, heart failure, and PVD.
“What this means is that looking at diabetes versus no diabetes alone is not sufficient to gauge the risk of amputation. We have to look at the patient’s comorbidity profile as a whole; greater comorbidity burden and different combinations of comorbidities [increase] amputation incidence, but there’s considerable risk [7.2%] even among otherwise healthy patients,” said lead investigator Toby Keeney-Bonthrone, a medical student at the university.
The ultimate goal of the work is to develop an osteomyelitis amputation risk calculator for physicians and patients to improve decision making, validated by nationwide data. “The question is if some patients would benefit from [an earlier,] more prophylactic amputation. Would it be better to just take off the limb and be done with it, and would that decrease overall morbidity?” he said at the annual clinical congress of the American College of Surgeons.
“We often find ourselves reacting to osteomyelitis as it progresses. I think patients deserve a better deal than that. They deserve for us to think one or two steps ahead,” Mr. Keeney-Bonthrone said.
The immediate goal of the study was to fill the data gap on long-term osteomyelitis outcomes, something that hasn’t been addressed much in the literature. The team reviewed adult patients from 2004 to 2015 who were followed for at least 2 years after diagnosis; 610 had diabetes, a known risk factor for osteomyelitis and amputation, and 576 did not.
Comorbidities were considerably more common in the diabetes group, including PVD and heart failure, but also chronic obstructive pulmonary disease, previous heart attack, prior amputation, and especially renal disease. The 2-year amputation incidence was also higher in the diabetes group (43.1% vs. 12.3%), as was 2-year mortality (22.3% vs. 15.5%).
Odds ratios for lower limb amputation climbed in a stepwise fashion on multivariate analysis, from almost a 100% increase in men and in black patients to a 158% increase among patients with past amputations; a 206% increase with PVD; a 256% increase in patients with type 2 diabetes, and a 349% increase among patients with type 1 diabetes. The investigators were puzzled that the amputation risk was higher among type 1 patients than in those with type 2, because comorbidity burdens are generally higher in type 2 diabetes.
No data was provided on treatment differences between the groups, including antibiotic use.
The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
SOURCE: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
BOSTON – The higher the comorbidity burden, the greater the likelihood that osteomyelitis will lead to amputation within 2 years, according to a review of 1,186 adult osteomyelitis patients at the University of Michigan, Ann Arbor.
The limb amputation incidence was 7.2% over 2 years in patients with no comorbidities, 21.4% among patients with heart failure, 36.1% in patients with diabetes, and 36.7% among those with peripheral vascular disease (PVD).
The 2-year incidence marched steadily upward with combined comorbidities to 47.4% in patients with diabetes and heart failure; 64.5% in patients with diabetes and PVD; and 75.0% in patients with diabetes, heart failure, and PVD.
“What this means is that looking at diabetes versus no diabetes alone is not sufficient to gauge the risk of amputation. We have to look at the patient’s comorbidity profile as a whole; greater comorbidity burden and different combinations of comorbidities [increase] amputation incidence, but there’s considerable risk [7.2%] even among otherwise healthy patients,” said lead investigator Toby Keeney-Bonthrone, a medical student at the university.
The ultimate goal of the work is to develop an osteomyelitis amputation risk calculator for physicians and patients to improve decision making, validated by nationwide data. “The question is if some patients would benefit from [an earlier,] more prophylactic amputation. Would it be better to just take off the limb and be done with it, and would that decrease overall morbidity?” he said at the annual clinical congress of the American College of Surgeons.
“We often find ourselves reacting to osteomyelitis as it progresses. I think patients deserve a better deal than that. They deserve for us to think one or two steps ahead,” Mr. Keeney-Bonthrone said.
The immediate goal of the study was to fill the data gap on long-term osteomyelitis outcomes, something that hasn’t been addressed much in the literature. The team reviewed adult patients from 2004 to 2015 who were followed for at least 2 years after diagnosis; 610 had diabetes, a known risk factor for osteomyelitis and amputation, and 576 did not.
Comorbidities were considerably more common in the diabetes group, including PVD and heart failure, but also chronic obstructive pulmonary disease, previous heart attack, prior amputation, and especially renal disease. The 2-year amputation incidence was also higher in the diabetes group (43.1% vs. 12.3%), as was 2-year mortality (22.3% vs. 15.5%).
Odds ratios for lower limb amputation climbed in a stepwise fashion on multivariate analysis, from almost a 100% increase in men and in black patients to a 158% increase among patients with past amputations; a 206% increase with PVD; a 256% increase in patients with type 2 diabetes, and a 349% increase among patients with type 1 diabetes. The investigators were puzzled that the amputation risk was higher among type 1 patients than in those with type 2, because comorbidity burdens are generally higher in type 2 diabetes.
No data was provided on treatment differences between the groups, including antibiotic use.
The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
SOURCE: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
REPORTING FROM THE 2018 ACS CLINICAL CONGRESS
Key clinical point:
Major finding: The 2-year incidence marched steadily upward with combined comorbidities to 47.5% in patients with diabetes and heart failure; 64.5% in patients with diabetes and peripheral vascular disease, and 75% in patients with diabetes, heart failure, and peripheral vascular disease.
Study details: A review of 1,186 adult osteomyelitis patients
Disclosures: The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
Source: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
Prenatal valproate and ADHD
Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
New diabetes drugs solidify their cardiovascular and renal benefits
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS