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Lessons learned from the PCSK9 inhibitor trials
LOS ANGELES – , according to the best available data.
In addition, there does not seem to be a floor of achieved LDL-C levels where cardiovascular outcomes are not decreased.
Those are two key lessons from recent trials of PCSK9 inhibitors that Norman E. Lepor, MD, highlighted at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Anti-PCSK9 antibodies have shown a significant lipid-lowering effect, lowering LDL-C by 45%-55% from baseline regardless of whether patients are on statins or ezetimibe. More than 70% of high-risk patients are able to achieve an LDL-C level less than 70 mg/dL.
In two randomized trials known as SPIRE-1 and SPIRE-2, researchers compared the PCSK9 inhibitor bococizumab with placebo (N Engl J Med 2017;376:1527-39). The main difference between these two trials was the baseline cardiovascular risk was higher in SPIRE-2, particularly the baseline LDL levels. “Both trials were stopped early because of the increased incidence of antibodies against bococizumab as well as adverse events associated with that, particularly injection site reactions,” said Dr. Lepor, a cardiologist who is professor of medicine at the Geffen School of Medicine at UCLA.
SPIRE-1 did not show a significant difference within a short time of that trial, but SPIRE-2 showed a profound reduction in cardiovascular events within a short time. “That led to the conclusion that the higher the LDL, the higher risk you are, the more likely that you’re going to attain a more robust reduction of cardiovascular events,” Dr. Lepor said. Bococizumab, a partially humanized antibody, did not come to market because of the high incidence of anti-drug antibody and associated diminution of therapeutic effect, he added.
Next came the FOURIER trial of evolocumab, a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dL or higher who were receiving statin therapy. Study participants received evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections (N Engl J Med. 2017;376:1713-22). “The reduction in LDL was very robust and occurred quite early, and there was consistency in terms of long-term effect,” said Dr. Lepor, a past president of the California chapter of the American College of Cardiology. Specifically, researchers observed a 15% reduction in the primary endpoints of a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (P less than .001), and a 20% reduction in the key secondary endpoints of a composite of cardiovascular death, MI, or stroke.
“It’s important to note that these are patients who were already well treated on statins,” he said. “There really does not seem to be a floor of LDL levels where we can say there is no further benefit. Achieved LDL-C at 4 weeks did lead to the ability to prognosticate benefit. We’re not seeing an increase in situations like diabetes, neurocognitive effects, and myalgias. The incidence of adverse events are similar to placebo. We feel very good that there do not seem to be safety issues for these agents, particularly in a population of patients with very low LDLs.” Dr. Lepor went on to note that FOURIER substudies have shown that there did not seem to be any increased incidence of neurocognitive disorders in patients taking evolocumab and that diabetes “tends to be a disease amplifier.”
In a more recent trial known as ODYSSEY OUTCOMES, 18,536 acute coronary syndrome (ACS) patients were randomized to alirocumab 75 mg once every 2 weeks or placebo (N Engl J Med. 2018;379:2097-107). The dose of alirocumab was increased to 150 mg every 2 weeks if the LDL was not lowered to less than 50 mg/dL. “The trial had other interesting aspects to it,” Dr. Lepor said. “If you had an LDL during the trial of less than 25 mg/dL, you were down-titrated from the 150-mg dose to the 75-mg dose, or if you were on the 75-mg dose with two consecutive LDLs less than 15 mg/dL, the alirocumab was stopped, all in blinded fashion.” The primary outcome was time to first occurrence of CHD death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina.
At baseline, patients had a median age of 58 years, 25% were women, their median LDL was 92 mg/dL. About 89% of patients were on high dose atorvastatin/rosuvastatin. Time from index ACS to randomization was a median of 2.6 months.
The primary efficacy endpoint was major adverse cardiac events including CHD death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. After a median follow-up of 2.8 years, the researchers observed highly significant 15% reduction of the primary endpoint with alirocumab compared with placebo (hazard ratio, 0.85; P = .0001), and a 15% reduction of death from any cause. In patients with a baseline LDL-C of 100 mg/dL or greater, the benefits of alirocumab were further amplified. “The higher your LDL, the higher your risk,” Dr. Lepor said. “The higher your risk, the greater your benefit from therapeutic intervention.”
He concluded his presentation by likening the treatment approach with PCSK9 inhibitors in ACS patients to that of chemotherapy in cancer patients. “In patients who have the very high risk of recurrence, those are the ones we want to attack with tougher chemotherapy,” he said. “Who are the patients who benefit most from PCSK9 inhibitors? ACS patients and those who are breaking through statin therapy with cardiovascular events, those with diabetes, CKD, and peripheral vascular disease.”
Dr. Lepor disclosed that he serves on the advisory board for Sanofi/Regeneron and is on the speakers bureau for Amgen and Sanofi/Regeneron.
LOS ANGELES – , according to the best available data.
In addition, there does not seem to be a floor of achieved LDL-C levels where cardiovascular outcomes are not decreased.
Those are two key lessons from recent trials of PCSK9 inhibitors that Norman E. Lepor, MD, highlighted at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Anti-PCSK9 antibodies have shown a significant lipid-lowering effect, lowering LDL-C by 45%-55% from baseline regardless of whether patients are on statins or ezetimibe. More than 70% of high-risk patients are able to achieve an LDL-C level less than 70 mg/dL.
In two randomized trials known as SPIRE-1 and SPIRE-2, researchers compared the PCSK9 inhibitor bococizumab with placebo (N Engl J Med 2017;376:1527-39). The main difference between these two trials was the baseline cardiovascular risk was higher in SPIRE-2, particularly the baseline LDL levels. “Both trials were stopped early because of the increased incidence of antibodies against bococizumab as well as adverse events associated with that, particularly injection site reactions,” said Dr. Lepor, a cardiologist who is professor of medicine at the Geffen School of Medicine at UCLA.
SPIRE-1 did not show a significant difference within a short time of that trial, but SPIRE-2 showed a profound reduction in cardiovascular events within a short time. “That led to the conclusion that the higher the LDL, the higher risk you are, the more likely that you’re going to attain a more robust reduction of cardiovascular events,” Dr. Lepor said. Bococizumab, a partially humanized antibody, did not come to market because of the high incidence of anti-drug antibody and associated diminution of therapeutic effect, he added.
Next came the FOURIER trial of evolocumab, a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dL or higher who were receiving statin therapy. Study participants received evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections (N Engl J Med. 2017;376:1713-22). “The reduction in LDL was very robust and occurred quite early, and there was consistency in terms of long-term effect,” said Dr. Lepor, a past president of the California chapter of the American College of Cardiology. Specifically, researchers observed a 15% reduction in the primary endpoints of a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (P less than .001), and a 20% reduction in the key secondary endpoints of a composite of cardiovascular death, MI, or stroke.
“It’s important to note that these are patients who were already well treated on statins,” he said. “There really does not seem to be a floor of LDL levels where we can say there is no further benefit. Achieved LDL-C at 4 weeks did lead to the ability to prognosticate benefit. We’re not seeing an increase in situations like diabetes, neurocognitive effects, and myalgias. The incidence of adverse events are similar to placebo. We feel very good that there do not seem to be safety issues for these agents, particularly in a population of patients with very low LDLs.” Dr. Lepor went on to note that FOURIER substudies have shown that there did not seem to be any increased incidence of neurocognitive disorders in patients taking evolocumab and that diabetes “tends to be a disease amplifier.”
In a more recent trial known as ODYSSEY OUTCOMES, 18,536 acute coronary syndrome (ACS) patients were randomized to alirocumab 75 mg once every 2 weeks or placebo (N Engl J Med. 2018;379:2097-107). The dose of alirocumab was increased to 150 mg every 2 weeks if the LDL was not lowered to less than 50 mg/dL. “The trial had other interesting aspects to it,” Dr. Lepor said. “If you had an LDL during the trial of less than 25 mg/dL, you were down-titrated from the 150-mg dose to the 75-mg dose, or if you were on the 75-mg dose with two consecutive LDLs less than 15 mg/dL, the alirocumab was stopped, all in blinded fashion.” The primary outcome was time to first occurrence of CHD death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina.
At baseline, patients had a median age of 58 years, 25% were women, their median LDL was 92 mg/dL. About 89% of patients were on high dose atorvastatin/rosuvastatin. Time from index ACS to randomization was a median of 2.6 months.
The primary efficacy endpoint was major adverse cardiac events including CHD death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. After a median follow-up of 2.8 years, the researchers observed highly significant 15% reduction of the primary endpoint with alirocumab compared with placebo (hazard ratio, 0.85; P = .0001), and a 15% reduction of death from any cause. In patients with a baseline LDL-C of 100 mg/dL or greater, the benefits of alirocumab were further amplified. “The higher your LDL, the higher your risk,” Dr. Lepor said. “The higher your risk, the greater your benefit from therapeutic intervention.”
He concluded his presentation by likening the treatment approach with PCSK9 inhibitors in ACS patients to that of chemotherapy in cancer patients. “In patients who have the very high risk of recurrence, those are the ones we want to attack with tougher chemotherapy,” he said. “Who are the patients who benefit most from PCSK9 inhibitors? ACS patients and those who are breaking through statin therapy with cardiovascular events, those with diabetes, CKD, and peripheral vascular disease.”
Dr. Lepor disclosed that he serves on the advisory board for Sanofi/Regeneron and is on the speakers bureau for Amgen and Sanofi/Regeneron.
LOS ANGELES – , according to the best available data.
In addition, there does not seem to be a floor of achieved LDL-C levels where cardiovascular outcomes are not decreased.
Those are two key lessons from recent trials of PCSK9 inhibitors that Norman E. Lepor, MD, highlighted at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Anti-PCSK9 antibodies have shown a significant lipid-lowering effect, lowering LDL-C by 45%-55% from baseline regardless of whether patients are on statins or ezetimibe. More than 70% of high-risk patients are able to achieve an LDL-C level less than 70 mg/dL.
In two randomized trials known as SPIRE-1 and SPIRE-2, researchers compared the PCSK9 inhibitor bococizumab with placebo (N Engl J Med 2017;376:1527-39). The main difference between these two trials was the baseline cardiovascular risk was higher in SPIRE-2, particularly the baseline LDL levels. “Both trials were stopped early because of the increased incidence of antibodies against bococizumab as well as adverse events associated with that, particularly injection site reactions,” said Dr. Lepor, a cardiologist who is professor of medicine at the Geffen School of Medicine at UCLA.
SPIRE-1 did not show a significant difference within a short time of that trial, but SPIRE-2 showed a profound reduction in cardiovascular events within a short time. “That led to the conclusion that the higher the LDL, the higher risk you are, the more likely that you’re going to attain a more robust reduction of cardiovascular events,” Dr. Lepor said. Bococizumab, a partially humanized antibody, did not come to market because of the high incidence of anti-drug antibody and associated diminution of therapeutic effect, he added.
Next came the FOURIER trial of evolocumab, a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dL or higher who were receiving statin therapy. Study participants received evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections (N Engl J Med. 2017;376:1713-22). “The reduction in LDL was very robust and occurred quite early, and there was consistency in terms of long-term effect,” said Dr. Lepor, a past president of the California chapter of the American College of Cardiology. Specifically, researchers observed a 15% reduction in the primary endpoints of a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (P less than .001), and a 20% reduction in the key secondary endpoints of a composite of cardiovascular death, MI, or stroke.
“It’s important to note that these are patients who were already well treated on statins,” he said. “There really does not seem to be a floor of LDL levels where we can say there is no further benefit. Achieved LDL-C at 4 weeks did lead to the ability to prognosticate benefit. We’re not seeing an increase in situations like diabetes, neurocognitive effects, and myalgias. The incidence of adverse events are similar to placebo. We feel very good that there do not seem to be safety issues for these agents, particularly in a population of patients with very low LDLs.” Dr. Lepor went on to note that FOURIER substudies have shown that there did not seem to be any increased incidence of neurocognitive disorders in patients taking evolocumab and that diabetes “tends to be a disease amplifier.”
In a more recent trial known as ODYSSEY OUTCOMES, 18,536 acute coronary syndrome (ACS) patients were randomized to alirocumab 75 mg once every 2 weeks or placebo (N Engl J Med. 2018;379:2097-107). The dose of alirocumab was increased to 150 mg every 2 weeks if the LDL was not lowered to less than 50 mg/dL. “The trial had other interesting aspects to it,” Dr. Lepor said. “If you had an LDL during the trial of less than 25 mg/dL, you were down-titrated from the 150-mg dose to the 75-mg dose, or if you were on the 75-mg dose with two consecutive LDLs less than 15 mg/dL, the alirocumab was stopped, all in blinded fashion.” The primary outcome was time to first occurrence of CHD death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina.
At baseline, patients had a median age of 58 years, 25% were women, their median LDL was 92 mg/dL. About 89% of patients were on high dose atorvastatin/rosuvastatin. Time from index ACS to randomization was a median of 2.6 months.
The primary efficacy endpoint was major adverse cardiac events including CHD death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. After a median follow-up of 2.8 years, the researchers observed highly significant 15% reduction of the primary endpoint with alirocumab compared with placebo (hazard ratio, 0.85; P = .0001), and a 15% reduction of death from any cause. In patients with a baseline LDL-C of 100 mg/dL or greater, the benefits of alirocumab were further amplified. “The higher your LDL, the higher your risk,” Dr. Lepor said. “The higher your risk, the greater your benefit from therapeutic intervention.”
He concluded his presentation by likening the treatment approach with PCSK9 inhibitors in ACS patients to that of chemotherapy in cancer patients. “In patients who have the very high risk of recurrence, those are the ones we want to attack with tougher chemotherapy,” he said. “Who are the patients who benefit most from PCSK9 inhibitors? ACS patients and those who are breaking through statin therapy with cardiovascular events, those with diabetes, CKD, and peripheral vascular disease.”
Dr. Lepor disclosed that he serves on the advisory board for Sanofi/Regeneron and is on the speakers bureau for Amgen and Sanofi/Regeneron.
EXPERT ANALYSIS FROM WCIRDC 2018
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
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
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
Expert calls for better ways to preserve beta cell function in youth
LOS ANGELES –
At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).
“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?
To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.
Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”
The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m2. The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.
“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”
Dr. Caprio reported having no disclosures.
LOS ANGELES –
At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).
“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?
To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.
Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”
The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m2. The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.
“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”
Dr. Caprio reported having no disclosures.
LOS ANGELES –
At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).
“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?
To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.
Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”
The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m2. The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.
“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”
Dr. Caprio reported having no disclosures.
EXPERT ANALYSIS FROM WCIRDC 2018
‘Payoff will be great’ if we can conquer childhood obesity, expert says
LOS ANGELES – Mounting evidence indicates that obesity in childhood and adolescence increases the risk for future cardiovascular disease (CVD), according to Stephen R. Daniels, MD, PhD.
“Some of this increased risk is related to the high level of tracking of obesity from childhood to adolescence to adulthood,” Dr. Daniels, who chairs the department of pediatrics at the University of Colorado, Aurora, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But I think it’s also clear that childhood obesity is associated with risk factors for adult CVD, including hypertension, dyslipidemia, and type 2 diabetes. There’s a combination of things going on over the life course.”
Numerous studies have demonstrated a dose-response relationship between increased weight and all-cause mortality in cardiovascular disease for men and women. This operates through a variety of mechanisms, Dr. Daniels said, including hypertension, dyslipidemia, left ventricular hypertrophy, vascular inflammation, type 2 diabetes, and obstructive sleep apnea. “While overt cardiovascular disease does not occur in children, many of the mechanisms recognized in adults are also present in children and adolescents,” he said. “The trends for increasing prevalence and severity of obesity in children and the comorbid conditions associated with obesity are worrisome.”
The current prevalence of obesity in children and adolescents stands at about 18%, according to the latest National Health and Nutrition Examination Survey. However, the prevalence of severe obesity in youth aged 2-19 years has been increasing “fairly dramatically,” and now stands at 9% among girls and 8% among boys. Hispanics and non-Hispanic blacks are disproportionately affected. That may turn out to be important in terms of the future, Dr. Daniels said, because according to simulation models, childhood obesity and overweight will continue to be a major public health problem in the future (N Engl J Med. 2017;377:2145-53).
Direct evidence is also beginning to emerge of a link between obesity in youth and adult cardiovascular disease. The factors in childhood that predict adult obesity include a higher level of body mass index, obesity present at an older age (adolescence vs. childhood), and the presence of obesity in parents, which reflects both genes and environment. Researchers led by Paul W. Franks, PhD, evaluated 4,857 American Indian children without diabetes who were born between 1945 and 1984 and followed them for death before age 55 (N Engl J Med. 2010;362[6]:485-93). They assessed whether BMI, glucose tolerance, blood pressure, and cholesterol levels predicted premature death. There were 166 deaths from endogenous causes (3.4%) over a median follow-up of 24 years. Factors significantly associated with mortality included obesity (incident rate ratio 2.30), glucose tolerance (IRR 1.73), and hypertension (IRR 1.57).
In a separate analysis, researchers investigated the long-term effects of childhood weight on coronary heart disease (CHD) by studying 276,835 Danish schoolchildren for whom measurements of height and weight were available. They followed the individuals until they turned age 25 or older and used national registries to assess the fatal and nonfatal rates of CHD events (N Engl J Med. 2007;357:2329-37). The researchers found that higher BMI during childhood was associated with an increased risk of CVD in adulthood. However, they did not have data on BMI in adulthood, “which leaves open the question of whether childhood obesity works through adult obesity or also has an independent effect,” said Dr. Daniels, who is also pediatrician-in-chief at Children’s Hospital Colorado, Denver.
More recently, investigators studied 37,674 apparently healthy Israeli men from age 17 into adulthood (N Engl J Med. 2011;364:1315-25). Outcomes were coronary disease and diabetes. They found that an elevated BMI in adolescence is an independent risk factor for CVD in later life, while an elevated BMI in adulthood is an independent risk factor for both CVD and diabetes.
In the Fels Longitudinal Study, researchers enrolled 151 adults with metabolic syndrome and 154 without metabolic syndrome, with a mean age of 51 years (J Pediatr. 2008;152:191-200). “The idea was to look back at this cohort and see when the first differences might be observable between boys and girls who ultimately would develop metabolic syndrome and those who would not,” said Dr. Daniels, who was one of the study investigators. The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome in adulthood if BMI were elevated in childhood ranged from 1.4 to 1.9 in boys and from 0.8 to 2.8 in girls. At the same time, odds ratios for the metabolic syndrome in adulthood if waist circumference was elevated ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls.
“I think it’s safe to say that BMI and waist circumference may be important in predicting metabolic syndrome later in life and, ultimately, cardiovascular disease,” Dr. Daniels said.
He noted that as the prevalence and severity of obesity have increased in childhood, the prevalence of type 2 diabetes has also increased. “The time from diagnosis of diabetes to a CVD event is approximately 10-15 years in adults, and there is often a prediagnosis period of hyperglycemia, which ranges from 5-10 years,” Dr. Daniels said. “If the time course of CVD related to diabetes is the same for adolescents as adults, it is anticipated that adolescents with diabetes will begin having substantial CVD morbidity and mortality in their 30s or 40s. This will be a public health disaster. Emerging evidence from the TODAY study (Treatment Options for type 2 Diabetes in Adolescents and Youth) and other studies is emphasizing that at least some individuals with adolescent type 2 diabetes may have a more malignant form of disease than in adults. This is striking and important to consider as we look at how to prevent cardiovascular disease.”
Obesity in childhood is also associated with structural and functional abnormalities of the vasculature, according to studies that measure vascular structure via intima-media thickness of the carotid arteries, femoral arteries, abdominal aorta, or other arteries, as well as those that measure vascular stiffness via measures of intrinsic “visco-elastic” properties of the arterial wall. In one study of individuals aged 10-24 years, Dr. Daniels and his associates performed carotid ultrasound for carotid intima-media thickness on 182 patients who were lean, 136 who were obese, and 128 who had type 2 diabetes (Circulation 2009;119(22):2913-9). It demonstrated that youth with obesity and obesity-related type 2 diabetes have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors.
“We all know that obesity is very difficult to treat,” he concluded. “That’s true in children and adolescents as it is in adults. I think this argues for prevention of obesity, for us starting earlier, creating an optimal cardiovascular health situation that we can maintain during the course of childhood and adolescence. The payoff will be great if we can accomplish that.”
Dr. Daniels reported having no disclosures.
LOS ANGELES – Mounting evidence indicates that obesity in childhood and adolescence increases the risk for future cardiovascular disease (CVD), according to Stephen R. Daniels, MD, PhD.
“Some of this increased risk is related to the high level of tracking of obesity from childhood to adolescence to adulthood,” Dr. Daniels, who chairs the department of pediatrics at the University of Colorado, Aurora, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But I think it’s also clear that childhood obesity is associated with risk factors for adult CVD, including hypertension, dyslipidemia, and type 2 diabetes. There’s a combination of things going on over the life course.”
Numerous studies have demonstrated a dose-response relationship between increased weight and all-cause mortality in cardiovascular disease for men and women. This operates through a variety of mechanisms, Dr. Daniels said, including hypertension, dyslipidemia, left ventricular hypertrophy, vascular inflammation, type 2 diabetes, and obstructive sleep apnea. “While overt cardiovascular disease does not occur in children, many of the mechanisms recognized in adults are also present in children and adolescents,” he said. “The trends for increasing prevalence and severity of obesity in children and the comorbid conditions associated with obesity are worrisome.”
The current prevalence of obesity in children and adolescents stands at about 18%, according to the latest National Health and Nutrition Examination Survey. However, the prevalence of severe obesity in youth aged 2-19 years has been increasing “fairly dramatically,” and now stands at 9% among girls and 8% among boys. Hispanics and non-Hispanic blacks are disproportionately affected. That may turn out to be important in terms of the future, Dr. Daniels said, because according to simulation models, childhood obesity and overweight will continue to be a major public health problem in the future (N Engl J Med. 2017;377:2145-53).
Direct evidence is also beginning to emerge of a link between obesity in youth and adult cardiovascular disease. The factors in childhood that predict adult obesity include a higher level of body mass index, obesity present at an older age (adolescence vs. childhood), and the presence of obesity in parents, which reflects both genes and environment. Researchers led by Paul W. Franks, PhD, evaluated 4,857 American Indian children without diabetes who were born between 1945 and 1984 and followed them for death before age 55 (N Engl J Med. 2010;362[6]:485-93). They assessed whether BMI, glucose tolerance, blood pressure, and cholesterol levels predicted premature death. There were 166 deaths from endogenous causes (3.4%) over a median follow-up of 24 years. Factors significantly associated with mortality included obesity (incident rate ratio 2.30), glucose tolerance (IRR 1.73), and hypertension (IRR 1.57).
In a separate analysis, researchers investigated the long-term effects of childhood weight on coronary heart disease (CHD) by studying 276,835 Danish schoolchildren for whom measurements of height and weight were available. They followed the individuals until they turned age 25 or older and used national registries to assess the fatal and nonfatal rates of CHD events (N Engl J Med. 2007;357:2329-37). The researchers found that higher BMI during childhood was associated with an increased risk of CVD in adulthood. However, they did not have data on BMI in adulthood, “which leaves open the question of whether childhood obesity works through adult obesity or also has an independent effect,” said Dr. Daniels, who is also pediatrician-in-chief at Children’s Hospital Colorado, Denver.
More recently, investigators studied 37,674 apparently healthy Israeli men from age 17 into adulthood (N Engl J Med. 2011;364:1315-25). Outcomes were coronary disease and diabetes. They found that an elevated BMI in adolescence is an independent risk factor for CVD in later life, while an elevated BMI in adulthood is an independent risk factor for both CVD and diabetes.
In the Fels Longitudinal Study, researchers enrolled 151 adults with metabolic syndrome and 154 without metabolic syndrome, with a mean age of 51 years (J Pediatr. 2008;152:191-200). “The idea was to look back at this cohort and see when the first differences might be observable between boys and girls who ultimately would develop metabolic syndrome and those who would not,” said Dr. Daniels, who was one of the study investigators. The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome in adulthood if BMI were elevated in childhood ranged from 1.4 to 1.9 in boys and from 0.8 to 2.8 in girls. At the same time, odds ratios for the metabolic syndrome in adulthood if waist circumference was elevated ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls.
“I think it’s safe to say that BMI and waist circumference may be important in predicting metabolic syndrome later in life and, ultimately, cardiovascular disease,” Dr. Daniels said.
He noted that as the prevalence and severity of obesity have increased in childhood, the prevalence of type 2 diabetes has also increased. “The time from diagnosis of diabetes to a CVD event is approximately 10-15 years in adults, and there is often a prediagnosis period of hyperglycemia, which ranges from 5-10 years,” Dr. Daniels said. “If the time course of CVD related to diabetes is the same for adolescents as adults, it is anticipated that adolescents with diabetes will begin having substantial CVD morbidity and mortality in their 30s or 40s. This will be a public health disaster. Emerging evidence from the TODAY study (Treatment Options for type 2 Diabetes in Adolescents and Youth) and other studies is emphasizing that at least some individuals with adolescent type 2 diabetes may have a more malignant form of disease than in adults. This is striking and important to consider as we look at how to prevent cardiovascular disease.”
Obesity in childhood is also associated with structural and functional abnormalities of the vasculature, according to studies that measure vascular structure via intima-media thickness of the carotid arteries, femoral arteries, abdominal aorta, or other arteries, as well as those that measure vascular stiffness via measures of intrinsic “visco-elastic” properties of the arterial wall. In one study of individuals aged 10-24 years, Dr. Daniels and his associates performed carotid ultrasound for carotid intima-media thickness on 182 patients who were lean, 136 who were obese, and 128 who had type 2 diabetes (Circulation 2009;119(22):2913-9). It demonstrated that youth with obesity and obesity-related type 2 diabetes have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors.
“We all know that obesity is very difficult to treat,” he concluded. “That’s true in children and adolescents as it is in adults. I think this argues for prevention of obesity, for us starting earlier, creating an optimal cardiovascular health situation that we can maintain during the course of childhood and adolescence. The payoff will be great if we can accomplish that.”
Dr. Daniels reported having no disclosures.
LOS ANGELES – Mounting evidence indicates that obesity in childhood and adolescence increases the risk for future cardiovascular disease (CVD), according to Stephen R. Daniels, MD, PhD.
“Some of this increased risk is related to the high level of tracking of obesity from childhood to adolescence to adulthood,” Dr. Daniels, who chairs the department of pediatrics at the University of Colorado, Aurora, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But I think it’s also clear that childhood obesity is associated with risk factors for adult CVD, including hypertension, dyslipidemia, and type 2 diabetes. There’s a combination of things going on over the life course.”
Numerous studies have demonstrated a dose-response relationship between increased weight and all-cause mortality in cardiovascular disease for men and women. This operates through a variety of mechanisms, Dr. Daniels said, including hypertension, dyslipidemia, left ventricular hypertrophy, vascular inflammation, type 2 diabetes, and obstructive sleep apnea. “While overt cardiovascular disease does not occur in children, many of the mechanisms recognized in adults are also present in children and adolescents,” he said. “The trends for increasing prevalence and severity of obesity in children and the comorbid conditions associated with obesity are worrisome.”
The current prevalence of obesity in children and adolescents stands at about 18%, according to the latest National Health and Nutrition Examination Survey. However, the prevalence of severe obesity in youth aged 2-19 years has been increasing “fairly dramatically,” and now stands at 9% among girls and 8% among boys. Hispanics and non-Hispanic blacks are disproportionately affected. That may turn out to be important in terms of the future, Dr. Daniels said, because according to simulation models, childhood obesity and overweight will continue to be a major public health problem in the future (N Engl J Med. 2017;377:2145-53).
Direct evidence is also beginning to emerge of a link between obesity in youth and adult cardiovascular disease. The factors in childhood that predict adult obesity include a higher level of body mass index, obesity present at an older age (adolescence vs. childhood), and the presence of obesity in parents, which reflects both genes and environment. Researchers led by Paul W. Franks, PhD, evaluated 4,857 American Indian children without diabetes who were born between 1945 and 1984 and followed them for death before age 55 (N Engl J Med. 2010;362[6]:485-93). They assessed whether BMI, glucose tolerance, blood pressure, and cholesterol levels predicted premature death. There were 166 deaths from endogenous causes (3.4%) over a median follow-up of 24 years. Factors significantly associated with mortality included obesity (incident rate ratio 2.30), glucose tolerance (IRR 1.73), and hypertension (IRR 1.57).
In a separate analysis, researchers investigated the long-term effects of childhood weight on coronary heart disease (CHD) by studying 276,835 Danish schoolchildren for whom measurements of height and weight were available. They followed the individuals until they turned age 25 or older and used national registries to assess the fatal and nonfatal rates of CHD events (N Engl J Med. 2007;357:2329-37). The researchers found that higher BMI during childhood was associated with an increased risk of CVD in adulthood. However, they did not have data on BMI in adulthood, “which leaves open the question of whether childhood obesity works through adult obesity or also has an independent effect,” said Dr. Daniels, who is also pediatrician-in-chief at Children’s Hospital Colorado, Denver.
More recently, investigators studied 37,674 apparently healthy Israeli men from age 17 into adulthood (N Engl J Med. 2011;364:1315-25). Outcomes were coronary disease and diabetes. They found that an elevated BMI in adolescence is an independent risk factor for CVD in later life, while an elevated BMI in adulthood is an independent risk factor for both CVD and diabetes.
In the Fels Longitudinal Study, researchers enrolled 151 adults with metabolic syndrome and 154 without metabolic syndrome, with a mean age of 51 years (J Pediatr. 2008;152:191-200). “The idea was to look back at this cohort and see when the first differences might be observable between boys and girls who ultimately would develop metabolic syndrome and those who would not,” said Dr. Daniels, who was one of the study investigators. The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome in adulthood if BMI were elevated in childhood ranged from 1.4 to 1.9 in boys and from 0.8 to 2.8 in girls. At the same time, odds ratios for the metabolic syndrome in adulthood if waist circumference was elevated ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls.
“I think it’s safe to say that BMI and waist circumference may be important in predicting metabolic syndrome later in life and, ultimately, cardiovascular disease,” Dr. Daniels said.
He noted that as the prevalence and severity of obesity have increased in childhood, the prevalence of type 2 diabetes has also increased. “The time from diagnosis of diabetes to a CVD event is approximately 10-15 years in adults, and there is often a prediagnosis period of hyperglycemia, which ranges from 5-10 years,” Dr. Daniels said. “If the time course of CVD related to diabetes is the same for adolescents as adults, it is anticipated that adolescents with diabetes will begin having substantial CVD morbidity and mortality in their 30s or 40s. This will be a public health disaster. Emerging evidence from the TODAY study (Treatment Options for type 2 Diabetes in Adolescents and Youth) and other studies is emphasizing that at least some individuals with adolescent type 2 diabetes may have a more malignant form of disease than in adults. This is striking and important to consider as we look at how to prevent cardiovascular disease.”
Obesity in childhood is also associated with structural and functional abnormalities of the vasculature, according to studies that measure vascular structure via intima-media thickness of the carotid arteries, femoral arteries, abdominal aorta, or other arteries, as well as those that measure vascular stiffness via measures of intrinsic “visco-elastic” properties of the arterial wall. In one study of individuals aged 10-24 years, Dr. Daniels and his associates performed carotid ultrasound for carotid intima-media thickness on 182 patients who were lean, 136 who were obese, and 128 who had type 2 diabetes (Circulation 2009;119(22):2913-9). It demonstrated that youth with obesity and obesity-related type 2 diabetes have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors.
“We all know that obesity is very difficult to treat,” he concluded. “That’s true in children and adolescents as it is in adults. I think this argues for prevention of obesity, for us starting earlier, creating an optimal cardiovascular health situation that we can maintain during the course of childhood and adolescence. The payoff will be great if we can accomplish that.”
Dr. Daniels reported having no disclosures.
EXPERT ANALYSIS FROM WCIRDC 2018
New risk-prediction model for diabetes under development
LOS ANGELES – Clinicians treating patients with diabetes rely heavily on the U.K. Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham Risk Score to predict outcomes, but the populations used for developing these tools differ significantly from the current U.S. diabetes population.
“All these risk engines have various degrees of accuracy along with several limitations, including that they are derived from data from various populations,” Vivian A. Fonseca, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Sometimes the results may not be generalizable. That’s one of the big problems with the risk engines we’re using.”
To address these shortcomings, Dr. Fonseca, Hui Shao, PhD, and Lizheng Shi, PhD, have developed the Building, Relating, Assessing, Validating Outcomes (BRAVO) of Diabetes Model, a patient-level microsimulation model based on data from the ACCORD trial. The model predicts both primary and secondary CVD events, microvascular events, the progress of hemoglobin A1c and other key biomarkers over time, quality-adjusted life-year (QALY) function decrements associated with complications, and an ability to predict outcomes in patients from other regions in the world. The risk engine contains three modules for 17 equations in total, including angina, blindness, and hypoglycemia (Pharmacoeconomics. 2018;36[9]:1125-34). “There are lots of data now showing that if you get hypoglycemia, your risk of a cardiovascular event goes up greatly over the subsequent 2 years,” said Dr. Fonseca, who is chief of the section of endocrinology at Tulane University Health Science Center, New Orleans. “No other risk engine has that.”
When he and his associates applied the UKPDS Risk Engine to the ACCORD cohort, they found that the UPKDS Risk Engine overpredicted the risk of stroke (2.3% vs. 1.4% observed), MI (6.5% vs. 4.9% observed), and all-cause mortality (10.3% vs. 4% observed); yet it underpredicted congestive heart failure (2.2% vs. 4% observed), end-stage renal disease (0.5% vs. 3% observed), and blindness (1.35% vs. 8.1% observed). In the ACCORD cohort, baseline duration varied from 0 to 35 years. “Using left truncated regression, we can piece together the segmented follow-up times for 10,251 patients to a complete diabetes progression track from 0 years to 40 years after diabetes onset,” he said.
Dr. Fonseca said that Internal validations studies found that BRAVO predicted outcomes from the ACCORD trial, including congestive heart failure, MI, stroke, angina, blindness, end-stage renal disease, and neuropathy. Data from the ASPEN, CARDS, and ADVANCE trials were used to conduct external validation, and the incidence rates of 28 endpoints correlated with that of BRAVO “extremely well.” In addition, BRAVO has been calibrated against 18 large randomized, controlled trials conducted after the year 2000. “Regional variation in CVD [cardiovascular disease] outcomes were included as an important risk factor in the simulation,” said Dr. Fonseca, who is also assistant dean for clinical research at Tulane. Results to date show a high prediction accuracy (R-squared value = .91).
He and his associates are currently examining ways to apply BRAVO in clinical practice, including for risk stratification. “Let’s say you have a large health system, and you want to separate out your patients who have high, medium, or low risk for diabetes and make sure they get they get the right care according to their stratification,” he explained. “A couple of large health systems are trying this out right now.”
BRAVO can also be used as a tool for cost-effectiveness analysis and program evaluation. In fact, he and his colleagues at five medical centers are working with the American Diabetes Association “to see what effect a certain intervention will have on outcomes in people with diabetes over a number of years, and how cost effective it might be.”
Finally, BRAVO can be used for diabetes management in clinical practice. “Based on an individual’s characteristics, the BRAVO model potentially simulates future outcomes such as complications and mortality, providing a transparent platform for shared decision making,” he said.
Dr. Fonseca disclosed that he has an ownership interest in the development of BRAVO.
LOS ANGELES – Clinicians treating patients with diabetes rely heavily on the U.K. Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham Risk Score to predict outcomes, but the populations used for developing these tools differ significantly from the current U.S. diabetes population.
“All these risk engines have various degrees of accuracy along with several limitations, including that they are derived from data from various populations,” Vivian A. Fonseca, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Sometimes the results may not be generalizable. That’s one of the big problems with the risk engines we’re using.”
To address these shortcomings, Dr. Fonseca, Hui Shao, PhD, and Lizheng Shi, PhD, have developed the Building, Relating, Assessing, Validating Outcomes (BRAVO) of Diabetes Model, a patient-level microsimulation model based on data from the ACCORD trial. The model predicts both primary and secondary CVD events, microvascular events, the progress of hemoglobin A1c and other key biomarkers over time, quality-adjusted life-year (QALY) function decrements associated with complications, and an ability to predict outcomes in patients from other regions in the world. The risk engine contains three modules for 17 equations in total, including angina, blindness, and hypoglycemia (Pharmacoeconomics. 2018;36[9]:1125-34). “There are lots of data now showing that if you get hypoglycemia, your risk of a cardiovascular event goes up greatly over the subsequent 2 years,” said Dr. Fonseca, who is chief of the section of endocrinology at Tulane University Health Science Center, New Orleans. “No other risk engine has that.”
When he and his associates applied the UKPDS Risk Engine to the ACCORD cohort, they found that the UPKDS Risk Engine overpredicted the risk of stroke (2.3% vs. 1.4% observed), MI (6.5% vs. 4.9% observed), and all-cause mortality (10.3% vs. 4% observed); yet it underpredicted congestive heart failure (2.2% vs. 4% observed), end-stage renal disease (0.5% vs. 3% observed), and blindness (1.35% vs. 8.1% observed). In the ACCORD cohort, baseline duration varied from 0 to 35 years. “Using left truncated regression, we can piece together the segmented follow-up times for 10,251 patients to a complete diabetes progression track from 0 years to 40 years after diabetes onset,” he said.
Dr. Fonseca said that Internal validations studies found that BRAVO predicted outcomes from the ACCORD trial, including congestive heart failure, MI, stroke, angina, blindness, end-stage renal disease, and neuropathy. Data from the ASPEN, CARDS, and ADVANCE trials were used to conduct external validation, and the incidence rates of 28 endpoints correlated with that of BRAVO “extremely well.” In addition, BRAVO has been calibrated against 18 large randomized, controlled trials conducted after the year 2000. “Regional variation in CVD [cardiovascular disease] outcomes were included as an important risk factor in the simulation,” said Dr. Fonseca, who is also assistant dean for clinical research at Tulane. Results to date show a high prediction accuracy (R-squared value = .91).
He and his associates are currently examining ways to apply BRAVO in clinical practice, including for risk stratification. “Let’s say you have a large health system, and you want to separate out your patients who have high, medium, or low risk for diabetes and make sure they get they get the right care according to their stratification,” he explained. “A couple of large health systems are trying this out right now.”
BRAVO can also be used as a tool for cost-effectiveness analysis and program evaluation. In fact, he and his colleagues at five medical centers are working with the American Diabetes Association “to see what effect a certain intervention will have on outcomes in people with diabetes over a number of years, and how cost effective it might be.”
Finally, BRAVO can be used for diabetes management in clinical practice. “Based on an individual’s characteristics, the BRAVO model potentially simulates future outcomes such as complications and mortality, providing a transparent platform for shared decision making,” he said.
Dr. Fonseca disclosed that he has an ownership interest in the development of BRAVO.
LOS ANGELES – Clinicians treating patients with diabetes rely heavily on the U.K. Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham Risk Score to predict outcomes, but the populations used for developing these tools differ significantly from the current U.S. diabetes population.
“All these risk engines have various degrees of accuracy along with several limitations, including that they are derived from data from various populations,” Vivian A. Fonseca, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Sometimes the results may not be generalizable. That’s one of the big problems with the risk engines we’re using.”
To address these shortcomings, Dr. Fonseca, Hui Shao, PhD, and Lizheng Shi, PhD, have developed the Building, Relating, Assessing, Validating Outcomes (BRAVO) of Diabetes Model, a patient-level microsimulation model based on data from the ACCORD trial. The model predicts both primary and secondary CVD events, microvascular events, the progress of hemoglobin A1c and other key biomarkers over time, quality-adjusted life-year (QALY) function decrements associated with complications, and an ability to predict outcomes in patients from other regions in the world. The risk engine contains three modules for 17 equations in total, including angina, blindness, and hypoglycemia (Pharmacoeconomics. 2018;36[9]:1125-34). “There are lots of data now showing that if you get hypoglycemia, your risk of a cardiovascular event goes up greatly over the subsequent 2 years,” said Dr. Fonseca, who is chief of the section of endocrinology at Tulane University Health Science Center, New Orleans. “No other risk engine has that.”
When he and his associates applied the UKPDS Risk Engine to the ACCORD cohort, they found that the UPKDS Risk Engine overpredicted the risk of stroke (2.3% vs. 1.4% observed), MI (6.5% vs. 4.9% observed), and all-cause mortality (10.3% vs. 4% observed); yet it underpredicted congestive heart failure (2.2% vs. 4% observed), end-stage renal disease (0.5% vs. 3% observed), and blindness (1.35% vs. 8.1% observed). In the ACCORD cohort, baseline duration varied from 0 to 35 years. “Using left truncated regression, we can piece together the segmented follow-up times for 10,251 patients to a complete diabetes progression track from 0 years to 40 years after diabetes onset,” he said.
Dr. Fonseca said that Internal validations studies found that BRAVO predicted outcomes from the ACCORD trial, including congestive heart failure, MI, stroke, angina, blindness, end-stage renal disease, and neuropathy. Data from the ASPEN, CARDS, and ADVANCE trials were used to conduct external validation, and the incidence rates of 28 endpoints correlated with that of BRAVO “extremely well.” In addition, BRAVO has been calibrated against 18 large randomized, controlled trials conducted after the year 2000. “Regional variation in CVD [cardiovascular disease] outcomes were included as an important risk factor in the simulation,” said Dr. Fonseca, who is also assistant dean for clinical research at Tulane. Results to date show a high prediction accuracy (R-squared value = .91).
He and his associates are currently examining ways to apply BRAVO in clinical practice, including for risk stratification. “Let’s say you have a large health system, and you want to separate out your patients who have high, medium, or low risk for diabetes and make sure they get they get the right care according to their stratification,” he explained. “A couple of large health systems are trying this out right now.”
BRAVO can also be used as a tool for cost-effectiveness analysis and program evaluation. In fact, he and his colleagues at five medical centers are working with the American Diabetes Association “to see what effect a certain intervention will have on outcomes in people with diabetes over a number of years, and how cost effective it might be.”
Finally, BRAVO can be used for diabetes management in clinical practice. “Based on an individual’s characteristics, the BRAVO model potentially simulates future outcomes such as complications and mortality, providing a transparent platform for shared decision making,” he said.
Dr. Fonseca disclosed that he has an ownership interest in the development of BRAVO.
EXPERT ANALYSIS FROM THE WCIRCD 2018
Decreased insulin clearance may be first step on path to insulin resistance
LOS ANGELES – As obese, nondiabetic individuals become more insulin resistant, a decrease in insulin clearance is the first change to occur, according to Sun H. Kim, MD.
“You will often hear about how insulin resistance enhances demand on beta cells to increase insulin secretion, which leads to hyperinsulinemia,” Dr. Kim said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “While well accepted, this model ignores the role of insulin clearance rate in maintaining hyperinsulinemia in insulin resistance states.”
In an effort to understand the physiologic adaptation to insulin resistance prior to the development of type 2 diabetes mellitus, Dr. Kim, an associate professor of endocrinology at Stanford (Calif) University, Stanford, and her colleagues enrolled 91 adults who had a body mass index of at least 30 kg/m2. The study was published in the March 2018 issue of Diabetologia. Each subject underwent a 75-g oral glucose tolerance test as well as the insulin suppression test to measure insulin resistance and the graded glucose infusion test to determine each subject’s insulin secretion rate and insulin clearance rate. For the graded glucose infusion test, the researchers increased the glucose infusion rate every 40 minutes, from 1 mg/kg per minute up to 8 mg/kg per minute. Next, they divided the cohort of obese individuals into tertiles of insulin resistance as quantified by the steady-state plasma glucose (SSPG): less than 9.7 mmol/L (tertile 1), 9.7-12.7 mmol/L (tertile 2), and 12.8 mmol/L or greater (tertile 3).
The mean age of subjects was 54 years. The mean SSPG level was 7.2 mmol/L among subjects in tertile 1, 11.3 mmol/L among those in tertile 2, and 14.3 mmol/L among those in tertile 3. The remainder of the demographics was similar. “Most importantly, body mass index among tertiles was nearly identical,” Dr. Kim said. “The only biomarker that was different was ALT, which increased with increasing tertiles. The individuals who were more insulin resistant likely had more fatty liver. We didn’t do imaging in this particular study.”
When the researchers evaluated oral glucose tolerance test data, they observed that subjects who were most insulin resistant had slightly higher glucose levels, “which we often see,” she said. “The body does try to keep glucose in a narrow range. What was dramatic were the insulin levels. The most insulin-resistant subjects had insulin levels that were double those of the least insulin-resistant subjects in tertile 1 during the oral glucose tolerance test.”
During the intravenous glucose infusion test, glucose levels rose similarly in the three groups, but those in tertile 3 had slightly higher glucose levels (P = .04). The insulin secretion rate, meanwhile, was similar among subjects in tertiles 1 and 2 but was increased significantly among subjects in tertile 3 (P less than .001). In contrast, the researchers observed a stepwise decline in insulin clearance rate from tertiles 1 to 3. Thus the insulin clearance rate was significantly different between subjects in tertile 1 and tertile 2 (P = .04) as well as between subjects in tertile 2 and those in tertile 3 (P less than .001).
“We propose that insulin resistance leads to an increase in intrahepatic fat, which decreases the insulin clearance rate and helps maintain euglycemia,” Dr. Kim concluded. “In the most insulin-resistant tertile, a decrease in insulin clearance rate is not sufficient, and an increase in the insulin secretion rate is also required. If you look at the relationship between insulin resistance and insulin clearance rate, there is a negative correlation, so the more insulin resistant you are, the lower your insulin clearance rate. However, there are insulin-resistant individuals who perhaps have higher insulin clearance rates than we think they should have. Could those individuals be at the highest risk to develop diabetes? That’s the story to which I don’t yet have an ending.” She reported having no financial disclosures.
SOURCE: Jung SH et al. Diabetologia. 2018;61(3):681-7.
LOS ANGELES – As obese, nondiabetic individuals become more insulin resistant, a decrease in insulin clearance is the first change to occur, according to Sun H. Kim, MD.
“You will often hear about how insulin resistance enhances demand on beta cells to increase insulin secretion, which leads to hyperinsulinemia,” Dr. Kim said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “While well accepted, this model ignores the role of insulin clearance rate in maintaining hyperinsulinemia in insulin resistance states.”
In an effort to understand the physiologic adaptation to insulin resistance prior to the development of type 2 diabetes mellitus, Dr. Kim, an associate professor of endocrinology at Stanford (Calif) University, Stanford, and her colleagues enrolled 91 adults who had a body mass index of at least 30 kg/m2. The study was published in the March 2018 issue of Diabetologia. Each subject underwent a 75-g oral glucose tolerance test as well as the insulin suppression test to measure insulin resistance and the graded glucose infusion test to determine each subject’s insulin secretion rate and insulin clearance rate. For the graded glucose infusion test, the researchers increased the glucose infusion rate every 40 minutes, from 1 mg/kg per minute up to 8 mg/kg per minute. Next, they divided the cohort of obese individuals into tertiles of insulin resistance as quantified by the steady-state plasma glucose (SSPG): less than 9.7 mmol/L (tertile 1), 9.7-12.7 mmol/L (tertile 2), and 12.8 mmol/L or greater (tertile 3).
The mean age of subjects was 54 years. The mean SSPG level was 7.2 mmol/L among subjects in tertile 1, 11.3 mmol/L among those in tertile 2, and 14.3 mmol/L among those in tertile 3. The remainder of the demographics was similar. “Most importantly, body mass index among tertiles was nearly identical,” Dr. Kim said. “The only biomarker that was different was ALT, which increased with increasing tertiles. The individuals who were more insulin resistant likely had more fatty liver. We didn’t do imaging in this particular study.”
When the researchers evaluated oral glucose tolerance test data, they observed that subjects who were most insulin resistant had slightly higher glucose levels, “which we often see,” she said. “The body does try to keep glucose in a narrow range. What was dramatic were the insulin levels. The most insulin-resistant subjects had insulin levels that were double those of the least insulin-resistant subjects in tertile 1 during the oral glucose tolerance test.”
During the intravenous glucose infusion test, glucose levels rose similarly in the three groups, but those in tertile 3 had slightly higher glucose levels (P = .04). The insulin secretion rate, meanwhile, was similar among subjects in tertiles 1 and 2 but was increased significantly among subjects in tertile 3 (P less than .001). In contrast, the researchers observed a stepwise decline in insulin clearance rate from tertiles 1 to 3. Thus the insulin clearance rate was significantly different between subjects in tertile 1 and tertile 2 (P = .04) as well as between subjects in tertile 2 and those in tertile 3 (P less than .001).
“We propose that insulin resistance leads to an increase in intrahepatic fat, which decreases the insulin clearance rate and helps maintain euglycemia,” Dr. Kim concluded. “In the most insulin-resistant tertile, a decrease in insulin clearance rate is not sufficient, and an increase in the insulin secretion rate is also required. If you look at the relationship between insulin resistance and insulin clearance rate, there is a negative correlation, so the more insulin resistant you are, the lower your insulin clearance rate. However, there are insulin-resistant individuals who perhaps have higher insulin clearance rates than we think they should have. Could those individuals be at the highest risk to develop diabetes? That’s the story to which I don’t yet have an ending.” She reported having no financial disclosures.
SOURCE: Jung SH et al. Diabetologia. 2018;61(3):681-7.
LOS ANGELES – As obese, nondiabetic individuals become more insulin resistant, a decrease in insulin clearance is the first change to occur, according to Sun H. Kim, MD.
“You will often hear about how insulin resistance enhances demand on beta cells to increase insulin secretion, which leads to hyperinsulinemia,” Dr. Kim said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “While well accepted, this model ignores the role of insulin clearance rate in maintaining hyperinsulinemia in insulin resistance states.”
In an effort to understand the physiologic adaptation to insulin resistance prior to the development of type 2 diabetes mellitus, Dr. Kim, an associate professor of endocrinology at Stanford (Calif) University, Stanford, and her colleagues enrolled 91 adults who had a body mass index of at least 30 kg/m2. The study was published in the March 2018 issue of Diabetologia. Each subject underwent a 75-g oral glucose tolerance test as well as the insulin suppression test to measure insulin resistance and the graded glucose infusion test to determine each subject’s insulin secretion rate and insulin clearance rate. For the graded glucose infusion test, the researchers increased the glucose infusion rate every 40 minutes, from 1 mg/kg per minute up to 8 mg/kg per minute. Next, they divided the cohort of obese individuals into tertiles of insulin resistance as quantified by the steady-state plasma glucose (SSPG): less than 9.7 mmol/L (tertile 1), 9.7-12.7 mmol/L (tertile 2), and 12.8 mmol/L or greater (tertile 3).
The mean age of subjects was 54 years. The mean SSPG level was 7.2 mmol/L among subjects in tertile 1, 11.3 mmol/L among those in tertile 2, and 14.3 mmol/L among those in tertile 3. The remainder of the demographics was similar. “Most importantly, body mass index among tertiles was nearly identical,” Dr. Kim said. “The only biomarker that was different was ALT, which increased with increasing tertiles. The individuals who were more insulin resistant likely had more fatty liver. We didn’t do imaging in this particular study.”
When the researchers evaluated oral glucose tolerance test data, they observed that subjects who were most insulin resistant had slightly higher glucose levels, “which we often see,” she said. “The body does try to keep glucose in a narrow range. What was dramatic were the insulin levels. The most insulin-resistant subjects had insulin levels that were double those of the least insulin-resistant subjects in tertile 1 during the oral glucose tolerance test.”
During the intravenous glucose infusion test, glucose levels rose similarly in the three groups, but those in tertile 3 had slightly higher glucose levels (P = .04). The insulin secretion rate, meanwhile, was similar among subjects in tertiles 1 and 2 but was increased significantly among subjects in tertile 3 (P less than .001). In contrast, the researchers observed a stepwise decline in insulin clearance rate from tertiles 1 to 3. Thus the insulin clearance rate was significantly different between subjects in tertile 1 and tertile 2 (P = .04) as well as between subjects in tertile 2 and those in tertile 3 (P less than .001).
“We propose that insulin resistance leads to an increase in intrahepatic fat, which decreases the insulin clearance rate and helps maintain euglycemia,” Dr. Kim concluded. “In the most insulin-resistant tertile, a decrease in insulin clearance rate is not sufficient, and an increase in the insulin secretion rate is also required. If you look at the relationship between insulin resistance and insulin clearance rate, there is a negative correlation, so the more insulin resistant you are, the lower your insulin clearance rate. However, there are insulin-resistant individuals who perhaps have higher insulin clearance rates than we think they should have. Could those individuals be at the highest risk to develop diabetes? That’s the story to which I don’t yet have an ending.” She reported having no financial disclosures.
SOURCE: Jung SH et al. Diabetologia. 2018;61(3):681-7.
REPORTING FROM WCIRDC 2018
Key clinical point:
Major finding: In the most insulin-resistant subgroup, the insulin secretion rate increases and the insulin clearance rate decreases to compensate for insulin resistance.
Study details: A study of 91 obese adults without diabetes.
Disclosures: Dr. Kim reported having no disclosures.
Source: Jung SH et al. Diabetologia. 2018;61(3):681-7.