Hertzel Gerstein

Effects of Cardiac Autonomic Dysfunction on Mortality Risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial

OBJECTIVE Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. RESEARCH DESIGN AND METHODS CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates. RESULTS During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55–2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P < 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (Pinteraction > 0.7). CONCLUSIONS Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

Effect of Rosiglitazone on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History Trial

Background— Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. Methods and Results— This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (−0.64%; 95% confidence interval, −1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (−5.1 mm3; 95% confidence interval, −10.0 to −0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (−1.7 mm3; 95% confidence interval, −3.9 to 0.5; P=0.13). Conclusions— Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique Identifier: NCT00116831.

Glycosylated Hemoglobin: Finally Ready for Prime Time as a Cardiovascular Risk Factor

More than 17 million people in the United States currently have diabetes, and this number is rapidly increasing (1). Affected individuals are at high risk for premature death as well as eye, kidney, nerve, cardiovascular, and other chronic diseases. Thus, the annual estimated costs of diabetes exceeded

Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study

130 billion in 2002 (2)an increase of greater than 30% since 1998 (3). This societal burden, and evidence that the diabetes epidemic is being fueled by our current lifestyle (4, 5), means that diabetes is now an urgent public health problem. But diabetes is just the measured tip of a much larger dysglycemic iceberg. Diabetes is diagnosed when the fasting plasma glucose level is consistently 7 mmol/L or greater ( 126 mg/dL) or when the 2-hour plasma glucose level (after drinking a 75-g glucose load) is consistently 11.1 mmol/L or greater ( 200 mg/dL). These thresholds are much higher than the normal fasting and 2-hour mean glucose levels of 5.1 mmol/L (92 mg/dL) and 5.4 mmol/L (97 mg/dL), respectively (6). These levels were chosen because they effectively differentiated individuals at high risk for eye disease from individuals at low risk (7). They were not chosen on the basis of risk for cardiovascular disease; as such, there is no a priori reason to believe that they would differentiate people at high versus low risk for cardiovascular disease. Indeed, it is now clear that fasting or 2-hour glucose levels that are well below the diabetes cutoffs are cardiovascular risk factors (8, 9) and that a progressive relationship between glucose and cardiovascular risk extends from normal glucose levels right into the diabetes range with no clear lower threshold (9, 10). Glycosylated hemoglobin is an easily measured biochemical marker that strongly correlates with the level of ambient glycemia during a 2- to 3-month period. As such, it (or hemoglobin A1c, a specific type of glycosylated hemoglobin) reflects the usual daily fasting and postprandial glucose levels. Tests for glycosylated hemoglobin are also inexpensive and can be done at any time of day. The level of glycosylated hemoglobin is strongly linked to risk for incident eye, kidney, and nerve disease in people with type 1 and type 2 diabetes mellitus. Moreover, randomized trials have clearly shown that decreasing the glycosylated hemoglobin level reduces these risks (11, 12). It is therefore a valuable progressive and responsive risk factor for eye, kidney, and nerve disease in people with diabetes. Two studies reported in this issue carefully examine whether glycosylated hemoglobin is also a progressive risk factor for cardiovascular disease in people with diabetes, as well as in people without diabetes (that is, akin to the glucose level). Selvin and colleagues (13) performed a careful meta-analysis of 10 cohort studies involving 7435 people with type 2 diabetes and 3 cohort studies involving 1688 people with type 1 diabetes. For type 2 diabetes, a 1percentage point absolute increase in glycosylated hemoglobin was associated with a significant 18% (95% CI, 10% to 26%) increase in the risk for coronary heart disease or stroke and a 28% increase in the risk for peripheral vascular disease. A similar but nonsignificant relationship was noted for type 1 diabetes. These data highlight the utility of the glycosylated hemoglobin level as a measure of risk for cardiovascular events in type 2 diabetes and suggest that it may also reflect cardiovascular risk in people with type 1 diabetes. Khaw and colleagues (14) carefully analyzed the relationship of 1 hemoglobin A1c measurement to incident cardiovascular events in a 6-year cohort study of 10 232 diabetic and nondiabetic men and women age 45 to 79 years. After adjustment for systolic blood pressure, cholesterol level, body mass index, waist-to-hip ratio, smoking, and previous myocardial infarction or stroke, there was a 21% increase in cardiovascular events for every 1percentage point increase in hemoglobin A1c level above 5% (P< 0.001). Similar relationships were observed for total mortality (22% for men [P< 0.001] and 28% for women [P< 0.01] per 1percentage point increase in hemoglobin A1c level). When both diabetes and the actual hemoglobin A1c level were included in statistical models, only the hemoglobin A1c level (and not diabetes) remained a significant predictor of incident cardiovascular events or death (implying that a hemoglobin A1c level of 6.59% in a nondiabetic individual predicts a higher cardiovascular risk than a hemoglobin A1c level of 5.5% in a well-controlled diabetic individual). Finally, even after individuals with a hemoglobin A1c level of 7% or greater, diabetes, or heart disease were excluded, the increase in risk for coronary heart disease, cardiovascular disease, and total mortality for every 1percentage point increase in hemoglobin A1c was 40% (P= 0.002), 16% (P= 0.08), and 26% (P= 0.02), respectively. What can we conclude from these 2 reports? First, they clearly prove that the glycosylated hemoglobin level is an independent progressive risk factor for incident cardiovascular events, regardless of diabetes status. They also provide a robust estimate of this relationship: Every 1percentage point absolute increase above a clearly normoglycemic level predicts a 20% relative increase in the incidence of cardiovascular events. Second, these reports show that the glycosylated hemoglobin level can now be added to the list of other clearly established indicators of cardiovascular risk, such as blood pressure and cholesterol level. Thus, the presence or absence of diabetes is likely to become less important than the level of glycosylated hemoglobin in the assessment of cardiovascular risk (similar to the fact that a diagnosis of hyperlipidemia has become less important than the level of low-density lipoprotein cholesterol). Third, these descriptive data highlight the relevance of several ongoing clinical trials that are directly testing the possibility that reducing glycosylated hemoglobin levels in both diabetic and nondiabetic persons may also reduce cardiovascular risk. Finally, as noted by Khaw and colleagues (14), very small shifts in the general populations average hemoglobin A1c level (for example, 0.1% to 0.2%) could dramatically affect the future incidence of cardiovascular disease. Unfortunately, these small population shifts are happening now. The increasing prevalence of diabetes means that the average hemoglobin A1c level of the much larger nondiabetic population is probably increasing as well. This dysglycemia epidemic may therefore be the harbinger of a future epidemic of cardiovascular disease. But this epidemic is not inevitableit may be thwarted if we take action now. We know that lifestyle changes can dramatically reduce the incidence of diabetes and slow the hemoglobin A1c increase in both nondiabetic and diabetic individuals (15-17). Broadly adopted lifestyle changes should therefore reduce diabetes-related eye, kidney, and nerve disease. Regardless of whether these lifestyle changes are ultimately proven to reduce cardiovascular disease in our society, public health approaches to facilitate them urgently need to be implemented. Structural changes to our society that reduce caloric intake and increase physical activity today will lower hemoglobin A1c levels and reduce societys rates of diabetes, the consequences of diabetes, and possibly cardiovascular disease tomorrow. If we wait 5 years for the results of the ongoing cardiovascular trials before acting, and the results are positive, we may have to apply them far too late and in far too many individuals.

Combined intensive blood pressure and glycemic control does not produce an additive benefit on microvascular outcomes in type 2 diabetic patients

Aims: In an international prospective cohort study we assessed the relationship between glucose levels and incident cardiovascular events and death. Methods and results: 18,990 men and women were screened for entry into the DREAM clinical trial from 21 different countries. All had clinical and biochemical information collected at baseline, including an oral glucose tolerance test (OGTT), and were prospectively followed over a median (IQR) of 3.5 (3.0–4.0) years for incident cardiovascular (CV) events including coronary artery disease (CAD), stroke, congestive heart failure (CHF) requiring hospitalization, and death. After OGTT screening, 8000 subjects were classified as normoglycaemic, 8427 had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and 2563 subjects had newly diagnosed type 2 diabetes mellitus (DM). There were incident events in 491 individuals: 282 CAD, 54 strokes, 19 CHF, and 164 died. The annualized CV or death event rate was 0.79/100 person-years in the overall cohort, 0.51/100 person-years in normoglycaemics, 0.92/100 person-years among subjects with IFG and/or IGT at baseline, and 1.27/100 person-years among those with DM (p for trend <0.0001). Among all subjects, a 1 mmol/l increase in fasting plasma glucose (FPG) or a 2.52 mmol/l increase in the 2-h post-OGTT glucose was associated with a hazard ratio increase in the risk of CV events or death of 1.17 (95% CI 1.13–1.22). Conclusions: In this large multiethnic cohort, the risk of CV events or death increased progressively among individuals who were normoglycaemic, IFG or IGT, and newly diagnosed diabetics. A 1 mmol/l increase in FPG was associated with a 17% increase in the risk of future CV events or death. Therapeutic or behavioural interventions designed to either prevent glucose levels from rising, or lower glucose among individuals with dysglycaemia should be evaluated.

Diabetes Risk Among Overweight and Obese Metabolically Healthy Young Adults

A reduction of either blood pressure or glycemia decreases some microvascular complications of type 2 diabetes, and we studied here their combined effects. In total, 4733 older adults with established type 2 diabetes and hypertension were randomly assigned to intensive (systolic blood pressure less than 120 mm Hg) or standard (systolic blood pressure less than 140 mm Hg) blood pressure control, and separately to intensive (HbA1c less than 0.060) or standard (HbA1c 0.070-0.079) glycemic control. Prespecified microvascular outcomes were a composite of renal failure and retinopathy and nine single outcomes. Proportional hazard regression models were used without correction for type I error due to multiple tests. During a mean follow-up of 4.7 years, the primary outcome occurred in 11.4% of intensive and 10.9% of standard blood pressure patients (hazard ratio 1.08), and in 11.1% of intensive and 11.2% of standard glycemia control patients. Intensive blood pressure control only reduced the incidence of microalbuminuria (hazard ratio 0.84), and intensive glycemic control reduced the incidence of macroalbuminuria and a few other microvascular outcomes. There was no interaction between blood pressure and glycemic control, and neither treatment prevented renal failure. Thus, in older patients with established type 2 diabetes and hypertension, intensive blood pressure control improved only 1 of 10 prespecified microvascular outcomes. None of the outcomes were significantly reduced by simultaneous intensive treatment of glycemia and blood pressure, signifying the lack of an additional beneficial effect from combined treatment.

Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum.

OBJECTIVE To determine diabetes incidence over time among obese young adults without metabolic risk factors. RESEARCH DESIGN AND METHODS Incident diabetes during a median follow-up of 6.1 years was assessed among 33,939 young men (mean age 30.9 ± 5.2 years) of the Metabolic, Lifestyle and Nutrition Assessment in Young Adults cohort who were stratified for BMI and the number of metabolic abnormalities (based on the Adult Treatment Panel-III). Metabolically healthy (MH) obesity was defined as BMI ≥30 kg/m2 in the presence of normoglycemia, normal blood pressure, and normal levels of fasting triglyceride and HDL-cholesterol levels (n = 631). RESULTS A total of 734 new cases of diabetes were diagnosed during 210,282 person-years of follow-up. The incidence rate of diabetes among participants with no metabolic risk factors was 1.15, 2.10, and 4.34 cases per 1,000 person-years among lean, overweight, and obese participants, respectively. In a multivariable model adjusted for age, region of origin, family history of diabetes, physical activity, fasting plasma glucose, triglyceride level, HDL-cholesterol, systolic blood pressure, and white blood cell count, a higher diabetes risk was observed among MH-overweight (hazard ratio [HR] 1.89 [95% CI 1.25–2.86]; P < 0.001) and MH-obese (HR 3.88 [95% CI 1.94–7.77]; P < 0.001) compared with MH-normal weight subjects. There was no interaction between BMI and the number of metabolic abnormalities at enrollment in predicting diabetes risk. CONCLUSIONS Healthy metabolic profile and the absence of diabetes risk factors do not protect young adults from incident diabetes associated with overweight and obesity.

Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors’ Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.

Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors’ Expert Forum

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors’ Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.

Dysglycaemia, vasculopenia, and the chronic consequences of diabetes

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors’ Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association’s Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date.