Hertzel C. Gerstein

Effects of intensive glucose lowering in type 2 diabetes

BACKGROUND Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. METHODS In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. RESULTS At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). CONCLUSIONS As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Effects of intensive blood-pressure control in type 2 diabetes mellitus.

BACKGROUND There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. METHODS A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview

BACKGROUND High blood glucose concentration may increase risk of death and poor outcome after acute myocardial infarction. We did a systematic review and meta-analysis to assess the risk of in-hospital mortality or congestive heart failure after myocardial infarction in patients with and without diabetes who had stress hyperglycaemia on admission. METHODS We did two searches of MEDLINE for English-language articles published from 1966 to October, 1998, a computerised search of Science Citation Index from 1980 to September, 1998, and manual searches of bibliographies. Two searchers identified all cohort studies or clinical trials reporting in-hospital mortality or rates of congestive heart failure after myocardial infarction in relation to glucose concentration on admission. We compared the relative risks of in-hospital mortality and congestive heart failure in hyperglycaemic and normoglycaemic patients with and without diabetes. FINDINGS 14 articles describing 15 studies were identified. Patients without diabetes who had glucose concentrations more than or equal to range 6.1-8.0 mmol/L had a 3.9-fold (95% CI 2.9-5.4) higher risk of death than patients without diabetes who had lower glucose concentrations. Glucose concentrations higher than values in the range of 8.0-10.0 mmol/L on admission were associated with increased risk of congestive heart failure or cardiogenic shock in patients without diabetes. In patients with diabetes who had glucose concentrations more than or equal to range 10.0-11.0 mmol/L the risk of death was moderately increased (relative risk 1.7 [1.2-2.4]). INTERPRETATION Stress hyperglycaemia with myocardial infarction is associated with an increased risk of in-hospital mortality in patients with and without diabetes; the risk of congestive heart failure or cardiogenic shock is also increased in patients without diabetes.

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.

BACKGROUND Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drugs ability to prevent type 2 diabetes in individuals at high risk of developing the condition. METHODS 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. FINDINGS At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01). INTERPRETATION Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril : the HOPE randomized trial

The future rate of cardiovascular events can be predicted by several well-established risk factors. Even in the absence of classic risk factors, patients with renal disease have an elevated risk for cardiovascular disease (1, 2). This renalcardiovascular association is well established in patients with advanced renal insufficiency (2). It has also been reported in patients in the Hypertension Detection and Follow-up Program (HDFP) (3), in which a serum creatinine concentration greater than 133 mol/L (1.5 mg/dL) was a strong predictor of cardiovascular disease. However, HDFP included only patients with hypertension. In contrast, a recent analysis of data from the Framingham Study did not detect a relationship between mild renal insufficiency (defined as a serum creatinine concentration of 124 to 265 mol/L [1.4 to 3.0 mg/dL]) and cardiovascular events (4). The Heart Outcomes and Prevention Evaluation (HOPE) study investigated the effects of ramipril and vitamin E on major cardiovascular outcomes in 9297 patients at high risk, including those with serum creatinine concentrations up to 200 mol/L (2.3 mg/dL) (5-7). Our study examined the hypothesis that previous evidence of renal disease (that is, an elevated serum creatinine concentration 124 mol/L [ 1.4 mg/dL]) would independently predict future cardiovascular disease. Since the connection between renal and cardiovascular disease is known to exist in patients with diabetes mellitus and those with hypertension, we analyzed nondiabetic and normotensive patients separately. We also examined whether ramipril continued to be effective in patients with impaired renal function. This was done to determine whether the common clinical practice of withholding angiotensin-converting enzyme (ACE) inhibitors in patients with impaired renal excretory function is justified. Methods Patients The design and primary outcomes of the HOPE study have been described elsewhere (5-7). Briefly, men and women at least 55 years of age from 267 centers were included if they had objective evidence of vascular disease or diabetes combined with another cardiovascular risk factor. The main exclusion criteria were heart failure, intolerance of ACE inhibitors or vitamin E, a serum creatinine concentration greater than 200 mol/L (2.3 mg/dL), or dipstick-positive proteinuria (>1+). Patients were treated with ramipril, vitamin E, or placebo in a double-blind, 2 2 factorial design. Follow-up was 3.5 to 5.5 years (median, 4.5 years), and the primary outcome measure was the incidence of cardiovascular death, myocardial infarction, or stroke. Secondary outcome measures included total mortality, hospitalization for heart failure, and revascularization. At the time of randomization, urine albumin level and creatinine concentration were measured once in all patients at four central laboratories. The ratio of urine albumin to creatinine was calculated, and a value of at least 2 mg/mmol was defined as microalbuminuria. Serum creatinine concentration was measured in all patients at local laboratories at the time of randomization. Renal Insufficiency Recent data suggest that in patients older than 55 years of age, a serum creatinine concentration of at least 124 mol/L (1.4 mg/dL) is a good indicator of a glomerular filtration rate less than 80 mL/min (8). Therefore, before beginning this post hoc analysis, we used a serum creatinine concentration of at least 124 mol/L (1.4 mg/dL) to differentiate between patients with and those without renal insufficiency. We also estimated creatinine clearance from serum creatinine concentrations by using the CockcroftGault formula (8), which derives the value from creatinine concentration, age, and body weight (140 age [in years] body weight [in kg]/serum creatinine concentration [in mg/dL] 72 [in men] or 0.85 [in women]). For calculated creatinine clearance, an a priori value of 65 mL/min was arbitrarily chosen as a definite indicator of renal insufficiency. Statistical Analysis Baseline serum creatinine values were missing in 10 of 9297 patients who were randomly assigned to receive ramipril, 10 mg/d, or placebo. Only data from the original intention-to-treat analysis (5) were included in our study. We compared baseline characteristics in patients with and those without renal insufficiency by using chi-square tests for discrete variables and t-tests for continuous variables. Because the ratio of albumin to creatinine was not normally distributed, it was compared by using a Wilcoxon test. In the final analysis, time-to-event in each group was estimated by using Cox regression stratified by center; this was done because rates of renal insufficiency varied significantly by center (P=0.006) but event rates did not. Association by center was tested by using logistic regression for renal insufficiency and Cox regression for events. Center was treated as a fixed effect in these models (9). Multivariate models to predict events were developed by using Cox regression and a backward elimination technique, beginning with univariate significant risk factors, including age; sex; waist-to-hip ratio; body mass index; and history of hypertension, diabetes, coronary artery disease, peripheral vascular disease, smoking, ramipril use, and renal insufficiency. Age, body mass index, waist-to-hip ratio, and blood pressure were treated as continuous variables. All covariates were tested for possible confounding with renal insufficiency, but no such pattern was found. We used Cox regression models to assess the effect of randomization to ramipril after controlling for serum creatinine concentration. Statistical tests for interaction were done in the Cox regression analysis to determine whether the effect of ramipril differed in patients with and those without renal insufficiency. We classified patients according to quartiles of serum creatinine concentration and then determined the effect of renal insufficiency on risk for the primary outcome. To do this, we analyzed the rate of the primary outcome across quartiles using Cox regression and testing linearity of the hazard ratios (HRs). Creatinine clearance was also estimated from serum creatinine concentration by using the CockcroftGault formula (8). Because age is used to calculate this value, age was excluded from all multivariate analyses that included creatinine clearance as a variable. All analyses were done by using SAS software for Unix, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Baseline Characteristics of Patients with Renal Disease As shown in Table 1, 980 patients had a serum creatinine concentration at least 124 mol/L (1.4 mg/dL) and 8307 patients did not. Baseline variables did not differ between the placebo and ramipril subgroups. Compared with patients who had no evidence of renal insufficiency, those with renal insufficiency were older; were more likely to be male; and had a higher baseline prevalence of hypertension, coronary artery disease, peripheral vascular disease, low high-density lipoprotein cholesterol level, and use of antiplatelet and antihypertensive agents. Systolic blood pressure, urine albumin level, and waist-to-hip ratio were also higher in this group. Table 1. Baseline Characteristics of Patients with and Those without Renal Insufficiency Event Rates in Patients with Renal Insufficiency Renal insufficiency was an important predictor of the primary outcome for all patients, as well as for the ramipril and placebo groups separately. The extent to which renal insufficiency was associated with the primary outcome is shown in Figure 1 and Table 2. Most impressive is the fact that cardiovascular and all-cause mortality rates were nearly twice as high in patients with renal insufficiency (HR, 1.90 [95% CI, 1.53 to 2.36] and 1.83 [CI, 1.54 to 2.17], respectively, by Cox regression controlling for ramipril use; P<0.001 for both comparisons), as were hospitalizations for heart failure (HR, 2.11 [CI, 1.56 to 2.81]; P<0.001). This effect of renal insufficiency was also observed when calculated creatinine clearance was used instead of serum creatinine concentration (Table 3). Figure 1. Primary outcome, myocardial infarction, cardiovascular death, and all death for patients with a serum creatinine concentration less than 1.4 mg/dL (<124 mol/L) or at least 1.4 mg/dL ( 124 mol/L). Table 2. Outcomes in Patients with and Those without Renal Insufficiency Table 3. Outcomes in Patients with a Creatinine Clearance 65 mL/min or > 65 mL/min Analysis of the group risk for the primary outcome clearly showed that as serum creatinine concentration increases, so does cardiovascular risk. As shown in Figure 2, the incidence of the primary outcome increased with each quartile of serum creatinine concentration (P<0.001 for linear trend of HR across quartiles). Figure 2. Primary outcome according to quartiles of serum creatinine concentration. P P We performed a multivariate analysis to determine whether the observed relationship between the incidence of the primary outcome and renal insufficiency could be explained by the association of impaired renal function with the variables identified in Table 1. In this analysis, an elevated serum creatinine concentration and microalbuminuria were highly significant, independent renal risk factors for the aggregate primary outcome of cardiovascular death, myocardial infarction, or stroke (HR, 1.40 [CI, 1.16 to 1.69] and 1.59 [CI, 1.37 to 1.84], respectively; P<0.001 for both comparisons). Other factors that independently and significantly predicted the primary outcome measure were coronary artery disease (HR, 1.51 [CI, 1.22 to 1.85]), peripheral vascular disease (HR, 1.49 [CI, 1.29 to 1.70]), diabetes mellitus (HR, 1.42 [CI, 1.23 to 1.65]), male sex (HR, 1.20 [CI, 1.01 to 1.43]), 1-year increase in age (HR

Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus A Scientific Statement From the American Heart Association and the American Diabetes Association

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

Basal insulin and cardiovascular and other outcomes in dysglycemia

BACKGROUND The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested. METHODS We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups. RESULTS The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97). CONCLUSIONS When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE)

BACKGROUND Cardiovascular disease rates vary greatly between ethnic groups in Canada. To establish whether this variation can be explained by differences in disease risk factors and subclinical atherosclerosis, we undertook a population-based study of three ethnic groups in Canada: South Asians, Chinese, and Europeans. METHODS 985 participants were recruited from three cities (Hamilton, Toronto, and Edmonton) by stratified random sampling. Clinical cardiovascular disease was defined by history or electrocardiographic findings. Carotid atherosclerosis was measured with B-mode ultrasonography. Conventional (smoking, hypertension, diabetes, raised cholesterol) and novel risk factors (markers of a prothrombotic state) were measured. FINDINGS Within each ethnic group and overall, the degree of carotid atherosclerosis was associated with a higher prevalence of cardiovascular disease. South Asians had the highest prevalence of this condition compared with Europeans and Chinese (11%, 5%, and 2%, respectively, p=0.0004). Despite this finding, Europeans had more atherosclerosis (mean of the maximum intimal medial thickness 0.75 [0.16] mm) than South Asians (0.72 [0.15] mm), and Chinese (0.69 [0.16] mm). South Asians had an increased prevalence of glucose intolerance, higher total and LDL cholesterol, higher triglycerides, and lower HDL cholesterol, and much greater abnormalities in novel risk factors including higher concentrations of fibrinogen, homocysteine, lipoprotein (a), and plasminogen activator inhibitor-1. INTERPRETATION Although there are differences in conventional and novel risk factors between ethnic groups, this variation and the degree of atherosclerosis only partly explains the higher rates of cardiovascular disease among South Asians compared with Europeans and Chinese. The increased risk of cardiovascular events could be due to factors affecting plaque rupture, the interaction between prothrombotic factors and atherosclerosis, or as yet undiscovered risk factors.

Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes

BACKGROUND Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events. METHODS We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial. RESULTS Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups. CONCLUSIONS As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.).