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.

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 intensivetherapy 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.

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 glucoselowering 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.

Cardiovascular risk factors and incident albuminuria in screen-detected type 2 diabetes.

BACKGROUND: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria five years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management. METHODS: In 1,826 participants with newly diagnosed, screen-detected diabetes without albumiuria, we explored associations between risk of new albuminuria (≥2.5 mg mmol(-1) males and ≥3.5 mg mmol(-1) females) and: 1) baseline cardio-metabolic risk factors and 2) changes from baseline to one year in systolic blood pressure (∆SBP) and glycated haemoglobin (∆HbA1c ) using logistic regression. RESULTS: Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in the five years after detection of diabetes. In a model adjusted for age, gender, and baseline HbA1c and blood pressure, a 1% decrease in HbA1c and 5 mmHg decrease in SBP during the first year were independently associated with lower risks of albuminuria (Odds Ratio (OR), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively). Further adjustment did not materially change these estimates. There was no interaction between ΔSBP and ΔHBA1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease. CONCLUSIONS: Baseline measurements and changes in HbA1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria four years later. Established multifactorial treatment for diabetes applies to cases identified through screening.Individual centres in Denmark, the Netherlands and the United Kingdom were responsible for funding. ADDITION-Denmark has been given unrestricted grants from Novo Nordisk AS, Novo Nordisk Scandinavia AB, Novo Nordisk U.K., AstraZeneca Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, Servier Denmark A/S, and HemoCue Denmark A/S. Part of the grant from Novo Nordisk was transferred to the other centers. ADDITIONNetherlands was supported by unrestricted grants from Novo Nordisk, GlaxoSmithKline, and Merck. ADDITION-Cambridge was supported by the Wellcome Trust (grant reference no: G061895) and the Medical Research Council (grant reference no: G0001164), the National Institute for Health Research (NIHR) Health Technology Assessment Programme (grantcare.diabetesjournals.org Sandbæk and Associates 2021 reference no: 08/116/300), and National Health Service research and development support funding (including the Primary Care Research and DiabetesResearch Networks), and the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0606-1259). ADDITION-Leicester was supported by the Department of Health and Support for Sciences, the NIHR Health Technology Assessment Programme (grant reference no: 08/116/300), National Health Service research and development support funding (including the Primary Care Research and Diabetes Research Networks Leicestershire, Northamptonshire and Rutland Collaborative for Leadership in Applied Health Research and Care) and the NIHR Leicester Loughborough Lifestyle Biomedical Research Unit. ADDITION-Netherlands was supported by the Julius Centre for Health Sciences and Primary Care, University Medical Centre, Utrecht and by unrestricted grants from Novo Nordisk and Glaxo Smith Kline

Has carbohydrate-restriction been forgotten as a treatment for diabetes mellitus? A perspective on the ACCORD study design

Prior to the discovery of medical treatment for diabetes, carbohydrate-restriction was the predominant treatment recommendation to treat diabetes mellitus. In this commentary we argue that carbohydrate-restriction should be reincorporated into contemporary treatment studies for diabetes mellitus

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal