Antihypertensive therapy, new-onset diabetes, and cardiovascular disease

Type 2 diabetes mellitus is a worldwide epidemic with considerable health and economic consequences. Diabetes is an important risk factor for cardiovascular disease, which is the leading cause of death in diabetic patients, and decreasing the incidence of diabetes may potentially reduce the burden of cardiovascular disease. This article discusses the clinical trial evidence for modalities associated with a reduction in the risk of new-onset diabetes, with a focus on the role of antihypertensive agents that block the renin–angiotensin system. Lifestyle interventions and the use of antidiabetic, anti-obesity, and lipid-lowering drugs are also reviewed. An unresolved question is whether decreasing the incidence of new-onset diabetes with non-pharmacologic or pharmacologic intervention will also lower the risk of cardiovascular disease. A large ongoing study is investigating whether the treatment with an oral antidiabetic drug or an angiotensin-receptor blocker will reduce the incidence of new-onset diabetes and cardiovascular disease in patients at high risk for developing diabetes

Rationale and design of REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Residual cardiovascular risk persists despite statins, yet outcome studies of lipid‐targeted therapies beyond low‐density lipoprotein cholesterol (LDL‐C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High‐dose eicosapentaenoic acid (EPA) reduces triglyceride‐rich lipoproteins without raising LDL‐C. Omega‐3s have postulated pleiotropic cardioprotective benefits beyond triglyceride‐lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE‐IT; NCT01492361) is a phase 3b randomized, double‐blinded, placebo‐controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA, vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin‐treated patients with high triglycerides at elevated cardiovascular risk. REDUCE‐IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150 mg/dL and 40 mg/dL and ≤100 mg/dL with stable statin (± ezetimibe) ≥4 weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow‐up will continue in this event‐driven trial until approximately 1612 adjudicated primary‐efficacy endpoint events have occurred

Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: A report from the DPP Outcomes Study

AIMS: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group. METHODS: This long-term follow-up (median 10 years, interquartile range 9.0–10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually. RESULTS: After 10 years’ follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (2–3 mmHg) and diastolic (5–6 mmHg) blood pressure, and for LDL cholesterol (0.47–0.54 mmol/l) and triglycerides (0.18–0.32 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.13–0.16 mmol/l) in all groups. Lipid (P < 0.012) and blood pressure (P < 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study. CONCLUSION: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups. (Clinical Trials Registry No; NCT 00038727)

Statins for the primary prevention of cardiovascular disease.

BACKGROUND: Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of CVD is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with CVD. The case for primary prevention was uncertain when the last version of this review was published (2011) and in light of new data an update of this review is required. OBJECTIVES: To assess the effects, both harms and benefits, of statins in people with no history of CVD. SEARCH METHODS: To avoid duplication of effort, we checked reference lists of previous systematic reviews. The searches conducted in 2007 were updated in January 2012. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2022, Issue 4), MEDLINE OVID (1950 to December Week 4 2011) and EMBASE OVID (1980 to 2012 Week 1).There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of statins versus placebo or usual care control with minimum treatment duration of one year and follow-up of six months, in adults with no restrictions on total, low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted data. Outcomes included all-cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), revascularisation, change in total and LDL cholesterol concentrations, adverse events, quality of life and costs. Odds ratios (OR) and risk ratios (RR) were calculated for dichotomous data, and for continuous data, pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated. We contacted trial authors to obtain missing data. MAIN RESULTS: The latest search found four new trials and updated follow-up data on three trials included in the original review. Eighteen randomised control trials (19 trial arms; 56,934 participants) were included. Fourteen trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (OR 0.86, 95% CI 0.79 to 0.94); as was combined fatal and non-fatal CVD RR 0.75 (95% CI 0.70 to 0.81), combined fatal and non-fatal CHD events RR 0.73 (95% CI 0.67 to 0.80) and combined fatal and non-fatal stroke (RR 0.78, 95% CI 0.68 to 0.89). Reduction of revascularisation rates (RR 0.62, 95% CI 0.54 to 0.72) was also seen. Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no evidence of any serious harm caused by statin prescription. Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event. AUTHORS' CONCLUSIONS: Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins