Curriculum in Cardiology
Cardiovascular drugs that increase the risk of new-onset diabetes

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The prevalence of type 2 diabetes is increasing worldwide, and diabetes is a strong adverse prognostic factor among patients with cardiovascular (CV) disease. Four classes of drugs that are commonly used for CV risk reduction, statins, niacin, thiazide diuretics, and ß-blockers, have been shown to increase the risk of new-onset diabetes (NOD) by 9% to 43% in meta-analyses or large-scale clinical trials. Clinical predictors for drug-related NOD appear to be similar to the predictors that have been described for NOD unrelated to drugs: fasting blood glucose >100 mg/dL and features of the metabolic syndrome such as body mass index >30 kg/m2, serum triglycerides >150 mg/dL, and elevated blood pressure, among others. The mechanisms whereby these drugs increase the risk of NOD are incompletely understood, although different hypotheses have been suggested. Lifestyle intervention consisting of diet and exercise has been shown in multiple studies to reduce the risk of NOD by approximately 50%, with persistent benefit during long-term follow-up. In patients at high risk for NOD, niacin should be avoided, and for hypertension, an angiotensin-converting enzyme inhibitor or even a ß1-selective blocker might be a better choice than a standard ß-blocker. For thiazide diuretics and particularly statins, benefit in terms of CV event reduction outweighs the risk of NOD.

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Predictors of NOD

Studies in different populations have consistently identified the same cluster of risk factors for NOD. Impaired fasting glucose (IFG; defined as a fasting blood sugar from 100 to 125 mg/dL), a family history of diabetes, and features of the metabolic syndrome are associated with an increased risk of NOD.4 Lifestyle factors, low body mass index (BMI), diet, nonsmoking, moderate alcohol consumption, and regular physical activity were all associated with a reduced risk of NOD in a large cohort

Statins and NOD

In a meta-analysis of 13 large randomized placebo-controlled statin trials with 91,140 participants, of whom 4,278 developed diabetes during a mean follow-up of 4 years,8 statin treatment was associated with a 9% increased risk of diabetes (odds ratio [OR] 1.09, 95% CI 1.02-1.17). It was concluded from this meta-analysis that treatment for 225 patients with a statin for 4 years would result in one extra case of diabetes. The risk appeared to be similar for lipophilic and hydrophilic statins.

Niacin and NOD

The Coronary Drug Project was completed in 1975, but the results with respect to NOD were not published until 2013.26 During a mean follow-up of 6.2 years, the incidence of NOD was 11.4% in niacin-treated patients and 8.62% in the placebo group (HR 1.37, 95% CI 1.12-1.68, P = .012). Randomization to niacin treatment was associated with an increase in NOD both in those with a normal FBG at baseline (6.8% vs 4.9%, HR 1.41, 95% CI 0.97-2.05, P = .07) and in those with IFG (19.8% vs 15.2%, HR 1.34,

Thiazide diuretics and NOD

Shortly after the introduction of thiazide diuretics in the 1950s, it became apparent that they could worsen the control of established type 2 diabetes29 and increase the incidence of NOD.30 Despite this, thiazide diuretics continue to be recommended as first-line therapy for hypertension,31 although at lower doses than those used in the early trials. Calibrating the risk of NOD from clinical trials of antihypertensive drugs is complicated because the comparator drug is rarely placebo and may

ß-Blockers and NOD

ß-Blockers were recommended as first-line therapy for hypertensive patients with ischemic heart disease, according to the seventh Joint National Committee guidelines published in 2003.31 However, in the United Kingdom, ß-blockers have not been first- or second-line treatment since 2006.48 Recent meta-analyses suggest that for uncomplicated hypertension, compared with other antihypertensive drugs, ß-blockers are associated with an increased risk of stroke, especially in the elderly, with no

Prevention of drug-related NOD

Irrespective of whether or not drug-related NOD affects long-term CV risk, its prevention is important. New-onset diabetes increases the health care burden at both a population level and an individual level. The patient with NOD will likely require more medications, more medical visits, more laboratory tests, and glucose monitoring. In some health care systems, such a patient may have to pay more for health insurance. The cumulative effect of these changes is likely to worsen quality of life,

Acknowledgements

No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this work, the drafting and editing of the manuscript, and its final contents.

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    K.L.O. was supported by the program grant (1037903) from the National Health and Medical Research Council of Australia and a Grant-in-Aid (G 12S 6681) from the National Heart Foundation of Australia.

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