Elsevier

The Lancet

Volume 385, Issue 9982, 23–29 May 2015, Pages 2107-2117
The Lancet

Review
Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy

https://doi.org/10.1016/S0140-6736(14)61402-1Get rights and content

Summary

Individuals with diabetes are not only at high risk of developing heart failure but are also at increased risk of dying from it. Fortunately, antiheart failure therapies such as angiotensin-converting-enzyme inhibitors, β blockers and mineralocorticoid-receptor antagonists work similarly well in individuals with diabetes as in individuals without the disease. Response to intensive glycaemic control and the various classes of antihyperglycaemic agent therapy is substantially less well understood. Insulin, for example, induces sodium retention and thiazolidinediones increase the risk of heart failure. The need for new glucose-lowering drugs to show cardiovascular safety has led to the unexpected finding of an increase in the risk of admission to hospital for heart failure in patients treated with the dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo. Here we review the relation between glycaemic control and heart failure risk, focusing on the state of knowledge for the various types of antihyperglycaemic drugs that are used at present.

Introduction

Not fitting neatly into the microvascular or macrovascular categories, heart failure, despite its frequency, morbidity, and high mortality rate has been relegated to an inferior position in the hierarchy of diabetes complications. This drawback, combined with the emphasis on the glucose-lowering effects of antihyperglycaemic drugs rather than their ability to reduce the long-term complications of diabetes, has led to uncertainty about the effect of diabetes pharmacotherapy on the development and progression of heart failure. Here, we review what is known about the effect of blood glucose lowering and the use of the many different classes of antihyperglycaemic drugs that we have at our disposal.

Section snippets

Epidemiology

As first reported in 1974 in the Framingham studies,1 diabetes confers roughly a two-fold increase in risk of heart failure in men and five-fold higher risk in women. Indeed, the UK Prospective Diabetes Study2 (UKPDS) reported the incidence of hospital admission for heart failure was similar to non-fatal myocardial infarction and non-fatal stroke. As with stroke and myocardial infarction, the presence of diabetes also portends a poor prognosis in a heart-failure setting in which mortality rates

Pathogenesis

The pathogenesis of heart failure in diabetes is multifactorial but can largely be attributed to a cardiotoxic tetrad of coronary artery disease, hypertension, diabetic cardiomyopathy and extracellular fluid volume expansion.9 Individuals with diabetes characteristically develop atherosclerotic coronary artery disease at an early age that is also more likely to include many and distal coronary segments.16 In combination with their more widespread disease, patients with diabetes develop fewer

Glycaemic control

Observational studies examining the effect of glycaemic control suggest a positive effect on the primary prevention of heart failure. In the UKPDS,24 which studied patients with newly diagnosed diabetes, a log-linear relation between heart-failure risk and long-term glycaemic control was evident such that a 1% reduction in haemoglobin A1c (HbA1c) was associated with a 16% risk reduction in the development of heart failure (figure 2).

Although observational studies suggest that intensive

Thiazolidinediones

The thiazolidinediones, rosiglitazone and pioglitazone, were approved by the US Food and Drug Administration (FDA) in 1999 and by the European Medicines Agency in 2000. At the time of their approval, these drugs were known to be associated with both fluid retention and an increased risk of heart failure.31 Accordingly, patients with New York Heart Association (NYHA) class III and IV disease were mostly excluded from the pivotal safety and efficacy trials, and although patients with class I or

Major outcome trials with DPP4 inhibitors

So far, two large DPP4-placebo comparator, cardiovascular outcome trials and a smaller mechanistic study in heart failure patients have been reported.

The SAVOR-TIMI 53 trial54 compared the DPP4 inhibitor, saxagliptin, with placebo in the setting of patients with a history of, or who are at risk of, cardiovascular events. No overall effect of saxagliptin versus placebo occurred on the primary endpoint of time-to-first-event of cardiovascular death, myocardial infarction, or ischaemic stroke.

Insulin

The association between insulin treatment and heart failure is complex not only because of the drug's effects on renal sodium handling but also as a result of the tendency to use it late in the course of type 2 diabetes where patients older than 60 years with increased duration of disease will be more prone than younger people to developing heart failure.

Extensive oedema is a well recognised but rare complication of insulin treatment that was first reported in 1928, not long after the treatment

Sodium-glucose linked cotransporter-2 inhibitors

By contrast with the thiazolidinediones that lead to a roughly 3% decrease in haematocrit, inhibitors of the sodium-glucose linked cotransporter-2 (SGLT2) result in a roughly 3% increase in haematocrit, suggestive of volume contraction. Since fluid overload is a key precipitant for heart failure deterioration, and diuretics are routine therapy in heart failure, a drug that provides volume reduction, such as an SGLT2 inhibitor, might be beneficial. Support of this notion is evident in the pooled

Conclusion

Guidance to industry for new drug approval needs proof that the therapy will not result in an unacceptable increase in cardiovascular risk. In an attempt to avoid interpretion of cardiovascular disease too broadly, the FDA has underlined the standard definition of MACE (major adverse cardiovascular events: cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) with or without unstable angina as an appropriate outcome in both registration and postmarketing trials.106

Search strategy and selection criteria

Focusing predominantly on original research articles published with abstracts in English, we searched publications in PubMed and Google Scholar between Dec 12, 2013, and March 19, 2015, with the search terms “diabetes”, “treatment”, “heart failure”, and “oedema”. We also searched ClinicalTrials.gov for information on present clinical trials in type 2 diabetes that included assessments of cardiac function.

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