Heart Failure Considerations of Antihyperglycemic Medications for Type 2 Diabetes

Abstract

Prevalent and incident heart failure (HF) is increased in people with type 2 diabetes mellitus, with riskdirectly associated with the severity of hyperglycemia. Furthermore, in patients with type 2 diabetes mellitus, mortality is increased ≈10-fold in patients with versus without HF. Reducing HF with antihyperglycemic therapies, however, has been unsuccessful until recently. In fact, HF as an important outcome in patients with type 2 diabetes mellitus seems to be heterogeneously modulated by antihyperglycemic medications, as evidenced by results from cardiovascular outcome trials (CVOTs) and large observational cohort studies. Appropriately powered and executed CVOTs are necessary to truly evaluate cardiovascular safety and efficacy of new antihyperglycemic medications, as reflected by the guidance of the US Food and Drug Administration and other regulatory agencies since 2008. In light of the best available evidence at present, metformin and the sodium-glucose-co-transporter 2-inhibitor empagliflozin seem to be especially advantageous with regard to HF effects, with their use associated with reduced HF events and improved mortality. Acarbose, the dipeptidyl-peptidase 4-inhibitor sitagliptin, the glucagon-like peptide 1-receptor agonist lixisenatide based on presently available CVOT results comprise reasonable additional options, as significant harm in terms of HF has been excluded for those drugs. Additions to this list are anticipated pending results of ongoing CVOTs. Although no HF harm was seen in CVOTs for insulin or sulfonylureas, they should be used only with caution in patients with HF, given their established high risk for hypoglycemia and some uncertainties on their safety in patients with HF derived from epidemiological observations. Pioglitazone is contraindicated in patients with HF>New York Heart Association I, despite some benefits suggested by CVOT subanalyses. (

Mortality Reduction Associated With β-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes

“…More than one-third of these people will also suffer from diabetes (3,4). A recent study of 1.9 million individuals demonstrated that CHF was second only to peripheral artery disease as a cardiovascular complication of type 2 diabetes (5).…”

GLP-1 receptor agonists and heart failure in diabetes

“…Diabetes may also cause cardiac dysfunction in the absence of overt macrovascular disease due to hyperglycaemia-related cardiomyopathy, even in patients in type 1 diabetes [3]. HF is of major interest as it is the one cardiovascular outcome for which the risk has unequivocally been shown to be increased by some glucose-lowering therapies, particularly thiazolidinediones (glitazones) [4,5], whereas metformin appears to be safe [6]. Recently, some concerns have also been raised with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin, following the publication of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) -Thrombolysis in Myocardial Infarction (TIMI) 53 trial [7], a finding that casts some suspicion on the entire incretin-based pharmacological class [8][9][10].…”

Prevalent and Incident Heart Failure in Cardiovascular Outcome Trials of Patients With Type 2 Diabetes

“…Concomitant presence of both conditions worsens prognosis and complicates treatment. Moreover, data suggest strict glycemic control may not meaningfully change risk of HF in patients with DM and multiple trials of glucose lowering therapies have now been associated with increased or decreased risk of HF events, compared with placebo (13–18). …”

“…Although recent publications have emphasized the need for improved description of HF events in DM trials, HF data capture within such trials has not been systematically characterized (18–20). We present a systematic review of the ascertainment of baseline HF, incident HF, and reporting of HF-related clinical events within published clinical trials of glucose lowering therapies.…”