Management of heart failure in the context of type 2 diabetes

Abstract The global prevalence of diabetes was almost 250 million individuals in 2017, which is almost 9% of the adult population worldwide. However, with the growing worldwide obesity epidemic, diabetes is becoming even more prevalent. Cardiovascular disease is the most life-threatening of diabetic complications, and diabetics are two to four times more likely to die of cardiovascular-related causes than nondiabetics are. Much improved and earlier primary prevention strategies for cardiovascular health have resulted in a decline in some adverse cardiovascular events though this is not the case with heart failure. Type 2 diabetes and heart failure remain the most prevalent chronic conditions affecting the aging population and we believe that the future global health and economic burden of these two diseases represent a significant and growing public health concern. Here, we assess a variety of contemporary antidiabetic medicines and evaluate their impact on cardiovascular risk. The timing of this review is appropriate given that the FDA has recently announced the availability of updated draft guidance for industry “Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control” to replace the previous guidances for industry, published over a decade ago. Current guidelines for managing patients with heart failure in the context of type 2 diabetes advocate for simultaneously targeting glycemic control and aggressively managing cardiovascular risk factors, particularly blood pressure and dyslipidemia while implementing lifestyle modifications for obesity/overweight and smoking cessation to achieve optimal clinical outcomes. The contemporary antidiabetic medicines metformin, sodium-glucose cotransport 2 inhibitors, and certain glucagon-like peptide 1 receptor agonists may have beneficial effects on cardiovascular outcomes including heart failure, while the sulfonylureas, thiazolidinediones, some glucagon-like peptide 1 receptor agonists and some dipeptidyl peptidase 4 inhibitors may actually increase risk. Interestingly, whatever glucose-lowering paradigm is employed, it appears that good glycemic control immediately following diabetes diagnosis is associated with a reduced risk of future diabetic complications. Undiagnosed diabetes and delayed treatment initiation reduce the effectiveness of any pharmacotherapy once implemented increasing the occurrence of adverse legacy effects. At present, both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are widely prescribed for the management of hypertension that predisposes to heart failure in diabetic patients. Generally, these drugs are considered first in the management of hypertension and are frequently preferred to beta-blockers because beta-blockers may mask the symptoms of an acute stress response to a hypoglycemic episode. The use of inexpensive thiazide diuretics, either alone or in combination in the management of hypertension in patients with type 2 diabetes has been challenged because of associated adverse metabolic events, including dyslipidemia, worsening glucose control in type 2 diabetes and of new-onset diabetes in nondiabetic patients. Moving forward, in order to slow down the rising incidence of type 2 diabetes and coexistent heart failure, a multifactorial approach is most likely to be most beneficial. This approach could leverage our improved understanding of the metabolic changes implicated in the development of diabetic cardiomyopathy and heart failure to identify novel intervention targets for new pharmacotherapies. Pharmacotherapies that reduce cellular fatty acid uptake, fatty acid entry into the mitochondria or inhibit mitochondrial fatty acid oxidation may be beneficial, as may those that increase glucose oxidation either directly or indirectly or inhibit the hexosamine biosynthetic pathway to reduce protein O-GlcNAcylation. Affordable, novel pharmacotherapies that target heart metabolism to reduce cardiovascular risk factors and facilitate glycemic control may constitute a significant addition to the drug armamentarium for heart failure management in the context of type 2 diabetes.