Cardiovascular protection by anti-diabetic drugs: key mechanisms and current clinical data

Diabetic cardiomyopathy is characterized by structural and functional alterations in the myocardium in patients with diabetes mellitus [1] and presents a significant and increasing health and economic burden [2]. In this section of Current Opinion in Pharmacology we present several up-to-date reviews on the cardiovascular and renal pharmacology of anti-diabetic drugs and how they can mediate cardiovascular protection. Several of these reviews focus on specific mechanisms of cardiovascular dysfunction in response to diabetes, and the knowns and unknowns of how anti-diabetic drugs reduce poor cardiovascular outcomes.

Chatham and colleagues from the University of Alabama at Birmingham [3] address an important mechanism occurring in hyperglycemia, where the increased presence of O-linked N-acetylglucosamine (O-GlcNAC) causes a post-translational modification of serine and threonine residues, known as O-GlcNAcylation. The regulatory mechanisms of O-GlcNAc homeostasis are numerous; the authors detail the known steps within the O-GlcNAcylation pathway that can be modified. Interestingly, although clear evidence exists for how these factors are modified, the results of these modifications on O-GlcNAc homeostasis is not always clear. This review utilizes a balanced approach that includes summative evidence for what is known concerning these modifications and what is still in need of further investigation. Most relevant is the examination of the pathological role of O-GlcNAc in diabetes, specifically in the cardiovascular system. O-GlcNAcylation of transcription factors, enzymes (including eNOS) and the kinase, AKT occur with diabetes and represent a key mechanism for vascular dysfunction. The heart is also directly affected as a result of increased O-GlcNAcylation via key mediators of calcium signaling, contractile and mitochondrial proteins. The authors conclude their review with a call for the necessary development of methodology that will further our understanding of O-GlcNAc during diabetes, and thus open up more therapeutic targets for the treatment of diabetic cardiomyopathy.

Wingar et al. from the East Tennessee State University, Johnson City Tennessee and the Veterans Affairs Medical Center, Mountain Home, Tennessee [4] discuss another important mechanism in the context of diabetic cardiomyopathy. Ataxia telangiectasia mutated kinase (ATM) is a cell cycle checkpoint regulator (G1/S) that is activated by genetic stressors such as reactive oxygen species (ROS) and double-strand DNA breaks. The authors compare ATM deficiency with diabetes, which have several shared pathological consequences. Thus, both these conditions converge to cause increased risk of heart failure. Though there are share mechanisms of ATM deficiency and diabetes in relation to heart failure, the specific role that ATM plays in diabetic patients is in need of further investigation as it may represent an important mediator in diabetic cardiomyopathy.

There is an intimate relationship between the autonomic nervous system (ANS) and both cardiovascular regulation and glucose metabolism. In their review [5], Espinoza and Boychuk the Department of Cellular and Integrative Physiology, University of Texas Health Science Center San Antonio, explore these relationships in the context of diabetes treatment. After detailing the functional anatomy of the ANS, the authors describe what is known about metabolic signal sensing, in that the cardiovascular system is affected from insulin, glucose, and leptin signals via the ANS. This places the brainstem as a key effector of the cardiometabolic consequences encountered during diabetes. The need for measurement of autonomic function in diabetic patients is apparent from this review, as current clinical evidence demonstrates a clear alteration in ANS function in diabetic patients. This is further detailed from the perspective of drugs used in diabetes treatment: metformin, incretins and sodium-glucose co-transporter inhibitors are presented in the context of how they affect neural circuits. The authors conclude with the idea that treatments for diabetes may fail to restore the ANS to a healthy state, and initiative toward further investigation of these pathways is imperative to the management of diabetes.

Key to diabetic cardiomyopathy is the involvement of metabolic imbalance. Nirengi and colleagues from The Ohio State University, Columbus, Ohio present a detailed discussion of substrate metabolism in the heart, including how the heart utilizes fatty acids and glucose to fuel its constant workload. Impaired glucose metabolism, increased dependency on fatty acid metabolism, and use of ketone bodies for energy occur in diabetic hearts, are described in detail in this review. The authors further describe the action of sodium-glucose transporter-2 (SGLT2) inhibitors on cardiac metabolism when used as a treatment for diabetes. SGLT2 inhibitors are able to reduce the risk of cardiovascular complications in diabetic patients, but this is only partially explained by glycemic control. As described in detail by the authors, SGLT2 inhibitors are able to increase ketone bodies and improve mitochondrial dysfunction. These processes are in need of further investigation in humans, but may represent important pathways in our understanding and treatment of diabetic cardiomyopathy.

Ray from the University of Pittsburgh School of Medicine provides a further review of SGLT2 inhibitors and their other cardioprotective actions. After demonstrating the clear cardiovascular benefit by summarizing recent clinical trials of SGLT2 inhibitors, mechanisms are discussed in detail. In agreement with the above review, data clearly indicate glucose control is only partially responsible for the reduction in cardiomyopathy endpoints by SGLT2 inhibitors. In addition, Ray provides a clear handling of the diuretic effect of SGLT2 inhibitors and suggests that this mechanism is also not responsible for the improvement in cardiovascular outcomes in diabetic patients. The review concludes with mechanisms that are possibly more important in this context, namely reduction of uric acid, direct effects on the heart, preservation of kidney function and magnesium deficiency.

Outcomes from another drug class, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are detailed in the review [8] from Vitale et al. from the Department of Clinical and Molecular Medicine, “La Sapienza” University, Rome, Italy Use of these drugs in diabetic patients has produced clear beneficial outcomes in renal function as detailed through a comprehensive summary by the authors. These results are supported by many animal studies of the action of GLP-1 and GLP-1 RAs, and detailed tables are provided. Moreover, mechanisms of these drugs on renal protection are discussed, including reduction in hyperglycemia, dyslipidemia and hypertension, as well as direct effects that mediate reduced oxidative stress, inflammation, and natriuresis via multiple affected pathways. The authors call attention to the fact that the clinical trials discussed in detail do not have kidney outcomes as their primary endpoint, and thus current and future trials will bring more light to this topic.

The prioritization of GLP1RAs and SGLT2 inhibitors versus metformin is discussed in an evidenced-based review [9] from the University of Dundee, Scotland, by Rena and colleagues. The authors detail the history of metformin use and focus on the continuing discovery of its mechanism of action, with works in progress nearly 100 years after its discovery. These include not only its effect on the liver, but inflammatory cells and the intestinal tract. A summary of the most recent findings of GLP1RAs and SGLT2 inhibitors is presented, followed by a necessary discussion of the “clinical equipoise” apparent by divergent guidelines for first-line treatment. The need for head-to-head trials of these drugs is made clear, including further examination of these novel drugs in nondiabetic patients.

It is clear from these exceptional review articles that treatment of diabetic cardiomyopathy with anti-diabetic drugs has advanced considerably, but much is yet to be known. Future studies on these mechanisms presented, including other protein targets, will hopefully help to reduce the cardiovascular disease burdens suffered by many diabetics.