Cardiology

Packer, M. (2018). “Worsening Heart Failure During the Use of DPP-4 Inhibitors: Pathophysiological Mechanisms, Clinical Risks, and Potential Influence of Concomitant Antidiabetic Medications.” JACC Heart Fail 6(6): 445-451.

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Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis. These potentially deleterious actions of DPP-4 inhibitors might not become clinically apparent if these drugs were to promote sodium excretion. However, the natriuretic effect of DPP-4 inhibitors is modest, because they act on the distal (rather than proximal) renal tubules. Accordingly, both clinical trials and observational studies have reported an increase in the risk of heart failure in patients with type 2 diabetes who were receiving DPP-4 inhibitors. This risk may be muted in trials with a high prevalence of metformin use or with low and declining background use of insulin and thiazolidinediones. Still, the most vulnerable patients (i.e., those with established heart failure) were not well represented in these studies. The only trial that specifically evaluated patients with pre-existing left ventricular dysfunction observed important drug-related adverse structural and clinical effects. In conclusion, an increased risk of worsening heart failure appears to be a class effect of DPP-4 inhibitors, even in patients without a history of heart failure. Additional clinical trials are urgently needed to elucidate the benefits and risks of DPP-4 inhibitors in patients with established left ventricular dysfunction.

Packer, M. (2018). “Potential mechanisms underlying differences in the effect of incretin-based antidiabetic drugs on the risk of major atherosclerotic ischemic events.” J Diabetes Complications 32(6): 616-617.

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Incretin-based drugs exert antihyperglycemic effects in type 2 diabetes by mimicking or potentiating the effects of glucagon-like peptide-1 (GLP-1), which acts on the pancreas to stimulate the release of insulin. Long-acting GLP-1 receptor agonists (e.g., exenatide, liraglutide and semaglutide) are resistant to endogenous degradation and produce prolonged stimulation of the GLP-1 receptor. Conversely, drugs that inhibit dipeptidyl peptidase-4 (DPP-4) (e.g., sitagliptin and saxagliptin) enhance the actions of endogenous GLP-1 and may also augment non-GLP-1 peptides that are normally degraded by DPP-4. Although the two classes of drugs are commonly considered to have similar effects, it is more useful to regard their actions as being distinct but overlapping. GLP-1 receptor agonists can produce substantially greater stimulation of the GLP-1 receptor than can be achieved by the potentiation of physiological levels of endogenous GLP-1 by DPP-4 inhibitors. In contrast, due to their enhancement of non-GLP-1 peptides, DPP-4 inhibitors produce additional biological effects that are likely to have clinical relevance. Most efforts to understand the similarities and differences between GLP-1 receptor agonists and DPP-4 inhibitors have focused on their actions to lower blood glucose. Presumably because of their greater capacity to enhance GLP-1 signaling, long-acting GLP-1 analogs produce a greater reduction in glycated hemoglobin than DPP-4 inhibitors.1 It is therefore noteworthy that, in large-scale cardiovascular outcome trials carried out in patients with clinically stable type 2 diabetes, treatment with GLP-1 receptor agonists (i.e., liraglutide, semaglutide and exenatide) for a median of 2–4 years have had favorable effects on the risk of major adverse cardiovascular events. Treatment with these drugs has decreased the combined risk of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, with the most marked effects being reported with semaglutide and the least pronounced effects being observed with exenatide (Table 1). In contrast, no benefit on the risk of atherosclerotic ischemic events has been observed in large-scale cardiovascular outcomes trials with the DPP-4 inhibitors (sitagliptin, saxagliptin and omarigliptin). Although the trials of the two types of incretin-based drugs were of similar size, design, duration and statistical power, DPP-4 inhibitors had no demonstrable influence on the combined risk of cardiovascular death, myocardial infarction and stroke. Why should two classes of antidiabetic drugs that both signal through the GLP-1 receptor exert different effects on the risk of major adverse cardiovascular outcomes? (Excerpt from text, p. 616; no abstract available.)

Packer, M. (2018). “Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium.” J Am Coll Cardiol 71(20): 2360-2372.

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Epicardial adipose tissue has unique properties that distinguish it from other depots of visceral fat. Rather than having distinct boundaries, the epicardium shares an unobstructed microcirculation with the underlying myocardium, and in healthy conditions, produces cytokines that nourish the heart. However, in chronic inflammatory disorders (especially those leading to heart failure with preserved ejection fraction), the epicardium becomes a site of deranged adipogenesis, leading to the secretion of proinflammatory adipokines that can cause atrial and ventricular fibrosis. Accordingly, in patients at risk of heart failure with preserved ejection fraction, drugs that promote the accumulation or inflammation of epicardial adipocytes may lead to heart failure, whereas treatments that ameliorate the proinflammatory characteristics of epicardial fat may reduce the risk of heart failure. These observations suggest that epicardial adipose tissue is a transducer of the adverse effects of systemic inflammation and metabolic disorders on the heart, and thus, represents an important target for therapeutic interventions.

Packer, M. (2018). “Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis.” Diabetes Obes Metab 20(6): 1361-1366.

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Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.

Packer, M. (2018). “The Alchemist’s Nightmare: Might Mesenchymal Stem Cells That Are Recruited to Repair the Injured Heart Be Transformed Into Fibroblasts Rather Than Cardiomyocytes?” Circulation 137(19): 2068-2073.

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The injection of mesenchymal stem cells into the injured myocardium to induce cardiac regeneration has yielded disappointing results, conceivably because cells with cardioreparative potential must be supplied for long periods of time to produce a salutary effect. Accordingly, investigators have devised ways of directing such cells to the heart on an ongoing basis: by enhancing the action of endogenous peptides that function as cardiac homing signals (eg, stromal cell-derived factor-1). Stromal cell-derived factor-1 is released during acute cardiac injury and heart failure, but it has a short half-life because of degradation by dipeptidyl peptidase-4. Inhibition of dipeptidyl peptidase-4 potentiates the actions of stromal cell-derived factor-1 and, theoretically, could enhance cardiac recovery. However, in large-scale trials in patients with type 2 diabetes mellitus, dipeptidyl peptidase-4 inhibitors have not reduced the risk of atherosclerotic ischemic events, and they have unexpectedly increased the risk of heart failure, most probably heart failure with a preserved ejection fraction. Such an outcome might be explained if the channeling of mesenchymal stem cells to the heart by the actions of stromal cell-derived factor-1 (especially from nearby adipose tissue) were followed by the transformation of these cells into fibroblasts rather than cardiomyocytes. This concern has been supported by experimental studies; the resulting fibrosis would be expected to exacerbate the pathophysiological derangements that lead to heart failure with a preserved ejection fraction. Given the widespread use of dipeptidyl peptidase-4 inhibitors, the possibility that these drugs potentiate the cardiac homing of mesenchymal stem cells that cause myocardial fibrosis (rather than repair) warrants further study.