Research Spotlight

Packer, M. (2018). “Should We Be Combining GLP-1 Receptor Agonists and SGLT2 Inhibitors in Treating Diabetes?” Am J Med 131(5): 461-463.

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Several lines of evidence provide a strong basis for the combined use of GLP-1 receptor agonists and SGLT2 inhibitors in the treatment of type 2 diabetes. Investigators have already argued for using these 2 classes of drugs in combination on the basis of their complementary benefits in large-scale clinical trials. SGLT2 inhibitors and GLP-1receptor agonists not only improve the control of blood glucose, blood pressure, and body weight, but also might act together to minimize the evolution and progression of diabetic nephropathy. Additionally, they reduce the risk of different types of clinically important adverse cardiovascular events, raising the possibility that combined therapy might produce more comprehensive benefits than when either type of drug is given alone. Simultaneous therapy with both classes might also neutralize several potentially deleterious actions of glucagon-like peptide-1 receptor agonists on the myocardium and on epicardial fat, which may underlie the risks of treatment with these drugs in patients with established heart failure. Despite these intriguing possibilities, no clinical trials have evaluated the long-term effects of combined use of the 2 drugs in patients with type 2 diabetes who are at meaningful cardiovascular risk. Given the commercial availability of these drugs and the fact that individual members of both classes have a Food and Drug Administration–approved indication to reduce cardiovascular risk, should we not know more about what happens when both classes of drugs are used together? (Excerpt from text, p. 462; no abstract available.)

Packer, M. (2018). “Response by Packer to Letter Regarding Article, “Activation and Inhibition of Sodium-Hydrogen Exchange Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure”.” Circulation 137(18): 1981-1982.

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In Response: I very much appreciate the kind comments from Drs Gazmuri and Karmazyn. I agree fully with their view that it is imperative to rekindle efforts to investigate the potential utility of inhibitors of the sodium-hydrogen exchanger isoforms 1 and 3 (NHE1 and NHE3) in the treatment of both heart failure and diabetes mellitus. That was my primary reason for writing the article. Drs Gazmuri and Karmazyn correctly note that the NHE1 inhibitor cariporide was shown to reduce myocardial injury and the short-term risk of cardiovascular death or injury in patients undergoing coronary artery bypass surgery. However, cariporide inhibited NHE1 in platelets and thereby increased their thrombogenic potential. Such an action likely explains the increased risk of stroke seen in postsurgical patients in a large-scale trial, because platelets are already marked activated in this clinical setting. The challenge for future development of NHE1 inhibitors is to minimize this thrombogenic effect, possibly by synthesizing analogs that are more organ selective. I am particularly excited about the potential of agents that can produce selective inhibition of NHE3 in the proximal renal tubule. Kidney-specific NHE3 knockout models have been developed. In theory, innovative agents can be synthesized that may target the binding proteins or kinases that are required for the phosphorylation, trafficking, or membrane localization of NHE3 in renal tubular cells. The development of such novel compounds might allow clinicians to directly address one of the primary mechanisms responsible for the glomerular hyperfiltration that leads to diabetic nephropathy. (Full text of response; no abstract available.)

Packer, M. (2018). “Leptin-Aldosterone-Neprilysin Axis: Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity.” Circulation 137(15): 1614-1631.

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Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits.

Packer, M. (2018). “Have we really demonstrated the cardiovascular safety of anti-hyperglycaemic drugs? Rethinking the concepts of macrovascular and microvascular disease in type 2 diabetes.” Diabetes Obes Metab 20(5): 1089-1095.

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A primary goal of the treatment of type 2 mellitus is the prevention of morbidity and mortality associated with cardiovascular disease; however, anti-hyperglycaemic drugs have the capacity to cause deleterious effects on the circulation, a risk that is not adequately reflected by the endpoints selected for emphasis in large-scale clinical trials that are designed to evaluate cardiovascular safety. The primary endpoint of the large-scale studies mandated by regulatory authorities focuses only on 3 to 4 events that depict only a limited view of the circulatory system. One of the most serious adverse effects of many glucose-lowering drugs is new-onset or worsening heart failure. Most antidiabetic drugs can aggravate heart failure because they exert anti-natriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain anti-hyperglycaemic agents may worsen peripheral vascular disease and trigger cardiac arrhythmias that may lead to sudden death. Initiation of treatment with antidiabetic medications may also cause deterioration of the function of the kidneys, retina and peripheral nerves, which are typically regarded as reflecting microvascular disease. The current confusion about the cardiovascular effects of glucose-lowering drugs may be exacerbated by conceptual uncertainties about the classification of large and small vessel disease in determining the clinical course of diabetes. Physicians should not be falsely reassured by claims that a new treatment appears to have passed a narrowly defined regulatory test. The management of people with diabetes often carries with it the risk of important cardiovascular consequences, even for drugs that do not overtly increase the risk of myocardial infarction or stroke.

Packer, M. (2018). “Derangements in adrenergic-adipokine signalling establish a neurohormonal basis for obesity-related heart failure with a preserved ejection fraction.” Eur J Heart Fail 20(5): 873-878.

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Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta2 -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis.