Research Spotlight

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 Mar 24. [Epub ahead of print].

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Among the incretin-based antidiabetic drugs, there is an understandable preference for the use of DPP-4 inhibitors over long-acting GLP-1 analogs, because the former are orally effective and do not require daily subcutaneous injections. However, physicians should not assume that incretin-based drugs have similar effects on the risk of atherosclerotic ischemic events simply because they share a common ability to enhance signaling through the GLP-1 receptor. Unlike DPP-4 inhibitors, long-acting GLP-1 analogs can reduce the risk of major adverse ischemic cardiovascular events, even when administered for only a few years. This benefit cannot be explained by their effects on blood glucose and cannot be replicated by sitagliptin and saxagliptin, possibly because DPP-4 inhibitors simultaneously enhance the plaque-destabilizing effects of endogenous proinflammatory chemokines. (Excerpt from text, p. 2; no abstract available.)

Packer, M. (2018). “Inferential characterization of the dose-response relationships of neurohormonal antagonists in chronic heart failure: A novel approach based on large-scale trials with active comparators.” Int J Cardiol. Mar 11. [Epub ahead of print].

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BACKGROUND: Current guidelines for the treatment of heart failure strongly recommend the use of inhibitors of the renin-angiotensin system and sympathetic nervous system in all patients with a reduced ejection fraction who can tolerate these drugs. Yet, there is no consensus about the efficacy of low doses of these drugs or the likely shape of the dose-response relationship for these agents. METHODS: Inferences were made by examining the effects of drugs in placebo-controlled trials before the protocol-specified opportunity for uptitration and by reassessing the results of large-scale trials with active comparators that inadvertently produced different intensities of neurohormonal blockade. RESULTS: In the case of inhibitors of the renin-angiotensin system, low starting doses appear to be effective in many patients, and 3-5 fold increases in dose do not have a mortality advantage over low doses. By contrast, in the case of beta-adrenergic blockers, although low starting doses appear effective in improving outcomes, achievement of target doses may yield substantial incremental mortality benefits, even such doses are accompanied by only small additional decreases in heart rate. CONCLUSION: When treating patients with heart failure to reduce mortality, the totality of evidence supports a relatively flat dose-response relationship for inhibitors of the renin-angiotensin system but a steep dose-response relationship for beta-adrenergic receptor blockers.

Packer, M. (2018). “Early Worsening of Renal Function After Treatment with Antihyperglycemic Drugs: A Consistent Finding in Large-Scale Trials.” Am J Med 131(4): 337-338.

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Prolonged hyperglycemia in type 2 diabetes exerts adverse structural and functional effects on the kidney, and sustained lowering of blood glucose for a decade or longer has been shown to reduce the risk of progression to end-stage renal disease. However, during the first months or years of treatment with an antihyperglycemic drug, patients may experience worsening of renal function regardless of the agent used to lower blood glucose. There is minimal recognition of this phenomenon in the medical literature. The most persuasive evidence supporting the occurrence of early worsening of renal function after initiation of treatment with antidiabetic drugs is derived from randomized controlled clinical trials with different antihyperglycemic agents. Sequential changes in estimated glomerular filtration rate (or in serum creatinine) have been reported in 5 large-scale trials completed since regulatory agencies issued a new guidance on diabetes in 2008. (Excerpt from text, p. 337; no abstract available.)

Packer, M. (2018). “Does a Target Dose or a Target Heart Rate Matter to Outcomes When Prescribing beta-Blockers to Patients With Chronic Heart Failure?” Circ Cardiovasc Qual Outcomes 11(4): e004605.

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For better or worse, many cardiovascular disorders are treated based on changes in a biomarker. Antihypertensive drugs are titrated to achieve specific decreases in blood pressure, and the doses of lipid-lowering drugs are often adjusted based on serum cholesterol. Investigators have proposed measuring natriuretic peptides and C-reactive protein to titrate drugs for heart failure and for high-risk coronary artery disease, respectively. Use of a biomarker often represents an effort to practice personalized medicine; theoretically, a drug is given only to people who need it and only in a dose that achieves what is perceived to be a worthwhile change. Yet, biomarkers present us with challenges. When observed in populations, even small differences in a biomarker—for example, 1- to 2-mm Hg difference in blood pressure—are clinically important; yet, when treating individuals, few physicians are inclined to increase the dose of an antihypertensive drug with the primary intent of achieving such a small additional decrease in blood pressure. The oldest biomarker in cardiovascular medicine is resting heart rate. Physicians have been monitoring the rapidity and quality of the pulse for several thousand years, and great emphasis has been placed on changes in heart rate as an indicator of impending improvement or deterioration. Many patients suffer when their heart rates are too fast or too slow. Yet, even in the absence of a tachyarrhythmia or bradyarrhythmia, physicians dutifully record the resting heart rate during normal sinus rhythm at nearly every patient encounter. The resting heart rate has recently gained attention as a biomarker in the management of patients with chronic heart failure. Heart rate (measured at rest and during sinus rhythm) has prognostic importance in patients with left ventricular systolic dysfunction, and changes in heart rate are predictive of outcomes. The If current antagonist ivabradine was specifically developed to modulate heart rate during sinus rhythm. When prescribed to patients with heart failure, the resting heart rate is not only used to identify those who might benefit from the drug but it is also typically used to titrate the appropriate dose of the agent. When administered to patients who are already receiving a β-blocker and who continue to demonstrate elevated heart rates, the decreases in sinus rate achieved by ivabradine are accompanied by a reduction in the combined risk of cardiovascular death and hospitalization for heart failure. (Excerpt from text, p. 1; no abstract available.)

Packer, M. (2018). “Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure.” Diabet Med. Mar 12. [Epub ahead of print].

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Three classes of anti-hyperglycaemic medications are distinguished by their urinary sodium excretion-enhancing and blood pressure-lowering actions: long-acting glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon-like peptide-1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium-glucose co-transporter-2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase-4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure. Similarly, the three classes of drugs differ in their early effects on renal function. Dipeptidyl peptidase-4 inhibitors produce a small decrease in renal function that persists for the duration of treatment, and they do not prevent serious adverse renal events. For glucagon-like peptide-1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes. In contrast, an initial decrease in glomerular filtration with sodium-glucose co-transporter-2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events. These differences may be related to different actions on the proximal tubular reabsorption of sodium, and thereby, on glomerular hyperfiltration. Anti-hyperglycaemic drugs that have natriuretic actions differ markedly in their ability to modulate macrovascular and microvascular risk. These contrasting profiles cannot be predicted by their effects on blood glucose or blood pressure.