Milton Packer M.D.

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.

Full text of this article.

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.

Full text of this article.

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].

Full text of this article.

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.

Packer, M. (2018). “Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure.” Eur J Heart Fail Mar 30. [Epub ahead of print].

Full text of this article.

Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.

Packer, M. (2018). “Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications.” Eur J Heart Fail Mar 22. [Epub ahead of print].

Full text of this article.

Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce with favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.