Milton Packer M.D.

Packer, M. (2018). “Have dipeptidyl peptidase-4 inhibitors ameliorated the vascular complications of type 2 diabetes in large-scale trials? The potential confounding effect of stem-cell chemokines.” Cardiovasc Diabetol 17(1): 9.

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Drugs that inhibit dipeptidyl peptidase-4 (DPP-4) are conventionally regarded as incretin-based agents that signal through the glucagon-like peptide-1 (GLP-1) receptor. However, inhibition of DPP-4 also potentiates the stem cell chemokine, stromal cell-derived factor-1 (SDF-1), which can promote inflammation, proliferative responses and neovascularization. In large-scale cardiovascular outcome trials, enhanced GLP-1 signaling has reduced the risk of atherosclerotic ischemic events, potentially because GLP-1 retards the growth and increases the stability of atherosclerotic plaques. However, DPP-4 inhibitors have not reduced the risk of major adverse cardiovascular events, possibly because potentiation of SDF-1 enhances plaque growth and instability, activates deleterious neurohormonal mechanisms, and promotes cardiac inflammation and fibrosis. Similarly, trials with GLP-1 agonists and sodium-glucose cotransporter 2 inhibitors have reported favorable effects on renal function, even after only 3-4 years of treatment. In contrast, no benefits on the rate of decline in glomerular filtration rate have been seen in trials of DPP-4 inhibitors, perhaps because the renal actions of DPP-4 inhibitors are primarily mediated by potentiation of SDF-1, not GLP-1. Experimentally, SDF-1 can promote podocyte injury and glomerulosclerosis. Furthermore, the natriuretic action of SDF-1 occurs primarily in the distal tubules, where it cannot utilize tubuloglomerular feedback to modulate the deleterious effects of glomerular hyperfiltration. Potentiation of SDF-1 in experimental models may also exacerbate both retinopathy and neuropathy. Therefore, although DPP-4 inhibitors have attractive clinical features, the benefits that might be expected from GLP-1 signaling may be undermined by their actions to enhance SDF-1.

Packer, M. (2018). “Do Sodium-Glucose Cotransporter-2 Inhibitors Prevent Heart Failure With a Preserved Ejection Fraction by Counterbalancing the Effects of Leptin? A Novel Hypothesis.” Diabetes Obes Metab. Jan 23. [Epub ahead of print].

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Sodium-glucose 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 likely 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 favorably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.

Packer, M. (2017). “The imminent demise of cardiovascular drug development.” JAMA Cardiol: 2017 Nov [Epub ahead of print].

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The development of new cardiovascular drugs is at its deepest nadir in decades.¹ Major pharmaceutical companies have ended research activities in cardiology,² and applications to and approvals by the US Food and Drug Administration for new cardiovascular pharmaceuticals have declined dramatically even as innovations in other therapeutic areas have soared.

Mogensen, U. M., P. S. Jhund, W. T. Abraham, A. S. Desai, K. Dickstein, M. Packer, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile, L. Kober and J. J. V. McMurray (2017). “Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction.” J Am Coll Cardiol 70(20): 2490-2500.

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BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF), but the outcome by type of AF is largely unknown. OBJECTIVES: This study investigated outcomes related to type of AF (paroxysmal, persistent or permanent, or new onset) in 2 recent large trials in patients with HF with reduced ejection fraction. METHODS: The study analyzed patients in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for outcomes related to AF type. RESULTS: Of 15,415 patients, 5,481 (35.6%) had a history of AF at randomization, and of these, 1,645 (30.0%) had paroxysmal AF. Compared with patients without AF, patients with paroxysmal AF at randomization had a higher risk of the primary composite endpoint of cardiovascular death or HF hospitalization (HR: 1.20; 95% confidence interval [CI]: 1.09 to 1.32; p < 0.001), HF hospitalization (HR: 1.34; 95% CI: 1.19 to 1.51; p < 0.001), and stroke (HR: 1.34; 95% CI: 1.02 to 1.76; p = 0.037), whereas the corresponding risks in patients with persistent or permanent AF were not elevated. Neither type of AF was associated with higher mortality. New onset AF was associated with the greatest risk of adverse outcomes: primary endpoint (HR: 2.21; 95% CI: 1.80 to 2.71), HF hospitalization (HR: 2.11; 95% CI: 1.58 to 2.81), stroke (HR: 2.20; 95% CI: 1.25 to 3.88), and all-cause mortality (HR: 2.26; 95% CI: 1.86 to 2.74), all p values < 0.001, compared with patients without AF. Anticoagulants were used less often in patients with paroxysmal (53%) and new onset (16%) AF than in patients with persistent or permanent AF (71%). CONCLUSIONS: Among HF patients with a history of AF, those with paroxysmal AF were at greater risk of HF hospitalization and stroke than were patients with persistent or permanent AF, underlining the importance of anticoagulant therapy. New onset AF was associated with increased risk of all outcomes.

Packer, M. (2017). “Are meta-analyses a form of medical fake news? Thoughts about how they should contribute to medical science and practice.” Circulation 136(22): 2097-2099.

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Many physicians believe (incorrectly) that there is something magical about a metaanalysis. A meta-analysis is an observational study, but the author does no original work. Someone simply notices that several articles have data that pertain to a common topic and that they might show similar patterns. How can the patterns be described? In the past, the favored approach was to depict these in a narrative, but this task required insight into the details of each trial and a willingness to ask whether differences in design or execution might have contributed to differences in a study’s findings. The current approach to meta-analysis requires no such intellectual effort; little knowledge is needed about any trial, except that it possesses certain minimum features. Advocates of meta-analyses claim that they select trials for inclusion or exclusion based solely on their methodological qualities without awareness of their results, but it is difficult to understand how that could happen. Can the author of a meta-analysis claim to have read only the methods section of an article, but ignored the title, abstract, results, and discussion?