Milton Packer M.D.

Packer, M. (2020). “Epicardial Adipose Tissue Inflammation Can Cause the Distinctive Pattern of Cardiovascular Disorders Seen in Psoriasis.” Am J Med 133(3): 267-272.

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Psoriasis is a systemic inflammatory disorder that can target adipose tissue; the resulting adipocyte dysfunction is manifest clinically as the metabolic syndrome, which is present in approximately 20%-40% of patients. Epicardial adipose tissue inflammation is likely responsible for a distinctive pattern of cardiovascular disorders consisting of 1) accelerated coronary atherosclerosis leading to myocardial infarction, 2) atrial myopathy leading to atrial fibrillation and thromboembolic stroke, and 3) ventricular myopathy leading to heart failure with a preserved ejection fraction. If cardiovascular inflammation drives these risks, then treatments that focus on blood pressure, lipids, and glucose will not ameliorate the burden of cardiovascular disease in patients with psoriasis, especially in those who are young and have severe inflammation. Instead, interventions that alleviate systemic and adipose tissue inflammation may not only minimize the risks of atrial fibrillation and heart failure but may also have favorable effects on the severity of psoriasis. Viewed from this perspective, the known link between psoriasis and cardiovascular disease is not related to the influence of the individual diagnostic components of the metabolic syndrome.

Packer, M. (2020). “Does Metformin Interfere With the Cardiovascular Benefits of SGLT2 Inhibitors? Questions About Its Role as the Cornerstone of Diabetes Treatment.” Am J Med Feb 12. [Epub ahead of print].

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Metformin is widely used as first-line therapy to lower blood glucose in type 2 diabetes, because it is inexpensive and does not cause weight gain. However, the evidentiary basis for the primacy of metformin is not persuasive. A clinical trial performed >20 years ago reported that initial therapy with metformin reduced the risk of myocardial infarction when compared with other glucose-lowering drugs. However, this finding represented a subgroup analysis that relied only a small number of events, with confidence intervals that did not exclude a neutral effect. Furthermore, the benefit of metformin was not confirmed in a parallel trial in which the drug was used as second-line therapy. Importantly, there is little evidence to support a benefit of metformin to prevent the most serious cardiovascular complication of type 2 diabetes — heart failure. Observational studies have reported that metformin use is associated with a lower risk of heart failure and its adverse consequences; however, these reports are difficult to interpret, since it is likely that physicians selectively prescribed metformin to low-risk patients, due to fears that its use causes lactic acidosis in patients with left ventricular dysfunction. Furthermore, in these studies, metformin was compared with insulin-signaling antihyperglycemic drugs that have themselves been linked to an increased risk of heart failure; thus, the finding of a lower risk of heart failure in metformin users may have been due to an adverse effect of the comparator rather than a benefit of the biguanide. Importantly, in two large meta-analyses of randomized controlled trials, metformin did not did not influence the risk or consequences of heart failure, and the use of metformin with sulfonylureas has been accompanied by an increased risk of death both in observational studies and clinical trials. In light of these observations, there is no reliable evidence that metformin prevents or ameliorates the clinical course of heart failure in type 2 diabetes. (Excerpt from text, n.p.; no abstract available.)

Packer, M. (2020). “Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors.” Eur J Heart Fail Feb 10. [Epub ahead of print].

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In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1alpha/2alpha. The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1alpha/2alpha to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.

Vaduganathan, M., B. L. Claggett, A. S. Desai, S. D. Anker, S. V. Perrone, S. Janssens, D. Milicic, J. L. Arango, M. Packer, V. C. Shi, M. P. Lefkowitz, J. J. V. McMurray and S. D. Solomon (2020). “Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared With Valsartan in HFpEF.” J Am Coll Cardiol 75(3): 245-254.

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BACKGROUND: The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. OBJECTIVES: This study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF). METHODS: In this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (>/=45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region. RESULTS: Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050). CONCLUSIONS: Recent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711).

Solomon, S. D., M. Vaduganathan, L. C. B, M. Packer, M. Zile, K. Swedberg, J. Rouleau, A. P. M, A. Desai, H. L. L, L. Kober, I. Anand, N. Sweitzer, G. Linssen, B. Merkely, J. Luis Arango, D. Vinereanu, C. H. Chen, M. Senni, A. Sibulo, S. Boytsov, V. Shi, A. Rizkala, M. Lefkowitz and J. J. V. McMurray (2020). “Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.” Circulation 141(5): 352-361.

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BACKGROUND: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. METHODS: We combined data from PARADIGM-HF (LVEF eligibility/=45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: 22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. RESULTS: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. CONCLUSIONS: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).