Milton Packer M.D.

Packer, M., Anker, S.D., Butler, J., Filippatos, G., Pocock, S.J., Carson, P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., Jamal, W., Kimura, K., Schnee, J., Zeller, C., Cotton, D., Bocchi, E., Böhm, M., Choi, D.J., Chopra, V., Chuquiure, E., Giannetti, N., Janssens, S., Zhang, J., Gonzalez Juanatey, J.R., Kaul, S., Brunner-La Rocca, H.P., Merkely, B., Nicholls, S.J., Perrone, S., Pina, I., Ponikowski, P., Sattar, N., Senni, M., Seronde, M.F., Spinar, J., Squire, I., Taddei, S., Wanner, C. and Zannad, F. (2020). “Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.” N Engl J Med Aug 29. [Epub ahead of print.].

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BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m(2) of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.

Zannad, F., Ferreira, J.P., Pocock, S.J., Anker, S.D., Butler, J., Filippatos, G., Brueckmann, M., Ofstad, A.P., Pfarr, E., Jamal, W. and Packer, M. (2020). “SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.” Lancet Aug 28;S0140-6736(20)31824-9. [Epub ahead of print.].

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BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran’s Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF.

Packer, M. (2020). “Mechanisms Leading to Differential Hypoxia Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics.” Am J Kidney Dis Jul 22;S0272-6386(20)30849-0. [Epub ahead of print.].

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure or glomerular filtration pressures. Their effects to promote erythrocytosis suggests that these drugs act on hypoxia inducible factors (specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α, and thereby, augment erythropoiesis, while muting organellar dysfunction, inflammation and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia-mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many of renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney.

Packer, M. (2020). “Beth Levine In Memoriam.” Eur Heart J 41(28): 2617.

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Beth Levine was widely recognized as a world leader in the field of autophagy research. Over a span of two decades, her findings repeatedly deciphered the mysteries of the molecular pathways that were essential to cellular health and survival. Her laboratory identified conserved mechanisms underlying the regulation of autophagy and provided the first evidence that autophagy genes are important in antiviral host defence, tumour suppression, lifespan extension, apoptotic corpse clearance, metazoan development, and the beneficial metabolic effects of exercise. In addition, she developed a potent autophagy-inducing cell permeable peptide, Tat-beclin 1, which has been shown to have numerous potential therapeutic applications in a range of human diseases. [No abstract; excerpt from article].

Vaduganathan, M., B. L. Claggett, P. S. Jhund, J. W. Cunningham, J. Pedro Ferreira, F. Zannad, M. Packer, G. C. Fonarow, J. J. V. McMurray and S. D. Solomon (2020). “Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.” Lancet May 21;S0140-6736(20)30748-0. [Epub ahead of print].

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BACKGROUND: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF. METHODS: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker). FINDINGS: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy. INTERPRETATION: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.