Milton Packer M.D.

Packer, M. (2020). “Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs.” Cardiovasc Diabetol 19(1): 62.

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Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)-effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.

Packer, M. (2020). “Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors.” J Am Soc Nephrol 31(5): 907-919.

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Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1alpha and HIF-2alpha)-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2alpha signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Packer, M. (2020). “Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework.” Diabetes Obes Metab 22(5): 734-742.

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Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphate-activated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes.

Packer, M. (2020). “Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy? Expectations and realities of a new standard of care.” Eur Heart J Apr 29. pii: ehaa344. [Epub ahead of print].

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With the completion of two large-scale trials of SGLT2 inhibitors in patients with chronic heart failure and a reduced ejection fraction, we are poised to add yet another drug to our portfolio of cardioprotective agents. These disease-modifying drugs target important, but distinct, pathways that promote cardiomyocyte dysfunction and demise, and it is critical that physicians prescribe all of them in combination to all appropriate patients who do not have demonstrable intolerance. Yet, <1% of patients with chronic heart failure are receiving currently recommended drugs at doses that have been shown to prolong life.1 According to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses may reduce the risk of death by as much as 75%. It is time that physicians who treat patients with heart failure took notice. (Excerpt from text; no abstract available.)

Lam, P. H., M. Packer, G. S. Gill, W. C. Wu, W. C. Levy, M. R. Zile, V. Brar, C. Arundel, Y. Cheng, S. N. Singh, R. M. Allman, G. C. Fonarow and A. Ahmed (2020). “Digoxin Initiation and Outcomes in Patients with Heart Failure with Preserved Ejection Fraction.” Am J Med Apr 6. pii: S0002-9343(20)30236-9. [Epub ahead of print].

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BACKGROUND: Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction (HFrEF). Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. METHODS: In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction >/=50% who were not receiving digoxin before admission. Of these, 5675 had a heart rate >/=50 beats/minute, an estimated glomerular filtration rate (eGFR) >/=30 mL/min/1.73 m(2) or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. RESULTS: Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR, 0.70; 95% CI, 0.45-1.10; p=0.124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; p=0.689) and 0.93 (0.55-1.56; p=0.773), respectively. Digoxin initiation had no association with 6-year outcomes. CONCLUSION: Digoxin initiation before hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.