The heart failure burden of type 2 diabetes mellitus—a review of pathophysiology and interventions

Diabetes and heart failure (HF) are both global epidemics with tremendous costs on society with increased rates of HF hospitalizations and worsened prognosis when co-existing, making it a significant “deadly duo.” The evidence for pharmacological treatment of HF in patients with type 2 diabetes mellitus (T2DM) stems typically from either subgroup analyses of patients that were recruited to randomized controlled trials of HF interventions, usually in patients with reduced ejection fraction (EF), or from subgroup analyses of HF patients recruited to cardiovascular (CV) outcome trials (CVOT) of glucose lowering agents involving patients with T2DM. Studies in patients with HF with preserved EF are sparse. This review summarizes the literature on pathophysiology and interventions aiming to reduce the HF burden in T2DM and includes HF trials of ACEi, digoxin, β-blocker, ARB, I f -blocker, MRA, and ARNI involving 38,600 patients, with or without prevalent diabetes, and CV outcome trials in T2DM involving 74,351 patients, with or without prevalent HF. In all HF trials, HF outcomes by prevalent diabetes were reported with an incremental risk of HF and death confessed by prevalent diabetes and a treatment effect similar to those without diabetes. All T2DM CVOTs reported on HF outcomes with heterogeneity between trials with two reporting benefits (empagliflozin and canagliflozin) and two reporting increased risk (saxagliptin, pioglitazone). In vulnerable T2DM patients with concomitant HF, guideline-recommended HF drugs are effective. When choosing glucose-lowering therapy, outcomes from available CVOTs should be considered. Open image in new window Fig. 1 a Incidence of HF hospitalization in the overall and DM subgroup in placebo/comparator-arms of HF trials of different interventions (ACEi [ 13 , 17 ], digoxin [ 18 , 19 ], β-blocker [ 20 , 21 ], ARB [ 10 , 22 ], I f -blocker [ 23 , 24 ], MRA [ 25 , 26 ], and ARNI [ 27 , 28 ]) and the relative incidence rate ratio for HF hospitalization for prevalent DM vs no DM. #: incidence rates in the overall groups (comparator + active), *: incidence rates include CV death. Abbreviations: HR: hazard ratio, HF: heart failure, SOLVD: Studies of Left Ventricular Dysfunction, DIG-trial: The Digitalis Investigation Group (DIG) trial, MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure, CHARM: Candesartan Assessment of Reduction in Mortality and morbidity, SHIFT: The Systolic Heart Failure Treatment With the I f Inhibitor Ivabradine Trial, EMPHASIS: Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure. b Incidence of HF hospitalization by prevalent HF in placebo arms of CV outcomes trials of glucose-lowering drugs (pioglitazone [ 29 , 30 ], lixisenatide [ 31 , 32 ], liraglutide [ 33 , 34 ], alogliptin [ 35 , 36 ], saxagliptin [ 37 , 38 ], sitagliptin [ 39 , 40 ], and empagliflozin [ 41 , 42 ]) and the relative incidence rate ratio for HF hospitalization for prevalent HF vs no HF. Abbreviations: HF: heart failure, CV: cardiovascular, n/a: not applicable, PROactive: PROspective pioglitAzone Clinical Trial In macroVascular Events, ELIXA: the Evaluation of LIXisenatide in Acute Coronary Syndrome trial, LEADER: the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results—a long term evaluation trial, EXAMINE: The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care, SAVOR-TIMI 53: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus 53 trial, TECOS: The Trial Evaluating Cardiovascular Outcomes With Sitagliptin, CANVAS: CANagliflozin cardioVascular Assessment Study Open image in new window Fig. 2 Overview over the mechanisms behind the clinical effects of evidence-based pharmacological treatment for prevention or treatment of HF, or HF-related events, in T2DM. Printed with permission from © Kari C. Toverud. Abbreviations: HF: heart failure, T2DM: type 2 diabetes, ACE: angiotensin converting enzyme, ARB: angiotensin receptor blocker Open image in new window Fig. 3 a Incidence rates of HF hospitalization and death in patients with T2DM participating in HF trials of different HF interventions (ACEi [ 13 , 17 ], digoxin [ 18 , 19 ], β-blocker [ 20 , 21 ], ARB [ 10 , 22 ], I f -blocker [ 23 , 24 ], MRA [ 25 , 26 ], and ARNI [ 27 , 28 ]) and their hazard ratios (95% confidence interval). *: composite outcome comprises HF hospitalization and CV death. Abbreviations: HR: hazard ratio, HF: heart failure, NR: not reported, SOLVD: Studies of Left Ventricular Dysfuction, DIG-trial: The Digitalis Investigation Group (DIG) trial, MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure, CHARM: Candesartan Assessment of Reduction in Mortality and morbidity, SHIFT: The Systolic Heart Failure Treatment With the I f Inhibitor Ivabradine Trial, EMPHASIS: Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure. b Incidence rates of HF hospitalization and death in patients participating in HF trials of different HF interventions (ACEi [ 13 , 17 ], digoxin [ 18 , 19 ], β-blocker [ 20 , 21 ], ARB [ 10 , 22 ], I f -blocker [ 23 , 24 ], MRA [ 25 , 26 ], and ARNI [ 27 , 28 ]) in the overall study population and in the subgroup with prevalent DM at baseline. *: composite outcome comprises HF hospitalization and CV death. Abbreviations: HR: hazard ratio, HF: heart failure, NR: not reported, SOLVD: Studies of Left Ventricular Dysfuction, DIG-trial: The Digitalis Investigation Group (DIG) trial, MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure, CHARM: Candesartan Assessment of Reduction in Mortality and morbidity, SHIFT: The Systolic Heart Failure Treatment With the I f Inhibitor Ivabradine Trial, EMPHASIS: Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Open image in new window Fig. 4 a Proportion of patients with HF hospitalization in the active and placebo arm in large CV outcome trials of different glucose-lowering drugs and their hazard ratios (95% confidence interval). Abbreviations: HF: heart failure, CV: cardiovascular, PROactive: PROspective pioglitAzone Clinical Trial In macroVascular Events, EXAMINE: The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care, SAVOR-TIMI 53: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus 53 trial, TECOS: The Trial Evaluating Cardiovascular Outcomes With Sitagliptin, ELIXA: the Evaluation of LIXisenatide in Acute Coronary Syndrome trial, LEADER: the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results—a long term evaluation trial, CANVAS: CANagliflozin cardioVascular Assessment Study. b Proportion of patients with HF hospitalization in the active and placebo arm according to presence of HF at baseline in large CV outcome trials of different glucose-lowering drugs. Abbreviations: HF: heart failure, CV: cardiovascular, n/a: not applicable, PROactive: PROspective pioglitAzone Clinical Trial In macroVascular Events, EXAMINE: The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care, SAVOR-TIMI 53: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus 53 trial, TECOS: The Trial Evaluating Cardiovascular Outcomes With Sitagliptin, ELIXA: the Evaluation of LIXisenatide in Acute Coronary Syndrome trial, LEADER: the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results—a long term evaluation trial, CANVAS: CANagliflozin cardioVascular Assessment Study Notes

DA has received speaker fees and honoraria from Boehringer Ingelheim, BMS/Pfizer, Bayer Healthcare, MSD, AstraZeneca, and Novartis. LG has participated in advisory boards for RES MED, Boehringer Ingelheim, and Sanofi Aventis. GL has received lecture and advisory board fees from Amgen, Boehringer Ingelheim, Janssen, and Sanofi Aventis. APO and OEJ are full-time employees of Boehringer Ingelheim and affiliated to Vestre Viken, Bærum Hospital, Department of Medical Research Bærum, Norway.

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