Heart failure and diabetes mellitus
Glycemic management and heart failure outcomes
Treating diabetes in patients with heart failure: Moving from risk to benefit
This review examines the effects of the newer classes of diabetes therapies on cardiovascular risk.
| Summary points |
- There is substantial evidence for the pathophysiological association between heart failure and diabetes mellitus. However, it is uncertain if glycemic control can improve cardiovascular outcomes.
- Among the older diabetes therapies, thiazolidinediones are known to increase the risk of heart failure, while metformin has been found in a number of studies to reduce the risk of heart failure.
- Dipeptidyl peptidase-4 inhibitors do not appear to increase the risk of heart failure based on currently available evidence, however, there may be differences in effects within this group.
- Glucagon-like peptide 1 agonists do not appear to have any cardioprotective properties.
- Of the sodium-glucose cotransporter 2 inhibitors, empagliflozin has been shown to reduce the risk of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for heart failure. Studies are ongoing studies to evaluate other representatives of this class.
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DeFilippis EM, Givertz MM. Curr Heart Fail Rep 2016; 13: 111–118. doi: 10.1007/s11897-016-0291-y
Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes
This review by Fitchett and colleagues summarizes the results of clinical trials that investigated the effects of various glucose-lowering therapies on cardiovascular outcomes.
| Summary points |
- Diabetes is a major risk factor for heart failure and a predictor of worse clinical outcomes in patients with heart failure.
- In patients with diabetes, subclinical left ventricular dysfunction is often observed and can progress to heart failure.
- There is little evidence at present to suggest that glycemc control itself reduces the risk of heart failure.
- In patients treated with insulin, the incidence of heart failure is higher and outcomes are worse compared with those treated with oral glucose-lowering therapies. However, this may be due to the sample selection bias, favoring older patients with impaired cardiac function.
- Metformin is likely to be safe to use in patients at risk of heart failure.
- Thiazolidinediones are associated with an increased incidence of acute heart failure.
- The impact of sulphonylureas on cardiovascular outcomes in patients with heart failure and those with established cardiovascular disease is unclear. However, the presence of other adverse effects has made these drugs less popular than other glucose-lowering therapies.
- The glucagon-like peptide 1 agonists do not appear to improve cardiovascular outcomes.
- Dipeptidyl peptidase-4 inhibitors sitagliptin and alogliptin have demonstrated non-inferiority versus placebo with respect to the incidence of cardiovascular events and as such, are considered to be safe in the short term. However, they do not appear to improve cardiovascular outcomes. Saxagliptin likely increases the risk of heart failure.
- The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced the incidence of heart failure and cardiovascular mortality in patients with and without a prior history of heart failure.
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Fitchett DH, Udell JA, Inzucchi SE. Eur J Heart Fail 2017; 19: 43–53. doi: 10.1002/ejhf.633
Novel anti-glycemic drugs and reduction of cardiovascular risk in diabetes: Expectations realized, promises unmet
This review presents the information on the cardiovascular safety and efficacy of anti-diabetic therapies, with an emphasis on newer drugs.
| Summary points |
- Following suggestions that some glucose-lowering agents might increase cardiovascular mortality, the US FDA introduced a requirement for cardiovascular safety to be shown before marketing approval can be granted. This requirement was that there was <80% increase in the risk of atherosclerotic cardiovascular disease demonstrated in phase II and phase III trials.
- Among older drugs, the evidence of improvement in cardiovascular outcomes with metformin is inconclusive, while sulfonylureas are associated with concerns about increased cardiovascular risk.
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors have positive effects on a number of cardiovascular risk factors, including blood pressure, body weight, visceral adiposity, hyperinsulinemia, albuminuria, serum uric acid and oxidative stress. Empagliflozin has been shown to have no negative effect on cardiovascular safety, however, further research is required to prove efficacy.
- The glucagon-like peptide 1 (GLP-1) agonists liraglutide and semaglutide have been shown to improve cardiovascular outcomes, while lixisenatide had no positive effect. Additional research is required.
- The results of randomized controlled clinical trials of dipeptidyl peptidase-4 (DPP-4) inhibitors are inconclusive with respect to cardiovascular safety, while observational studies consistently show benefit compared with sulfonylureas.
- Thiazolidinediones have highly pleiotropic effects, which, in combination with ambiguous clinical trial data, have led to limited application of these drugs.
- Liraglutide, semaglutide, lixisenatide, and empagliflozin can be considered safe with respect to cardiovascular outcomes, while the safety of DPP4 inhibitors remains uncertain. The clinical data supporting the efficacy of SGLT2 inhibitors and GLP-1 receptor agonists is encouraging but not decisive.
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Flory JH, Ukena JK, Floyd JS. Curr Atheroscler Rep 2016; 18: 79. doi: 10.1007/s11883-016-0633-y
Promise of SGLT2 inhibitors in heart failure: Diabetes and beyond
This review describes the effects of sodium-glucose transporter-2 inhibitors with particular emphasis on improvement of cardiovascular function.
| Summary points |
- By blocking the sodium-glucose transporter-2 (SGLT2), which leads to decreased reabsorption of glucose in the proximal tubules, SGLT2 inhibitors induce glycosuria of approximately 60–90 g/day.
- At present, a significant reduction in cardiovascular mortality has been demonstrated for the SGLT2 inhibitor empagliflozin (relative risk reduction 38% after 3 years) and the glucagon-like peptide-1 agonist liraglutide (relative risk reduction 22% after 4 years).
- Intensive glycemic control can increase the risk of heart failure.
- In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study, empagliflozin was associated with a 14% reduction in the risk of composite outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke).
- The non-glycemic effects of SGLT2 inhibitors include reduction of plasma volume, increased hematocrit, protection against glomerular hypertension, improvement of diuretic efficiency, cardiac metabolism and endothelial function and reduction of arterial stiffness.
- SGLT2 inhibitors have been shown to cause genital infections, usually with Candida species.
- SGLT2 inhibitors represent an attractive option for the treatment of diabetes in patients with heart failure, as well as other cardiovascular diseases.
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Martens P, Mathieu C, Verbrugge FH. Curr Treat Options Cardiovasc Med 2017; 19: 23. doi: 10.1007/s11936-017-0522-x
Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: Systematic review and meta-analysis of randomized and observational studies
This article presents the results of a meta-analysis of 25 eligible studies of glucagon-like peptide 1 agonists, conducted to assess their effects on heart failure in patients with type 2 diabetes.
| Summary points |
- MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov databases were searched for randomized controlled trials, cohort studies, and case–control studies of glucagon-like peptide 1 (GLP-1) receptor agonists in adults with type 2 diabetes that explicitly reported heart failure or hospitalization for heart failure.
- Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to rate the quality of evidence.
- Overall, 25 studies were selected: 21 RCTs (n=18,270) and 4 observational studies (n=111,029).
- Low quality evidence from 20 randomized controlled trials (RCTs) suggests a lower incidence of heart failure with GLP-1 agonists versus control.
- Moderate-quality evidence from one RCT suggests that GLP-1 agonists are not associated with hospitalization for heart failure.
- Very low quality evidence from three cohort studies comparing GLP-1 agonists to alternative agents suggests that GLP-1 agonists do not increase the incidence of heart failure.
- Very low quality evidence from one case-control study suggests that GLP-1 agonists are not associated with hospitalization for heart failure.
- The evidence reviewed in this article indicates that GLP-1 agonists do not increase the risk of heart failure or hospitalization for heart failure in patients with type 2 diabetes; however, this was based on low-quality evidence.
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Li L et al. BMC Cardiovasc Disord 2016; 16: 91. doi: 10.1186/s12872-016-0260-0
Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: Systematic review and meta-analysis of randomized and observational studies
This paper presents the results of a systematic review and meta-analysis of randomized and observational studies of dipeptidyl peptidase-4 inhibitors conducted to assess their effect on the risk of heart failure and hospital admission for heart failure in patients with type 2 diabetes.
| Summary points |
- Based on randomized controlled and observational studies, the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on heart failure are uncertain.
- Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched for randomized controlled trials, non-randomized controlled trials, cohort studies and case-control studies that compared DPP-4 inhibitors with placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes and explicitly reported the outcome of heart failure or hospital admission for heart failure.
- Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence.
- A total of 55 studies were included in the analysis: 43 randomized controlled trials (n=68,775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1,777,358).
- Low-quality evidence from 38 trials reporting heart failure outcomes suggested a possible similar risk with DPP-4 inhibitors and control. Moderate-quality evidence from five trials reporting admission for heart failure indicated an increased risk in patients treated with DPP-4 inhibitors compared with control.
- Very low quality evidence from the observational studies that provided effect estimates was consistent with the findings in trials.
- Very low quality evidence from pooling of adjusted estimates from observational studies suggested an increased risk of admission for heart failure in patients treated with sitagliptin compared with no use.
- The results of this meta-analysis suggest that, compared with no use, DPP-4 inhibitors may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for cardiovascular diseases.
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Li L et al. BMJ. 2016; 352: i610. doi: 10.1136/bmj.i610
Association of HbA1c with hospitalization and mortality among patients with heart failure and diabetes
This retrospective cohort study of outpatients with heart failure and diabetes examined the association between glycemic control and cardiovascular outcomes, focusing on low-income and ethnic-minority patients.
| Summary points |
- The patient population consisted of 4723 adult individuals (mean age 64 years) with heart failure and diabetes, of whom 42.6% were black and 30.5% were Hispanic/Latino.
- The association between HbA1c levels and all-cause hospitalization, heart failure hospitalization and mortality was measured using Cox proportional hazard models.
- Of those included in the study, 21.8%, 12.7%, 22.6%, 15.0% and 28.0 % had HbA1c levels of <6.5%, 6.5%–6.9%, 7.0%–7.9%, 8.0%–8.9, and ≥9.0 %, respectively. Overall rates of all-cause hospitalization were similar across HbA1c groups.
- Only patients with an HbA1c ≥9.0% had a significant increased risk of hospitalization (adjusted HR 1.13; 95 % CI 1.00–1.28) compared with patients with HbA1c level of 8.0%–8.9%.
- Compared with patients with an HbA1c 8.0%–8.9%, patients with an HbA1c of <6.5%, 6.5%–6.9%, 7.0%–7.9% and ≥9.0% had an adjusted hazard ratio (95 % CI) for all-cause hospitalization of 1.03 (0.90–1.17), 1.05 (0.91–1.22), 1.03 (0.90–1.17), and 1.13 (1.00–1.28), respectively.
- In a cohort of primarily ethnic-minority and low income patients with heart failure and diabetes, only patients with HbA1c >9 % were found to be at an increased risk of all-cause hospitalization.
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Blecker S, Park H, Katz SD. BMC Cardiovasc Disord 2016; 16: 99. doi: 10.1186/s12872-016-0275-6