Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies

Li, Ling; Li, Sheyu; Deng, Ke; Liu, Jiali; Vandvik, Per Olav; Zhao, Pujing; Zhang, Longhao; Shen, Jiantong; Bała, Małgorzata M; Sohani, Zahra N.; Wong, Eric; Busse, Jason W.; Ebrahim, Shanil; Málaga, Germán; Rios, Lorena P.; Wang, Yingqiang; Chen, Qunfei; Guyatt, Gordon; Sun, Xin

doi:10.1136/bmj.i610

Cited by 201 publications

(118 citation statements)

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“…This statement was first raised by the poor cardiovascular performance of rosiglitazone, which was reported to increase the risk for heart failure and MI 5, 6. Cardiovascular concern has also been raised regarding DPP4 (dipeptidyl peptidase 4) inhibitors taken as a class,35 and particularly for saxagliptin,36 regarding the risk of admission to the hospital for heart failure. In this context, however, we found that SGLT2 inhibitors did not increase the risk of any but instead reduced the risk of a range of cardiovascular outcomes, including individual mortality outcomes.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

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BackgroundThe cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented.Methods and ResultsFor cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

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“…Different considerations can be made: (1) the clinical relevance of CV benefit in terms of HHF is not as large as expected from the risk reduction estimates when compared to MACE and all‐cause mortality; (2) the lowest (outstanding) NNTBs came from the EASEL study; this may be interpreted taking into consideration that the population was a high‐risk cohort; (3) the CVD‐REAL studies provided similar findings, with the Nordic cohort showing the best estimates, especially the sub‐study on dapagliflozin; the reasons are uncertain although the comparison with DPP4‐Is may play a role: all published CVOTs on DPP4‐Is demonstrate non‐inferiority versus placebo, and the relative effect on the risk of HHF remains uncertain, with ongoing controversy over the increased risk for saxagliptin39, 40, 41; (4) only the UK cohort in the THIN database showed no significant risk reduction for MACE (expressed as incident CVD); (5) the highest NNTBs emerged for canagliflozin in the US cohort compared with DPP4‐Is; and (6) overall, it appears that the NNTBs are roughly comparable with those derived from the UKPDS follow‐up42 (in the metformin group comparing intensive vs. conventional therapy, the NNTB for the endpoint death from any cause was 139).…”

Section: Clinical Insight Into Observational Researchmentioning

confidence: 96%

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

Raschi

Poluzzi

Fadini

et al. 2018

Diabetes Obesity Metabolism

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Sodium glucose co‐transporter‐2 inhibitors have attracted the interest of the scientific community following the results from dedicated cardiovascular outcome trials, which demonstrated remarkable reduction in all‐cause mortality and other cardiovascular (CV) endpoints with empagliflozin and canagliflozin. These impressive results raised further expectations on real world data from large observational cohort studies. They were designed to address the possible existence of a class effect, and the uncertainty on whether this benefit can be extended from secondary to primary CV prevention of patients with type 2 diabetes. In this review, we collated data from existing observational studies (including the celebrated CVD‐REAL cohorts) and critically appraised results and methodological issues with the aim of providing clinical insight, including unsettled aspects, and proposing a research agenda for future investigations.

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“…The DPP-4i saxagliptin has been suspected to increase the risk of heart failure [21] whereas SGLT2i exert an osmotic diuretic effect that could prevent the development of heart failure [20]. Although the risk of heart failure associated with DPP-4i remains uncertain [52], if present, it should be minimized by the addition of a SGLT2i, which has the capacity to promote both diuresis and natriuresis [12,22].…”

Section: Expert Opinionmentioning

confidence: 99%

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Scheen

2016

Expert Opinion on Drug Metabolism & Toxicology

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SUMMARYIntroduction : Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach.Area covered: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations.Expert opinion: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects.Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin.Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the antihyperglycaemic therapy and improve drug compliance. Article highlights box -Type 2 diabetes (T2D) often requires the combination of several medications with complementary actions to reach glucose control targets while limiting side effects -The combination of a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) is an attractive approach for the management of T2D. Keywords-Both saxagliptin plus dapagliflozin and linagliptin plus empagliflozin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC : bioequivalence studies).-DPP-4i -SGLT2i combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Initial DPP-4i -SGLT2i combination may be considered or one compound may the added to the other. However, which one should be used in first place remains an open question.

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Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies

Abstract: ObjeCtivesTo examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes. DesignSystematic review and meta-analysis of randomised and observational studies. Data sOurCes

Cited by 201 publications

References 80 publications

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

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