What would be the fate of the association between saxagliptin and heart failure admission in the SAVOR-TIMI 53 trial if appropriate statistical methods should have been applied?

Cebrián-Cuenca, Ana M; Núñez, Eduardo; Nunez-Villota, J; Consuegra-Sánchez, Luciano

doi:10.1016/j.diabres.2017.02.029

Cited by 4 publications

(5 citation statements)

References 12 publications

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“… 80 From a methodological point of view, the statistical analysis has been criticized. 81 , 82 By using an alternative measure to the HR, no substantial clinically relevant difference in the risk of hospitalization for HF was shown between saxagliptin and placebo, as it was for alogliptin and sitagliptin. 83 The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and CV harm that may have predicted or may explain this imbalance in the rate of hospitalization for HF seen in SAVOR-TIMI 53.…”

Section: Results Of Dedicated CV Outcome Trials With Dpp-4 Inhibitorsmentioning

confidence: 99%

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Scheen

2018

Circulation Research

246

157

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Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.

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Section: Results Of Dedicated CV Outcome Trials With Dpp-4 Inhibitorsmentioning

confidence: 99%

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Scheen

2018

Circulation Research

246

157

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“…One hypothesize was a chance effect or a statistical error in SAVOR-TIMI trial. The inappropriate statistical methods were suggested as the cause of increased HF hospitalization risk (22). In the study of Kaneko et al (21), authors reevaluated the TECOS, EXAMINE and SAVOR-TIMI study groups for cardiovascular risk including hospitalization for HF risk with a different method and did not find any significant risk.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulation of these substrates by DPP-4 inhibition was suggested to cause alterations on cardiovascular system (13)(14)(15)(16)(17)(18)(19)(20). Also, chance effect or statistical methodology errors were suggested as possible explanations for increased risk of HF in SAVOR-TIMI 53 and EXAMINE trials (21,22).…”

Section: Introductionmentioning

confidence: 99%

Effects of DPP-4 inhibitors on brain natriuretic peptide, neuropeptide Y, glucagon like peptide-1, substance P levels and global longitudinal strain measurements in type 2 diabetes mellitus patients

KALKAN

Aydoğan

Dinçer

et al. 2022

Journal of Health Sciences and Medicine

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Introduction: Previously, a significant relationship between saxagliptin treatment and increased rate of hospitalization for congestive heart failure was reported. We aimed to investigate effects of vildagliptin and saxagliptin on brain natriuretic peptide (BNP), neuropeptide Y (NPY), substance P (SP), glucagon like peptide-1 (GLP-1) levels and left ventricular global longitudinal strain (GLS), assessed by 3-dimensional speckle tracking echocardiography in uncontrolled type 2 Diabetes mellitus (T2DM). Material and method: Thirty seven uncontrolled T2DM (HbA1c>7,5%) patients who were recently prescribed to either vildagliptin 50 mg BID (n=21) or saxagliptin 5 mg QD (n=16) were included in this study. Levels of BNP, NPY, SP, GLP-1 levels were measured at admission, first and third months of treatment. GLS was measured at admission and third month. Results: In whole group, BNP and NPY values increased significantly at third month of treatment (p< 0.001, 0.004; respectively). In the vildagliptin group, BNP and NPY values increased significantly at third month of treatment (p=0.02 and p=0.04, respectively). In the saxagliptin group only BNP levels increased significantly (p=0.015). In both groups; SP, GLP-1 levels and GLS measurements did not change significantly during follow-up period. Conclusion: The current study demonstrated that treatment with saxagliptin and vildagliptin, was associated with increased levels of BNP and NPY levels. No evidence of subclinical myocardial damage or cardiac dysfunction could be detected by GLS measurements. Since our study population had no previous clinical cardiac disorders, increases in BNP and NPY levels with these two DPP4 inhibitors can be considered as a safety signal.

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“…It is also possible that hHF issue with saxagliptin could be due to statistical error and not the reality, as raised and questioned by several authors in recent past. [353637] There remains a possibility that apparent deviation from the initial statistical analysis may have caused an insufficient Bonferroni correction that may have caused type 1 error. This could be further supported by the fact that by applying the Bradford Hill criteria, this association of hHF and saxagliptin use no longer remains highly significant.…”

Section: Discussionmentioning

confidence: 99%

“…This could be further supported by the fact that by applying the Bradford Hill criteria, this association of hHF and saxagliptin use no longer remains highly significant. [3536] Moreover, by applying an alternative measure to the hazard ratio, there seems to be no substantial clinically relevant differences in the risk of hHF between saxagliptin, alogliptin, or sitagliptin versus placebo in SAVOR-TIMI, EXAMINE, and TECOS, respectively. [37]…”

Section: Discussionmentioning

confidence: 99%

Heart failure hospitalization with DPP-4 inhibitors: A systematic review and meta-analysis of randomized controlled trials

Singh

2019

Indian J Endocr Metab

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Background: Heart failure hospitalization (hHF) with dipeptyl-dipeptidase-4 inhibitors (DPP-4Is) remains at the center stage since the publication of Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction (SAVOR-TIMI) in 2013 showing significant increase with saxagliptin, compared to placebo. This outcome led to additional label of hHF to both saxagliptin and alogliptin in April 2016 and eventual labelling of hHF to all the four approved DPP-4Is in United States in August 2017, by US Food Drug Administration. To note, neither Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), nor Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA), showed any signals of hHF with these two agents. These developments have seriously generated an uncertainty among clinicians with regards to hHF effect of DPP-4Is in type 2 diabetic patients with high risk of cardiovascular (CV) disease. Aims and Objectives: We systematically searched the database of PubMed, Embase, Cochrane Central library, ClinicalTrials.gov, and International conference presentation from the inception up to October 25, 2018 using MeSH and specific key words. We retrieved all those studies that explicitly looked for hHF as a prespecified end point and were conducted for ≥52 weeks. Subsequently, we conducted the meta-analysis using comprehensive meta-analysis software Version 3, using different sensitivity analysis to study the effect of DPP-4Is on hHF in both dedicated CV outcome trials as well as randomized controlled trials. Results: The meta-analysis of four exclusive dedicated CV outcome trials ( N = 43,522) did not find significant increase in hHF with DPP-4 inhibitors (Fixed model Relative Risk [RR] 1.06; 95% Confidence Interval [CI], 0.96-1.17; P = 0.25; I 2 : 53.95%, tau 2 : 0.012, P = 0.089). Meta-analysis of all randomized controlled trials that explicitly looked for hHF for ≥52 weeks ( N = 48,199) also did not show any significant increase in hHF (fixed model peto odds ratio 1.05; 95% CI 0.95–1.15, P = 0.36; I 2 : 43.74%, tau 2 : 0.016, P = 0.10). Conclusions: This meta-analysis suggests no significant increase in hHF with DPP-4 inhibitors, although a nonsignificant heterogeneity across the trials might limit this observation.

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What would be the fate of the association between saxagliptin and heart failure admission in the SAVOR-TIMI 53 trial if appropriate statistical methods should have been applied?

Cited by 4 publications

References 12 publications

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Effects of DPP-4 inhibitors on brain natriuretic peptide, neuropeptide Y, glucagon like peptide-1, substance P levels and global longitudinal strain measurements in type 2 diabetes mellitus patients

Heart failure hospitalization with DPP-4 inhibitors: A systematic review and meta-analysis of randomized controlled trials

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