Metabolic effects of antihyperglycemic agents and mortality: meta-analysis of randomized controlled trials

Rados, Dimitris Rucks Varvaki; Viecceli, Camila; Pinto, Louise Lapagesse de Camargo; Gerchman, Fernando; Leitão, Cristiane Bauermann; Gross, Jorge Luiz

doi:10.1038/s41598-020-69738-w

Cited by 4 publications

(5 citation statements)

References 73 publications

(36 reference statements)

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“…SGLT2i also may exert anti-inflammatory effects via increased fat utilization, shifts in energy metabolism, increases in hematocrit, selective reduction of interstitial volume with minimal changes in blood volume, and maintenance of cytosolic pH ( 16 , 35 ). In addition, both SGLT2i and GLP1-RA are associated with reduced risk of cardiovascular events and chronic kidney disease progression in patients at high risk ( 14 ), a population associated with higher mortality in individuals with COVID-19 ( 2 ). A recent population-based cohort study in Denmark compared the association of GLP1-RA and DPP4-i use and COVID-19 outcomes with that of SGLT2i use and COVID-19 outcomes and found that the use of incretin-based therapies was not associated with improved clinical outcomes ( 36 ), although statistical power was limited by a small sample size.…”

Section: Discussionmentioning

confidence: 99%

“…Two classes of antihyperglycemic medications, glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i), have been associated with a reduction of cardiorenal events and mortality in large trials of cardiovascular outcomes ( 5 – 8 ), heart failure ( 9 , 10 ), and renal outcomes ( 11 , 12 ) in populations at high risk of cardiorenal events. Benefits associated with these medications appear most pronounced among individuals with type 2 diabetes and comorbid cardiovascular disease, heart failure, chronic kidney disease, and obesity ( 1 , 2 , 4 , 13 , 14 ), conditions that also incur the highest risk for severe COVID-19. Additionally, plausible mechanisms for the protective effects of GLP1-RA and SGLT2i in COVID-19, independent of their glycemic effects, have been speculated ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium–Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes

et al. 2021

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To determine the respective associations of premorbid glucagon-like peptide-1 receptor agonist (GLP1-RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) use, compared with premorbid dipeptidyl peptidase 4 inhibitor (DPP4i) use, with severity of outcomes in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESEARCH DESIGN AND METHODSWe analyzed observational data from SARS-CoV-2-positive adults in the National COVID Cohort Collaborative (N3C), a multicenter, longitudinal U.S. cohort (January 2018-February 2021), with a prescription for GLP1-RA, SGLT2i, or DPP4i within 24 months of positive SARS-CoV-2 PCR test. The primary outcome was 60day mortality, measured from positive SARS-CoV-2 test date. Secondary outcomes were total mortality during the observation period and emergency room visits, hospitalization, and mechanical ventilation within 14 days. Associations were quantified with odds ratios (ORs) estimated with targeted maximum likelihood estimation using a super learner approach, accounting for baseline characteristics. RESULTSThe study included 12,446 individuals (53.4% female, 62.5% White, mean ± SD age 58.6 ± 13.1 years). The 60-day mortality was 3.11% (387 of 12,446), with 2.06% (138 of 6,692) for GLP1-RA use, 2.32% (85 of 3,665) for SGLT2i use, and 5.67% (199 of 3,511) for DPP4i use. Both GLP1-RA and SGLT2i use were associated with lower 60-day mortality compared with DPP4i use (OR 0.54 [95% CI 0.37-0.80] and 0.66 [0.50-0.86], respectively). Use of both medications was also associated with decreased total mortality, emergency room visits, and hospitalizations. CONCLUSIONSAmong SARS-CoV-2-positive adults, premorbid GLP1-RA and SGLT2i use, compared with DPP4i use, was associated with lower odds of mortality and other adverse outcomes, although DPP4i users were older and generally sicker.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium–Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes

et al. 2021

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“…However, it is possible that these beneficial effects are not due to glucose lowering but rather to other concomitant treatments, such as antihypertensive agents [ 11 , 25 ]. Second, as known from the ACCORD and ADVANCE trials, achieving good blood glucose control could be at the cost of the number of hypoglycemic events and weight gain and thus not result in reduced mortality [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Is HbA1c a valid surrogate for mortality in type 2 diabetes? Evidence from a meta-analysis of randomized trials

Bächle

2022

Acta Diabetol

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Aims Hemoglobin A1c (HbA1c) has been repeatedly questioned as a valid surrogate marker, especially for patient-relevant outcomes. The aim of this study was to validate the HbA1c value as a surrogate for all-cause mortality in people with type 2 diabetes. Methods The effect estimates for HbA1c lowering after treatment as well as reductions in all-cause mortality of randomized trials were extracted from a systematic review and updated. For the measurement of actual surrogacy, weighted linear regression models with a random intercept for the study effect were used with the all-cause mortality estimate (risk difference and log relative risk) as the outcome and the estimate for HbA1c difference as the covariate. Surrogacy was assessed according to the criteria of Daniels and Hughes. Results A total of 346 HbA1c-mortality-pairs from 205 single randomized trials were included in the analysis. Regarding the risk difference of all-cause mortality, there was no evidence for surrogacy of the HbA1c value. For the log relative risk, a small positive association between HbA1c and the all-cause mortality estimate (slope 0.129 [95% confidence interval −0.043; 0.302]) was observed. However, there was no sign of valid surrogacy. Conclusions Based on the results of more than 200 randomized trials, HbA1c is not a valid surrogate marker for all-cause mortality in people with type 2 diabetes.

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“…In addition, two meta-analyses reported that SGLT-2i was associated with reduced risk of cardiovascular events and chronic kidney disease progression in diabetic patients. 57,58 SGLT-2i was mainly adopted in nonsevere patients with COVID-19. 59 This study has several limitations.…”

Section: Discussionmentioning

confidence: 99%

Effect of Antidiabetic Therapy on Clinical Outcomes of COVID-19 Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis

Zhan

Weng

Li³

et al. 2022

Ann Pharmacother

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Background: No study has yet systematically evaluated the effect of antidiabetic therapy on clinical outcomes of COVID-19 patients with type 2 diabetes (T2D). Objective: We aimed to evaluate the effect of different antidiabetic therapy on clinical outcomes of COVID-19 patients with T2D. Methods: We comprehensively retrieved the published research which examined the effect of antidiabetic therapy on clinical outcomes of COVID-19 patients with T2D. The odds ratio (OR) and its 95% confidence interval (95% CI) for clinical outcomes were calculated using the random-effects model, and meta-regression was adopted to evaluate the potential sources of heterogeneity between studies. Results: A total of 54 studies were included in this study. We found that the use of metformin (OR = 0.66, 95% CI: 0.58-0.75), SGLT-2i (OR = 0.80, 95% CI: 0.73-0.88), and GLP-1ra (OR = 0.83, 95% CI: 0.70-0.98) were significantly associated with lower mortality risk in COVID-19 patients with T2D, while insulin use might unexpectedly increase the ICU admission rate (OR = 2.32, 95% CI: 1.34-4.01) and risk of death (OR = 1.52, 95% CI: 1.32-1.75). No statistically significant associations were identified for DPP-4i, SUs, AGIs, and TZDs. Conclusion and Relevance: We demonstrated that the usage of metformin, SGLT-2i, and GLP-1ra could significantly decrease mortality in COVID-19 patients with T2D. The heterogeneity across the studies, baseline characteristics of the included patients, shortage of dosage and the duration of antidiabetic drugs and autonomy of drug selection might limit the objectivity and accuracy of results. Further adequately powered and high-quality randomized controlled trials are warranted for conclusive findings.

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Metabolic effects of antihyperglycemic agents and mortality: meta-analysis of randomized controlled trials

Cited by 4 publications

References 73 publications

Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium–Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes

Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium–Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes

Is HbA1c a valid surrogate for mortality in type 2 diabetes? Evidence from a meta-analysis of randomized trials

Effect of Antidiabetic Therapy on Clinical Outcomes of COVID-19 Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis

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