scholarly journals Comparative Effectiveness and Safety of Sodium–Glucose Cotransporter 2 Inhibitors Versus Glucagon-Like Peptide 1 Receptor Agonists in Older Adults

2021 ◽  
Author(s):  
Elisabetta Patorno ◽  
Ajinkya Pawar ◽  
Lily G. Bessette ◽  
Dae H. Kim ◽  
Chintan Dave ◽  
...  
Keyword(s):  
Older Adults ◽  
Comparative Effectiveness ◽  
Kidney Injury ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Major Adverse Cardiovascular Events ◽  
Receptor Agonists ◽  
Increased Risk ◽  
Glucagon Like Peptide 1 ◽  
Tract Infections

<b>Objective</b>: Both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1RA) demonstrated cardiovascular benefits in RCTs of patients with type 2 diabetes (T2D) generally <65 years and mostly with cardiovascular disease (CVD). We aimed to evaluate the comparative effectiveness and safety of SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1RA) among real-world older adults. <p><b>Methods</b>: Using Medicare data (4/2013-12/2016), we identified 90,094 1:1 propensity score-matched T2D patients ≥66 years initiating SGLT2i or GLP-1RA. Primary outcomes were major adverse cardiovascular events (MACE, i.e., myocardial infarction, stroke or cardiovascular death) and hospitalization for heart failure (HHF). Other outcomes included diabetic ketoacidosis (DKA), genital infections (GI), fractures, lower-limb amputations (LLA), acute kidney injury (AKI), severe urinary tract infections (UTI), and overall mortality. We estimated hazard ratios (HR) and rate differences (RD) per 1000 person-years, controlling for 140 baseline covariates. </p> <p><a><b>Results</b></a>: Compared with GLP-1RA, SGLT2i initiators had similar MACE risk [HR (95% CI)=0.98 (0.87-1.10); RD (95% CI)= -0.38 (-2.48,1.72)] and reduced HHF risk [HR=0.68 (0.57-0.80)]; RD= -3.23 (-4.68,-1.77)], over a median follow up of approximately 6 months. They also had 0.7 [RD=0.72 (0.02, 1.41)] more DKA, 0.9 [RD=0.90 (0.10, 1.70)] more LLA, 57.1 [RD=57.08 (53.45, 60.70)] more GI, and 7.1 [RD=-7.05 (-10.27, -3.83)] fewer AKI events. </p> <p><b>Conclusions</b>: Among older adults, SGLT2i had similar MACE risk, decreased HHF risk, and increased risk of DKA, LLA, and GI, vs. GLP-1RA. </p>

scholarly journals Comparative Effectiveness and Safety of Sodium–Glucose Cotransporter 2 Inhibitors Versus Glucagon-Like Peptide 1 Receptor Agonists in Older Adults

2021 ◽  
Author(s):  
Elisabetta Patorno ◽  
Ajinkya Pawar ◽  
Lily G. Bessette ◽  
Dae H. Kim ◽  
Chintan Dave ◽  
...  
Keyword(s):  
Older Adults ◽  
Comparative Effectiveness ◽  
Kidney Injury ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Major Adverse Cardiovascular Events ◽  
Receptor Agonists ◽  
Increased Risk ◽  
Glucagon Like Peptide 1 ◽  
Tract Infections

<b>Objective</b>: Both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1RA) demonstrated cardiovascular benefits in RCTs of patients with type 2 diabetes (T2D) generally <65 years and mostly with cardiovascular disease (CVD). We aimed to evaluate the comparative effectiveness and safety of SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1RA) among real-world older adults. <p><b>Methods</b>: Using Medicare data (4/2013-12/2016), we identified 90,094 1:1 propensity score-matched T2D patients ≥66 years initiating SGLT2i or GLP-1RA. Primary outcomes were major adverse cardiovascular events (MACE, i.e., myocardial infarction, stroke or cardiovascular death) and hospitalization for heart failure (HHF). Other outcomes included diabetic ketoacidosis (DKA), genital infections (GI), fractures, lower-limb amputations (LLA), acute kidney injury (AKI), severe urinary tract infections (UTI), and overall mortality. We estimated hazard ratios (HR) and rate differences (RD) per 1000 person-years, controlling for 140 baseline covariates. </p> <p><a><b>Results</b></a>: Compared with GLP-1RA, SGLT2i initiators had similar MACE risk [HR (95% CI)=0.98 (0.87-1.10); RD (95% CI)= -0.38 (-2.48,1.72)] and reduced HHF risk [HR=0.68 (0.57-0.80)]; RD= -3.23 (-4.68,-1.77)], over a median follow up of approximately 6 months. They also had 0.7 [RD=0.72 (0.02, 1.41)] more DKA, 0.9 [RD=0.90 (0.10, 1.70)] more LLA, 57.1 [RD=57.08 (53.45, 60.70)] more GI, and 7.1 [RD=-7.05 (-10.27, -3.83)] fewer AKI events. </p> <p><b>Conclusions</b>: Among older adults, SGLT2i had similar MACE risk, decreased HHF risk, and increased risk of DKA, LLA, and GI, vs. GLP-1RA. </p>

scholarly journals Comparative Effectiveness and Safety of Sodium–Glucose Cotransporter 2 Inhibitors Versus Glucagon-Like Peptide 1 Receptor Agonists in Older Adults

Diabetes Care ◽  
2021 ◽  
Vol 44 (3) ◽  
pp. 826-835 ◽  
Author(s):  
Elisabetta Patorno ◽  
Ajinkya Pawar ◽  
Lily G. Bessette ◽  
Dae H. Kim ◽  
Chintan Dave ◽  
...  
Keyword(s):  
Older Adults ◽  
Comparative Effectiveness ◽  
Receptor Agonists ◽  
Sodium Glucose Cotransporter ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis

BMJ Open ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. e022577 ◽  
Author(s):  
Jennifer R Donnan ◽  
Catherine A Grandy ◽  
Eugene Chibrikov ◽  
Carlo A Marra ◽  
Kris Aubrey-Bassler ◽  
...  
Keyword(s):  
Systematic Review ◽  
Bone Fractures ◽  
Meta Analysis ◽  
Kidney Injury ◽  
Sglt2 Inhibitors ◽  
Current Evidence ◽  
Random Effects Models ◽  
Relative Risks ◽  
Increased Risk ◽  
Tract Infections

ObjectiveTo estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.DesignWe conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).InterventionSGLT2 inhibitors, compared with placebo or active comparators.Primary outcomesAcute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.ResultsWe screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.ConclusionsCurrent evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.PROSPERO registration numberCRD42016038715.

scholarly journals A systematic review and meta-analysis of the impact of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiovascular outcomes in biologically healthy older adults

2021 ◽  
Author(s):  
William D Strain ◽  
Jonathan Griffiths
Keyword(s):  
Systematic Review ◽  
Older Adults ◽  
Weight Loss ◽  
Meta Analysis ◽  
Major Adverse Cardiovascular Events ◽  
Receptor Agonists ◽  
Central Registry ◽  
Glucagon Like Peptide 1 ◽  
Poor Outcomes ◽  
The Impact

Background: Unintentional weight loss is a hallmark of frailty and is associated with poor outcomes in older adults with type 2 diabetes. As such, the role of pharmacological therapies that facilitate weight loss – namely, sodium- glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists – remains uncertain in fitter older adults. We performed a systematic review and meta-analysis to evaluate these agents on major adverse cardiovascular events (MACE) in older adults eligible for participation in cardiovascular outcome trials.Methods: A literature search was performed in MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials (CENTRAL) and CNKI from inception to 29 June 2020. A class-specific meta-analysis was conducted in older adults (>65 years at recruitment) and compared with the similar analysis in younger (<65 years) adults.Results: Of 761 unique studies identified, nine met the criteria for inclusion, five using GLP-1 receptor agonists and four with SGLT-2 inhibitors. GLP-1 receptor agonists in older adults were associated with a 15.3% (OR 0.847 (95% CI 0.788 to 0.910)) reduction in MACE events, similar to the 16% benefit seen in younger adults. The use of SGLT-2 inhibitors reduced MACE in older participants by 16.9% (OR 0.831 (95% CI 0.699 to 0.989)), numerically superior to the impact in younger patients (OR 0.936 (95% CI 0.787 to 1.113).Conclusions: GLP-1 receptor agonists and SGLT-2 inhibitors reduced MACE outcomes in older adults who were eligible to participate in clinical trials. Whereas this is reassuring for the biologically robust, it should not be extrapolated to frail older adults without further investigation.

scholarly journals Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study

BMJ ◽  
2018 ◽  
pp. k4365 ◽  
Author(s):  
Peter Ueda ◽  
Henrik Svanström ◽  
Mads Melbye ◽  
Björn Eliasson ◽  
Ann-Marie Svensson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Diabetic Ketoacidosis ◽  
Lower Limb ◽  
Kidney Injury ◽  
Sglt2 Inhibitors ◽  
Lower Limb Amputation ◽  
Limb Amputation ◽  
Serious Adverse Events ◽  
Receptor Agonists ◽  
Increased Risk

Abstract Objective To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern. Design Register based cohort study. Setting Sweden and Denmark from July 2013 to December 2016. Participants A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists. Main outcome measures The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. Results Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 v 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 v 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 v 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 v 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 v 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 v 1.2, 1.16, 0.64 to 2.12). Conclusions In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.

scholarly journals Comparative Effectiveness of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Risk of Kidney Outcomes: Emulation of a Target Trial Using Health Care Databases

Diabetes Care ◽  
2020 ◽  
Vol 43 (11) ◽  
pp. 2859-2869 ◽  
Author(s):  
Yan Xie ◽  
Benjamin Bowe ◽  
Andrew K. Gibson ◽  
Janet B. McGill ◽  
Geetha Maddukuri ◽  
...  
Keyword(s):  
Health Care ◽  
Comparative Effectiveness ◽  
Sglt2 Inhibitors ◽  
Target Trial ◽  
Receptor Agonists

Abstract 15526: Glucagon-like Peptide-1 Receptor Agonists Reduce Adverse Cardiovascular Disease (CVD) Events in Patients With Type 2 Diabetes: An Assessment of Heterogeneity Among CVD Outcomes and a Meta-regression Analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Simran Grewal ◽  
Ninad Zaman ◽  
Louis Borgatta ◽  
Matthew Nudy ◽  
Brandon Peterson
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Cardiovascular Death ◽  
Nonfatal Stroke ◽  
Significant Heterogeneity ◽  
Receptor Agonists ◽  
Meta Regression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Introduction: Recent evidence suggests glucagon-like peptide-1 receptor agonists (GLP-1 RA) reduce adverse cardiovascular disease (CVD) events. The objective of this study is to analyze randomized controlled trials (RCTs) testing GLP-1 RA’s effects on CVD among participants with type 2 diabetes (T2DM). Methods: RCTs comparing GLP-1 RA versus placebo among participants with T2DM were identified using PubMed and Cochrane databases. The endpoints of this analysis included major adverse cardiovascular events (MACE; a composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke), and the individual components of MACE. The primary analysis calculated risk ratios (RR) and 95% confidence intervals (CI) for each endpoint. Heterogeneity for each endpoint was calculated using Chi 2 and I 2 tests. For any endpoint with significant heterogeneity, a meta-regression was performed using baseline hemoglobin A1C (A1C) in each RCT as the moderator and a R 2 value was calculated. Results: 7 RCTs (N = 56,004) were identified with 174,163 patient years of follow-up. GLP-1 RA reduced MACE [RR 0.89, 95% CI 0.83-0.95], cardiovascular death [RR 0.88, 95% CI 0.81-0.95], and nonfatal stroke [RR 0.85, 95% CI 0.77-0.94]. There was no significant heterogeneity among these RCTs (Figure 1). GLP-1 RA did not reduce nonfatal MI [RR 0.91, 95% CI 0.82-1.02]. However, there was significant heterogeneity among these RCTS (Chi 2 =12.94, p=0.04, I 2 =54%). When accounting for A1C in the regression model, there was no longer significant heterogeneity for this endpoint (p=0.23, I 2 =27%). A relationship between A1C and GLP-1 RA’s effect on nonfatal MI (R 2 =0.64, Figure 1) was observed when performing the meta-regression. Conclusion: GLP-1 RA reduced MACE, cardiovascular death, and nonfatal stroke in patients with T2DM with minimal heterogeneity among RCTs. GLP-1 RA did not reduce nonfatal MI, however there may be an association between A1C and GLP-1 RA’s effect on nonfatal MI.

scholarly journals How Do SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors and GLP-1 (Glucagon-Like Peptide-1) Receptor Agonists Reduce Cardiovascular Outcomes?

2020 ◽  
Vol 40 (3) ◽  
pp. 506-522 ◽  
Author(s):  
Matthew M.Y. Lee ◽  
Mark C. Petrie ◽  
John J.V. McMurray ◽  
Naveed Sattar
Keyword(s):  
Diabetes Mellitus ◽  
Mechanisms Of Action ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Left Ventricular Ejection ◽  
Cardiac Effects ◽  
Receptor Agonists ◽  
Sodium Glucose Cotransporter ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Objective: There is substantial interest in how GLP-1RA (glucagon-like peptide-1 receptor agonists) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure–lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated. Conclusions: We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.

scholarly journals Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs

2019 ◽  
Vol 5 (1) ◽  
pp. 27-30 ◽  
Author(s):  
Thomas A Zelniker ◽  
Eugene Braunwald
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Renal Failure ◽  
Cardiovascular Death ◽  
Cardiovascular Outcomes ◽  
Sodium Glucose Cotransporter ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Glucagon Like Peptide 1

Patients with type 2 diabetes are at increased risk of developing heart failure, cardiovascular death and renal failure. The recent results of three large sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials have demonstrated a reduction in heart failure hospitalisation and progressive renal failure. One trial also showed a fall in cardiovascular and total death. A broad spectrum of patients with diabetes benefit from these salutary effects in cardiac and renal function and so these trials have important implications for the management of patients with type 2 diabetes. Selected glucagon-like peptide 1 receptor agonists have also been shown to reduce adverse cardiovascular outcomes.

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