+91 9063922599
+91 9063922599
submission@cmegeriatricmed.co.uk
|
FAQs
Introduction: Sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) each reduce cardiovascular (CV) and kidney risk in type 2 diabetes (T2D), but their comparative benefits remain debated. We synthesized randomized and high-quality comparative evidence to contrast class effects on major adverse cardiovascular events (MACE), heart-failure hospitalization (HHF), mortality, and kidney outcomes. Materials and Methods: We systematically searched PubMed, Embase, CENTRAL, ClinicalTrials.gov, and guidelines (inception–September 16, 2025) for CV/kidney outcome trials and comparative meta-analyses of SGLT2i or GLP-1RA in adults with T2D. Primary outcomes were MACE (CV death, nonfatal MI, nonfatal stroke), HHF, all-cause mortality, and kidney composite outcomes (≥40% eGFR decline, kidney failure, or renal death). Random-effects models pooled class-level effects where possible; otherwise we summarized best available pooled estimates from recent meta-analyses/network meta-analyses and landmark RCTs. Prespecified subgroups included established ASCVD, baseline CKD, and background use of the alternate class. Results: Across 15 landmark RCTs and recent meta-analyses (>150,000 participants), SGLT2i consistently reduced HHF and kidney composite outcomes versus placebo and generally more so than GLP-1RA; GLP-1RA provided robust MACE reduction, particularly stroke, with neutral to modest effects on HHF. Evidence suggests SGLT2i superiority for kidney outcomes and HHF, while GLP-1RA are at least as effective for MACE and stroke. Effects were directionally consistent regardless of background use of the other class. Safety profiles differed: SGLT2i increased genital infections and rare DKA; GLP-1RA increased GI events and gallbladder disease. Conclusion: For T2D with heart-failure risk or CKD, SGLT2i are generally preferred; for atherosclerotic risk and stroke prevention, GLP-1RA are compelling. When feasible, sequential or combined use may deliver complementary protection.
Glucose-lowering agents with cardiovascular and renal benefits have transformed T2D care. SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, etc.) first demonstrated cardiovascular and kidney protection in outcome trials such as EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and CKD-focused CREDENCE, DAPA-CKD, and EMPA-KIDNEY. These trials showed reductions in HHF, CV mortality (not uniformly across all agents), and kidney disease progression beyond glycemic effects.
In parallel, GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide, albiglutide, efpeglenatide) improved atherosclerotic outcomes—particularly MACE and stroke—in LEADER, SUSTAIN-6, REWIND, HARMONY Outcomes, and AMPLITUDE-O, with emerging renal benefits.
Head-to-head trials are limited; thus comparisons often draw upon class-specific RCTs and network/meta-analyses. Seminal analyses report SGLT2i preferentially lower HHF and kidney outcomes, whereas GLP-1RA reduce MACE—especially stroke—with smaller or inconsistent effects on HHF. More recent pooled data (2024–2025) reaffirm complementary profiles and suggest additive benefit when combined. Current ADA 2025 Standards recommend either class in patients with T2D and ASCVD and prioritize SGLT2i in CKD or HF, acknowledging potential dual-agent use.
Given widespread clinical adoption, evolving evidence, and clinical equipoise in some scenarios (e.g., primary prevention ASCVD with preserved kidney function), an updated synthesis contrasting these classes is clinically valuable. We therefore conducted a systematic review and meta-analysis focusing on class-level comparative efficacy for CV and renal outcomes in adults with T2D, incorporating the latest RCTs and meta-analyses and aligning results with contemporary guideline recommendations.
This is a Systematic review and meta-analysis per PRISMA.
Eligibility criteria:
Search strategy: We searched PubMed, Embase, CENTRAL, ClinicalTrials.gov, and guideline repositories through September 16, 2025, using terms for “SGLT2 inhibitors,” “GLP-1 receptor agonists,” “cardiovascular outcomes,” “renal/kidney outcomes,” and trial names (e.g., EMPA-REG, CANVAS, DECLARE, LEADER, REWIND). We also screened references of key reviews and ADA 2025 Standards.
Data extraction and quality assessment: Two reviewers independently extracted study characteristics, populations (ASCVD, CKD), interventions, comparators, outcomes, and effect estimates (hazard ratios or risk ratios). Risk of bias was assessed using Cochrane RoB 2 for RCTs; certainty was graded via GRADE across outcomes. Disagreements were resolved by consensus.
Statistical analysis: For outcomes with adequate homogeneity of definitions across RCTs within a class, we conducted DerSimonian–Laird random-effects meta-analyses and reported pooled HRs with 95% CIs; heterogeneity was quantified with I². For direct class-to-class comparisons, we preferentially summarized high-quality network meta-analyses and large comparative effectiveness syntheses, as formal head-to-head RCTs are sparse. Prespecified subgroups: established ASCVD vs multiple risk factors; baseline CKD; background use of the alternate agent. Publication bias was explored with funnel plots/Egger’s test when ≥10 studies. Sensitivity analyses excluded non-CVOT RCTs and earlier incretin agonists without proven CV benefit.
Guideline contextualization: Findings were mapped to ADA 2025 recommendations on agent selection in ASCVD, heart failure, and CKD.
We included 15 pivotal RCTs (8 SGLT2i-focused efficacy trials, 7 GLP-1RA CVOTs) and 8 up-to-date meta-analyses/network meta-analyses/guidelines. Key SGLT2i RCTs: EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58 (CVOTs) and kidney-focused CREDENCE, DAPA-CKD (also included nondiabetic CKD), with consistent HHF and kidney benefits.
Key GLP-1RA RCTs: LEADER, SUSTAIN-6, REWIND, HARMONY Outcomes, AMPLITUDE-O—each reporting MACE reduction to varying extents.
Quantitative synthesis (class-level, representative pooled evidence)
Safety
SGLT2i increased genital mycotic infections and rare DKA; amputation signal observed with canagliflozin in CANVAS (not universal). GLP-1RA increased GI adverse events (nausea/vomiting) and gallbladder disease; pancreatitis risk remains low/uncertain.
Tables
Table 1. Key Cardiovascular Outcome Trials by Class (population, n, primary outcome, follow-up, main finding)
Interpretation: SGLT2i trials consistently reduce HHF; some (e.g., empagliflozin) reduce CV death; GLP-1RA trials robustly reduce MACE and stroke.
Table 2. Kidney-Focused Trials and Renal Composites (CREDENCE, DAPA-CKD; include inclusion eGFR/albuminuria and primary kidney outcomes)
Interpretation: SGLT2i substantially slow CKD progression and reduce kidney failure across diabetic and nondiabetic CKD; GLP-1RA renal benefits are emerging but less pronounced in CKD-specific RCTs.
Table 3. Summary of Class Effects vs Placebo (Representative Pooled Estimates)
Table 4. Subgroup Effects (Established ASCVD vs multiple risk factors; baseline CKD; background SGLT2i/GLP-1RA)
Interpretation: SGLT2i benefits on HHF/kidney are independent of ASCVD status; GLP-1RA MACE reduction extends to lower-risk populations (e.g., REWIND). Benefits of each class persist regardless of background use of the other.
Table 5. Safety Profiles by Class (genital infections, DKA, amputation, fractures vs GI events, gallbladder disease)
Table 6. GRADE Summary of Findings (Outcome, effect direction, certainty: high/moderate/low)
Interpretation: High-certainty evidence supports SGLT2i for HHF/kidney outcomes and GLP-1RA for MACE/stroke; certainty is moderate for mortality and renal benefits with GLP-1RA.
This meta-analysis integrates landmark RCTs and contemporary syntheses to contrast SGLT2i and GLP-1RA class effects. We observed consistent, biologically plausible differences. SGLT2i robustly reduce HHF and kidney disease progression—benefits seen across diverse CVOTs and CKD-specific trials (CREDENCE, DAPA-CKD), likely via natriuresis, reduced intraglomerular pressure, hemodynamic effects, and cardiorenal crosstalk modulation. In contrast, GLP-1RA produce pronounced atherosclerotic risk reduction (MACE), with notable stroke benefit and modest effects on HHF, mediated through weight loss, blood pressure and lipid improvements, anti-inflammatory effects, and possible direct vascular actions.
Comparative reviews—including updated meta-analyses to 2024–2025—support these complementary profiles: SGLT2i outperform GLP-1RA for HHF and kidney endpoints; GLP-1RA are at least as effective and often better for MACE and stroke. Importantly, several analyses indicate that benefits persist irrespective of concomitant use of the alternate class, suggesting additive protection with combined or sequential therapy when clinically and economically feasible.
Our synthesis aligns with ADA 2025 guidance, which recommends either class for T2D with established ASCVD and prioritizes SGLT2i for patients with HF (any EF) or CKD (eGFR down to trial thresholds), while allowing dual-class use for maximal risk reduction. Renal benefits from GLP-1RA have become more evident in pooled analyses and AMPLITUDE-O, but the magnitude remains smaller than with SGLT2i in CKD-specific trials; ongoing dedicated renal outcome trials of GLP-1RA will refine this picture.
Safety considerations are crucial. SGLT2i increase genital infections and rarely DKA; canagliflozin’s amputation signal in CANVAS has not been generalizable across the class but warrants caution in high-risk patients. GLP-1RA commonly cause GI adverse effects and may increase gallbladder disease risk; pancreatitis risk appears low but is monitored. These differences should guide individualized therapy, alongside patient preferences (injectable vs oral), weight goals, cost/access, and comorbid conditions.
Limitations include limited direct head-to-head RCTs and heterogeneity in kidney outcome definitions across trials. Nonetheless, triangulation across multiple high-quality RCTs and recent meta-analyses provides consistent, actionable conclusions.
Clinical implications: Select SGLT2i first in T2D with HF or CKD; select GLP-1RA first when ASCVD (particularly stroke risk) predominates or substantial weight loss is desired; combine when clinically indicated and affordable.
SGLT2 inhibitors and GLP-1 receptor agonists both confer substantial cardiovascular and renal benefits in T2D. SGLT2i deliver larger reductions in HHF and kidney disease progression, whereas GLP-1RA excel at atherosclerotic event (MACE) reduction—especially stroke. Therapy should be individualized to a patient’s dominant risk phenotype, with strong rationale for combined or sequential use in high-risk patients.
Download
Download
Download
Download
Download XML
