Comprehensive Review of SGLT2 Inhibitors and GLP-1 Receptor Agonists: Monotherapy vs. Combination Therapy in CKD and Cardiovascular Disease

Introduction

Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as crucial pharmacological agents in managing type 2 diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD). These drug classes provide independent and complementary benefits, and recent studies suggest that their combination may further enhance clinical outcomes. This article reviews key research on the individual and combined effects of SGLT2 inhibitors and GLP-1 receptor agonists, highlighting their impact on CKD progression, cardiovascular health, and the potential benefits of combination therapy.

1. SGLT2 Inhibitors: Key Research Findings

Study Name (Year)	Participants	Key Findings
EMPA-REG OUTCOME (2015)	Type 2 diabetes + High cardiovascular risk	Reduced cardiovascular mortality and all-cause mortality, 39% reduction in CKD progression, slower decline in eGFR
CANVAS Program (2017)	Type 2 diabetes + Cardiovascular disease or high risk	14% reduction in MACE risk, 40% reduction in CKD progression, decreased albuminuria
CREDENCE (2019)	Type 2 diabetes + CKD (eGFR 30–90 ml/min/1.73m²)	34% reduced risk of kidney-related death, dialysis, or kidney failure, delayed progression to ESKD, improved eGFR decline rate
DAPA-CKD (2020)	CKD (diabetic and non-diabetic, eGFR 25–75 ml/min/1.73m²)	39% reduction in CKD progression and kidney/cardiovascular mortality, effective in non-diabetic CKD patients
EMPA-KIDNEY (2022)	CKD patients (eGFR 20–45 ml/min/1.73m²)	28% reduction in CKD progression and kidney-related death, significant reductions in cardiovascular mortality and hospitalizations

2. GLP-1 Receptor Agonists: Key Research Findings

Study Name (Year)	Participants	Key Findings
LEADER (2016)	Type 2 diabetes + High cardiovascular risk	Liraglutide reduced cardiovascular mortality by 22%, slowed albuminuria progression by 26%
SUSTAIN-6 (2016)	Type 2 diabetes + High cardiovascular risk	Semaglutide reduced MACE risk by 26%, reduced albuminuria progression by 46%
REWIND (2019)	Type 2 diabetes + High cardiovascular risk	Dulaglutide reduced MACE risk, slowed albuminuria progression by 23%
FLOW (2024, Ongoing)	CKD + Type 2 diabetes (eGFR 50–75 ml/min/1.73m²)	Investigating semaglutide’s kidney-protective effects, final results pending
AWARD/AMPLITUDE Series	Type 2 diabetes (tirzepatide/efpeglenatide)	Demonstrated benefits in weight loss, glycemic control, and cardiovascular protection, potential CKD benefits still under investigation

3. Efficacy and Safety of Combination Therapy

3.1 Background of Combination Therapy

SGLT2 inhibitors and GLP-1 receptor agonists have distinct mechanisms of action. SGLT2 inhibitors reduce glucose reabsorption in the kidneys, promoting osmotic diuresis, improving glomerular hyperfiltration, and decreasing heart failure risk. GLP-1 receptor agonists enhance insulin secretion, suppress glucagon release, slow gastric emptying, promote weight loss, and reduce atherosclerotic cardiovascular events. The potential synergy between these two drug classes suggests enhanced renal and cardiovascular protection when used together.

3.2 Findings from FLOW Sub-Analysis and SMART-C Meta-Analysis

FLOW Trial Sub-Analysis (Mann JFE, et al., Nat Med. 2024)

• Investigated semaglutide in patients with and without SGLT2 inhibitor use.
• Cardiovascular benefits were similar in both groups, but renal benefits were more pronounced in those not taking SGLT2 inhibitors.
• Conclusion: Semaglutide provided kidney protection independently of SGLT2 inhibitors, but statistical synergy was not confirmed.

SMART-C Collaborative Meta-Analysis (Apperlo EM, et al., Lancet Diabetes Endocrinol. 2024)

• Pooled data from 12 RCTs comparing SGLT2 inhibitors in type 2 diabetes patients with and without GLP-1 receptor agonists.
• Consistent reductions in cardiovascular events and CKD progression, regardless of GLP-1 receptor agonist use.
• No significant difference in adverse effects between monotherapy and combination therapy groups.
• Combination therapy showed a trend toward greater kidney protection (HR 0.65, 95% CI 0.46-0.94), but further confirmation is needed.

3.3 Need for Large-Scale RCTs

Despite promising findings, large head-to-head RCTs directly comparing monotherapy vs. combination therapy remain necessary. Future studies should focus on:

• Patients with advanced CKD or severe heart failure.
• High-risk ASCVD patients to determine additional benefits of dual therapy.
• Confirming the synergistic kidney-protective effects suggested by meta-analyses.

4. References

1. Mann JFE, Rossing P, Bakris G, et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med. 2024;30:2849–2856.
2. Apperlo EM, Neuen BL, Fletcher RA, et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomized controlled trials. Lancet Diabetes Endocrinol. 2024;12:545–557.
3. Talat Alp Ikizler. The combination of SGLT2 inhibitors and glucagon-like peptide 1 receptor agonists: are 2 drugs better than 1? Kidney Int. 2025;107:385–388.

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