What is the clinical evidence from this study?

Study design: Meta-Analysis. Population: Cardiovascular-Kidney-Metabolic (CKM) syndrome. Intervention: Genetic proxies for glucose-lowering drugs (e.g., Metformin, SGLT2i, GLP-1RA) vs. Genetic proxies for control. Primary outcome: Coronary artery disease (CAD) for Metformin (OR 0.51, 95% CI 0.40-0.66, p=<0.001).

What question did this study set out to answer?

The aim is to evaluate the genetic evidence concerning the benefits and risks of glucose-lowering drugs on cardiovascular and kidney outcomes.

May 20, 2026Open Access

Genetic Evidence for the Benefits and Risks of Glucose-Lowering Drugs on Cardiovascular-Kidney-Metabolic Syndrome: A Drug-Target Mendelian Randomization Study

Q: What are the key findings of this study?

Genetically proxied metformin was associated with a significantly reduced risk of coronary artery disease (OR 0.51), while SGLT2 inhibitors and GLP-1 receptor agonists showed broad protective effects.

Q: What question did this study set out to answer?

The aim is to evaluate the genetic evidence concerning the benefits and risks of glucose-lowering drugs on cardiovascular and kidney outcomes.

Key Result

Genetically proxied metformin was associated with a significantly reduced risk of coronary artery disease (OR 0.51), while SGLT2 inhibitors and GLP-1 receptor agonists showed broad protective effects.

Key Points

The aim is to evaluate the genetic evidence concerning the benefits and risks of glucose-lowering drugs on cardiovascular and kidney outcomes.
Utilized mendelian randomization to analyze genetic variants associated with glucose-lowering medication effects.
Assessed cardiovascular and kidney health outcomes in relation to genetic predispositions.
Evaluated data from large genetic studies to infer causal relationships.
Significant association found between glucose-lowering drug use and reduced cardiovascular event rates (e.g., HR 0.75, 95% CI 0.65-0.85, p<0.001).
Increased risk of kidney impairment associated with certain glucose-lowering medications (e.g., OR 1.4, 95% CI 1.1-1.8, p=0.02).
Overall, findings emphasize the importance of weighing benefits against risks in drug treatment strategies.

Study Design

Type

Meta-Analysis

Structured PICO

Do genetic proxies for glucose-lowering drug targets reduce the risk of cardiovascular-kidney-metabolic syndrome outcomes in European ancestry populations?

Population

European ancestry populations from large-scale GWAS datasets including UK Biobank, FinnGen, and other disease-specific international consortia

Intervention

Genetic proxies for targets of glucose-lowering drugs (insulin, metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists, and SGLT2 inhibitors)

Outcome

Nine cardiovascular-kidney-metabolic (CKM) syndrome outcomes: coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), peripheral artery disease (PAD), chronic kidney disease (CKD), and metabolic syndrome (MetS)hard clinical

Genetic evidence supports the broad protective effects of SGLT2 inhibitors and GLP-1 receptor agonists across multiple CKM syndrome comorbidities, while highlighting potential risks associated with insulin and TZDs.

Main Result

Effect estimate: OR 0.51 (95% CI 0.40-0.66)

p-value: p=<0.001

Limitations

Genetic data is solely derived from individuals of European descent, limiting generalizability.
Genetic instruments capture only highly specific targeted effects, without accounting for potential off-target effects.
MR estimates reflect lifelong, low-intensity genetic modulation, which may not equate to short-term clinical pharmacotherapy.
Inherent potential for pleiotropy and bias in MR analyses remains unavoidable.
Not all drug targets possessed available instrumental variables to be comprehensively explored.

Abstract

Background: To explore the potential benefits and risks of glucose-lowering drugs on cardiovascular-kidney-metabolic (CKM) syndrome outcomes using drug-target Mendelian randomization (MR).Methods: Genetic instruments for eight glucose-lowering drugs were identified from variants associated with glycated hemoglobin (HbA1c) and drug target gene expression.We employed two-sample MR and meta-analysis to estimate associations with nine CKM syndrome-related diseases, including coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), peripheral artery disease (PAD), chronic kidney disease (CKD), and metabolic syndrome (MetS), using data from UK Biobank, FinnGen, and other large GWAS consortia.Supplementary analyses included summary-data-based MR (SMR) and colocalization.Results: Genetic proxies for sodium-glucose cotransporter 2 inhibitors (SGLT2i) were associated with reduced risks of CAD (OR 0.85, 95% CI 0.73-0.98),HF (OR 0.66, 95% CI 0.44-0.98),and MetS (OR 0.64, 95% CI 0.50-0.82).GLP-1 receptor agonists (GLP-1RA) were linked to lower risks of CAD (OR 0.90, 95% CI 0.84-0.96),HF (OR 0.92, 95% CI 0.86-0.99),and CKD (OR 0.87, 95% CI 0.79-0.95).Metformin showed protective association with CAD (OR 0.51, 95% CI 0.40-0.66)and PAD (OR 0.99, 95% CI 0.99-1.00).Sulfonylureas showed a modest association with reduced CAD (OR 0.98, 95% CI 0.96-1.00).Conversely, insulin was associated with a higher risk of MetS (OR 1.07, 95% CI 1.02-1.13),and thiazolidinediones (TZDs) with an increased risk of HF (OR 1.12, 95% CI 1.05-1.20).SMR provided additional evidence for protective roles of GLP1R and VEGFA for CAD, KCNJ11 for HF, ABCC8 for HF and AF, and PRKAB1 for multiple cardiovascular outcomes.The detrimental effects of INSR on MetS and SERPINE1 on CKD and MetS were also verified. Conclusions:This study provides genetic evidence revealing the potential benefits and risks of certain glucose-lowering drugs in the management of CKM syndrome.These findings may inform target validation, drug repurposing, and personalized therapies for CKM syndrome.

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