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CETP and SGLT2 inhibitor combination therapy increases glycemic control: a 2x2 factorial Mendelian randomization

Bohdan B Khomtchouk1,2,3,4,5, Patrick Sun6, Zane A Maggio6

  • 1Department of BioHealth Informatics, Luddy School of Informatics, Computing, and Engineering, Indiana University, Indianapolis, IN, United States.

Frontiers in Endocrinology
|July 4, 2024
PubMed
Abstract

Insights

Combining cholesteryl ester transfer protein (CETP) and sodium-glucose cotransporter 2 (SGLT2) inhibitors genetically improves glycemic control and reduces diabetes risk. This dual inhibition offers a promising oral therapeutic strategy for metabolic diseases.

Area of Science:

  • Cardiovascular Pharmacology
  • Metabolic Disease Research
  • Genetic Epidemiology

Background:

  • Cholesteryl ester transfer protein (CETP) inhibitors show potential for repurposing in metabolic disease treatment.
  • CETP inhibitors may complement oral sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying insulin therapy.
  • Existing therapies for hyperlipidemia and diabetes present opportunities for combined treatment strategies.

Purpose of the Study:

  • To evaluate the combined effect of genetic inhibition of CETP and SGLT2 on glycemic control.
  • To compare dual inhibition against single-agent inhibition and control groups.
  • To assess the impact of combined CETP and SGLT2 inhibition on diabetes incidence.

Main Methods:

  • Utilized a 2x2 factorial Mendelian Randomization analysis.
  • Included 233,765 participants from the UK Biobank.
  • Assessed genetic variants associated with CETP and SGLT2 inhibition.

Main Results:

  • Dual genetic inhibition of CETP and SGLT2 significantly reduced glycated hemoglobin levels.
  • Combined inhibition showed a greater reduction in glycated hemoglobin compared to single-agent inhibition and controls.
  • The incidence of diabetes was lower with combined inhibition versus controls and SGLT2 inhibition alone.

Conclusions:

  • Combining CETP and SGLT2 inhibitor therapies may provide superior glycemic control compared to SGLT2 inhibitors alone.
  • Repurposing CETP inhibitors offers a potential oral therapeutic option for metabolic diseases.
  • This approach could benefit high-risk patients by delaying the need for injectable therapies.
Keywords:
CETPMendelian randomizationSGLT2cardioinformaticscombination therapydiabetesepidemiologyglycemic control

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