Metformin Effects According to SLC16A11 Carrier Status

Type 2 diabetes (T2D) is a major global health problem and is closely associated with obesity and an increased risk of microvascular and macrovascular complications. A risk haplotype located in the SLC16A11 gene has been associated with a higher susceptibility to T2D and may contribute substantially to the increased prevalence of the disease in the Mexican population. The SLC16A11 gene encodes a bidirectional solute transporter involved in the transport of monocarboxylates such as pyruvate and lactate. However, it is not yet clear whether this genetic variation influences the metabolic response to metformin.

This prospective, analytical, observational study aims to compare the effect of metformin treatment between adults with T2D who are carriers and noncarriers of the SLC16A11 risk variant. A total of 154 participants are planned to be included. Eligible participants will be men and women aged 18 to 65 years with T2D, glycated hemoglobin of 8% or lower, and an estimated glomerular filtration rate greater than 60 mL/min. Participants may be untreated or receiving metformin alone or as part of dual pharmacological therapy.

All participants will receive extended-release metformin with gradual dose titration according to tolerance. Treatment will begin with 750 mg at night during the first week, increase to 750 mg in the morning and 750 mg at night during the second week, and may reach 750 mg three times daily from the third week onward. The target dose will be the maximum tolerated dose, ranging from 1,500 to 2,250 mg/day. Telephone follow-up will be conducted during titration to assess tolerance and guide dose adjustment.

Participants will be followed for 6 months. The primary objective is to compare the change in glycated hemoglobin between carriers and noncarriers of the SLC16A11 risk variant. Additional outcomes will include the seven-point capillary glucose profile, liver enzymes, visceral fat, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and lactate concentrations.

The study is based on the hypothesis that carriers of the SLC16A11 risk variant will have a smaller reduction in glycated hemoglobin, estimated at 0.5 percentage points, after 6 months of metformin treatment compared with noncarriers. Understanding whether this genetic variant modifies the response to metformin may contribute to a more personalized therapeutic approach and improve knowledge of the mechanisms involved in metformin-mediated glucose regulation.

Participants receiving three glucose-lowering medications or insulin, as well as those who are pregnant, breastfeeding, have a body mass index of 45 kg/m² or higher, are participating in another study, or have selected chronic diseases such as HIV infection, cancer, or rheumatologic disease, will be excluded. Participants who cannot tolerate at least 1,500 mg/day of metformin, develop an estimated glomerular filtration rate below 30 mL/min during follow-up, or experience a serious adverse event related to metformin will be withdrawn from the study.

Inclusion criteria

• Male and female participants
• Aged 18 to 65 years
• Diagnosis of type 2 diabetes
• Estimated glomerular filtration rate (eGFR) >60 mL/min
• Glycated hemoglobin (HbA1c) ≤8%
• Participants who are treatment-naïve, receiving metformin monotherapy, or receiving dual glucose-lowering therapy
• Participants who agree to take part in the study

Exclusion criteria

• Participants receiving treatment with three glucose-lowering medications
• Participants receiving insulin therapy
• Pregnancy
• Breastfeeding
• Chronic conditions such as HIV infection, cancer, or rheumatologic diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)
• Body mass index (BMI) ≥45 kg/m²
• Concurrent participation in another research study