Effect of Early Combination Antihyperglycemic Treatment on Metabolic Control in Individuals With Type 2 Diabetes

Type 2 diabetes (T2D) is a progressive chronic disease and represents a significant risk factor for morbidity and mortality due to cardiovascular disease. In addition to managing glycemia, the use of antihyperglycemic medications with further and independent cardiovascular benefits is recommended in managing individuals with T2D. These medications primarily include sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). Traditionally, treatment of T2D followed a stepwise intensification by adding antihyperglycemic drugs if optimal glycemic control was not achieved. However, current American Diabetes Association guidelines recommend considering early combination therapy at treatment initiation, particularly at high baseline glycated hemoglobin (HbA1c) levels, to shorten the time to achieve glycemic goals.

In everyday clinical practice, however, treatment intensification is often delayed due to clinical inertia, even when glycemic control is suboptimal. Early intensive treatment of T2D has been shown to improve glycemic control, reduce mortality, and lower the risk of both microvascular and macrovascular complications, while also improving the durability of the glycemic effect.

Previous randomized clinical trials on early combination therapy for T2D have primarily focused on glycemic control, as determined by traditional glycemic parameters such as fasting glucose and HbA1c. However, new insights suggest that these measures alone are insufficient for a holistic assessment of glycemic control in diabetes. There is now a recognized need to consider additional indicators of glycemic control, obtained through continuous glucose monitoring (CGM) systems. Furthermore, data are lacking on the direct comparison of the early combination treatment with either SGLT2i or GLP-1RA on top of metformin.

In this 26-week, prospective, open-label, interventional, randomized, single-center clinical trial with a 3-week run-in period, we aim to investigate the effect of early combination treatment with metformin and GLP-1RA or SGLT2i compared to standard monotherapy with metformin and subsequent escalation of antihyperglycemic treatment on glycemic control, as assessed by continuous glucose monitoring systems and HbA1c, body weight, body composition, lipid profile, oxidative stress, inflammation, metabolic control, insulin resistance, and pancreatic beta-cell function in adults with short duration T2D. The primary outcome of the study will be glycemic control, assessed by time in range (TIR).

The study will include individuals of both sexes, of any race or ethnicity, aged between 18 and 70, with a duration of T2D of less than 2 years, HbA1c levels ≤8.0%, on monotherapy with metformin, and naive to treatment with GLP-1RA and SGLT2i.

After the initial 3-week run-in period, patients will be randomized (based on sex, age, and TIR during the run-in period) into three intervention groups in a 1:1:1 ratio:

(i) a control group, continuing metformin monotherapy; (ii) the first study group, receiving metformin and oral semaglutide; and (iii) the second study group, receiving metformin and empagliflozin.

Patients will then be monitored approximately every 13 weeks (3 months) up to 26 weeks (6 months). Prior to randomization, participants will receive a study package containing 3 sensors and 1 reader of the CGM system. The first sensor will be placed on the participants at the start of the run-in period, and subsequent sensors will be self-applied by participants at least 14 days before the last two study visits (at week 13 and week 26).

At each study visit, a review of medical records, a clinical examination, and blood collection for laboratory tests will be conducted. At randomization (week 0) and during the final study visit (week 26), all participants will undergo a modified oral glucose tolerance test (mOGTT) to assess insulin resistance and pancreatic beta-cell function. Additionally, the first 20 participants from each intervention group will undergo whole-body imaging to evaluate body composition. In the case of inadequately controlled glycemia, rescue treatment with gliclazide from the sulfonylurea class will be initiated.

Inclusion criteria

• Diagnosed with type 2 diabetes for up to 2 years (prior to randomization);
• Aged between 18 and 70 years, both sexes, of any race or ethnicity;
• HbA1c ≤8.0% at randomization;
• Baseline treatment with metformin at a steady daily dose of ≥1500 mg;
• Signed informed consent to participate in the study.

Exclusion criteria

• Treatment at any time in the past with SGLT2i, GLP-1RA, or DPP-4 inhibitors;
• Insulin treatment for longer than 2 weeks in the past;
• Body Mass Index below 22 kg/m2 or BMI above 40 kg/m2;
• Chronic kidney disease stages 3-5 (eGFR below 60 ml/min or the presence of albuminuria (urine albumin-to-creatinine ratio above 34 g/mmol);
• Known cardiovascular disease (angina pectoris, history of myocardial infarction, ischemic heart disease, heart failure, known carotid atherosclerosis, objectively proven peripheral arterial disease, or other known atherosclerotic disease at other locations);
• Moderate or severe liver disease (Child-Pugh stage B or C);
• Personal history of pancreatitis;
• Advanced heart failure (NYHA III-IV);
• Retinopathy or maculopathy or their active treatment;
• Pregnancy, expected pregnancy, or breastfeeding;
• Presence of active malignancy or personal history of malignancy within 5 years of study enrollment;
• Personal history of thyroid cancer; personal or family history of multiple endocrine neoplasia type 2 or family history of medullary thyroid carcinoma;
• Chronic inflammatory bowel disease;
• History of bariatric surgery or other gastrointestinal surgery that could affect drug or nutrient absorption;
• Frequent or severe urinary tract infections;
• Presence of a urinary catheter;
• Troublesome and recurrent genital fungal infections;
• Personal history of ketoacidosis;
• Symptomatic hypotension or predisposition to hypovolemia;
• History of organ transplantation;
• Allergy to any component in the semaglutide or empagliflozin oral tablet;
• Any medical or social circumstance that may limit participation in the study (e.g., inability to attend regular study visits);
• Any other condition that, in the opinion of the principal and responsible investigators, may affect the safety or efficacy of the treatment.