Clinical trial NCT06613854: Effect of Early Combination Antihyperglycemic Treatment on Metabolic Control in Individuals With Type 2 Diabetes
Official title: Effect of Early Combination Antihyperglycemic Treatment With Metformin and Oral Semaglutide vs. Metformin and Empagliflozin on Glycemic and Metabolic Control in Individuals With Short Duration Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus (T2DM)
Keywords: E-SEMPA
Early Combination Antihyperglycemic Treatment
Metformin
Semaglutide
Empagliflozin
Glycemic Control
Metabolic Control
Type 2 Diabetes
Insulin Resistance
Time in Range
CGM
Continuous Glucose Monitoring
UMC Ljubljana
Lead sponsor: University Medical Centre Ljubljana
Sponsor class: OTHER
First posted: 2024-09-26
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to learn if early combination with two antidiabetic drugs further improves blood glucose control compared to a single drug regimen in adults with short duration of type 2 diabetes. It will also learn about the effect of the combination treatment on body weight, body composition, blood lipids, oxidative stress, inflammation, metabolic control, insulin resistance and insulin secretion from pancreas, together with its safety profile. The main questions it aims to answer are:

* Does early combination with two antidiabetic drugs improve blood glucose levels, determined by continuous glucose monitoring system?
* Is early combination treatment as safe as treatment with a single antidiabetic drug?
* Does early combination treatment reduces the need for rescue therapy?
* Does early combination treatment reduces body weight and improves body composition?
* Does early combination treatment improves blood lipid parameters, oxidative stress and inflammation?
* Does early combination treatment improves metabolic parameters?
* Does early combination treatment improves insulin resistance and insulin secretion?

Researchers will compare early combination treatment with metformin and either peroral semaglutide or empagliflozin to a single drug regimen with only metformin to see if the combination treatment works to treat type 2 diabetes.

Participants will:

* Take the combination of two antidiabetic drugs or only metformin for every day for 26 weeks.
* Visit the clinic four times during the study duration for checkups and tests.
* Carry a continuous glucose monitoring sensor for 14 days prior to study visits.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time in Range (TIR)
timeFrame: Period of 14 days prior to last study visit (week 26)
Secondary outcomes:
measure: Absolute Change in Time in Range (TIR)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Absolute Change in Glycated hemoglobin (HbA1c)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Time above Range (TAR)
timeFrame: Last study visit (week 26)
measure: Time below Range (TBR)
timeFrame: Last study visit (week 26)
measure: Time above Range (TAR) - Level 1 Hyperglycemia
timeFrame: Last study visit (week 26)
measure: Time above Range (TAR) - Level 2 Hyperglycemia
timeFrame: Last study visit (week 26)
measure: Time below Range (TBR) - Level 1 Hypoglycemia
timeFrame: Last study visit (week 26)
measure: Time below Range (TBR) - Level 2 Hypoglycemia
timeFrame: Last study visit (week 26)
measure: Time in Tight Range (TITR)
timeFrame: Last study visit (week 26)
measure: Coefficient of variation (CV)
timeFrame: Last study visit (week 26)
measure: Mean Time in Range (TIR)
timeFrame: Study visit at week 13 and week 26
measure: Mean glucose concentration
timeFrame: Last study visit (week 26)
measure: Proportion of participants with Coefficient of variation (CV) below or equal to 36%
timeFrame: Last study visit (week 26)
measure: Standard deviation of mean glucose concentration
timeFrame: Last study visit (week 26)
measure: Proportion of participants with Time in Range (TIR) above 70%
timeFrame: Last study visit (week 26)
measure: Proportion of participants with Time in Range (TIR) above 90%
timeFrame: Last study visit (week 26)
measure: Proportion of participants with Glycated hemoglobin (HbA1c) below 6.5%
timeFrame: Last study visit (week 26)
measure: Proportion of participants with Glycated hemoglobin (HbA1c) below 5.7%
timeFrame: Last study visit (week 26)
measure: Proportion of participants requiring rescue therapy with gliclazide
timeFrame: Baseline (week 0) to last study visit (week 26)
measure: Proportion of participants with severe hypoglycemia
timeFrame: Baseline (week 0) to last study visit (week 26)
measure: Proportion of participants with severe adverse events
timeFrame: Baseline (week 0) to last study visit (week 26)
measure: Proportion of patients withdrawing from the trial due to adverse events of the interventional drugs
timeFrame: Baseline (week 0) to last study visit (week 26)
Other outcomes:
measure: Change in Body Weight
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Proportion of participants with a reduction of Body Weight above or equal to 5%
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Proportion of participants with a reduction of Body Weight above or equal to 10%
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Waist Circumference
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Visceral Adipose Tissue Mass
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in the Proportion of the Total Body Fat Mass
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Total Cholesterol (TC)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of High Density Lipoprotein Cholesterol (HDL-C)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Low Density Lipoprotein Cholesterol (LDL-C)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Triglycerides (TG)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Apolipoprotein A1 (ApoA1)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Apolipoprotein B (ApoB)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Total Antioxidant Status
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Glutathione Peroxidase Activity in Erythrocytes
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Superoxide Dismutase Activity in Erythrocytes
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Uric Acid
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Advanced Oxidation Protein Products (AOPP)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Advanced Glycosylation End Products (AGE)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of 8-Isoprostane
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of high-sensitivity C-reactive protein (hs-CRP)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Interleukin-6 (IL-6)
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Beta-hydroxybutyrate
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Free Fatty Acids
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change of Insulin Resistance - Matsuda Index
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change of Insulin Resistance - HOMA-IR
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change of Insulin Sensitivity - HOMA2-%S
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change of Pancreatic Beta Cell Function - HOMA2-%B
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Alanine
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Leucine
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Isoleucine
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Valine
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Phenylalanine
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Methionine
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Lysine
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Glutamate
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Acylcarnitine C5
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Acylcarnitine C8:1
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Acylcarnitine C5-OH
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Acylcarnitine C4-OH
timeFrame: Baseline (week 0) and last study visit (week 26)
measure: Change in Concentration of Acylcarnitine C4-DC
timeFrame: Baseline (week 0) and last study visit (week 26)
Locations:
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana, Diabetes Outpatient Clinic
Study officials:
References: