Semaglutide and Dapagliflozin in Diabetic Patients With Different Pathophysiology

Current anti-diabetic treatment fails to stop the progressive course of the disease. Recent studies have revealed a surprisingly high variability in the diabetic phenotype. The investigators propose that anti-diabetic treatment should ideally target the underlying pathophysiology of each individual patient. The investigators will therefore test whether the effect of two approved anti-diabetic drugs differs between individuals at different ends of the pathophysiological spectrum: 1) patients with poor insulin secretion, here termed SIDD and 2) patients with high insulin resistance, here termed SIRD. The study may open up a new avenue for more precise treatment of diabetic patients that would be of immediate clinical relevance.

Study Overview

• Status: Active, not recruiting
• Conditions: Type2 Diabetes
• Intervention / Treatment: Drug: Semaglutide; Drug: Dapagliflozin

Detailed Description

The trial is a clinical phase II study that will be randomized and open-label with fixed stratification variables (SIDD and SIRD) to analyze if the response to anti-diabetic drugs differs between patients with distinct pathophysiology, as captured by SIDD and SIRD. The compounds used are semaglutide and dapagliflozin, which will be randomized to patients of each subgroup using a parallel group design.

The clusters (SIDD and SIRD) will be used as a practical tool to distinguish individuals who are at different ends of the pathophysiological spectrum.

The investigators will recruit 200 patients from the ANDIS registry with HbA1c ≥42 mmol/mol on metformin monotherapy. Half of them will have SIDD and half will have SIRD characteristics. The patients will be randomized (open-label) to receive semaglutide or dapagliflozin for six months in addition to metformin.

The investigators will recruit participants on metformin monotherapy with stable dose for the last three months. Metformin dose at inclusion (as prescribed by their regular physician) is maintained throughout the study; the investigatorswill correct for metformin dose in the analyses. Patients randomized to add semaglutide will receive injection training at the study site and inject 0.25 mg subcutaneously once weekly during the first four weeks, followed by 0.5 mg weekly for the subsequent four weeks and finally 1.0 mg weekly throughout the study. Those randomized to dapagliflozin will receive 10 mg orally once daily in addition to metformin. The participants will attend a screening visit followed by three study visits at 0, 3, 6 months. At the first and last study visit they will undergo an OGTT. HbA1c will be measured at all study visits.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Skane
    • Malmö, Skane, Sweden, 20502
      • Anders Rosengrentest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• • Diabetes mellitus based on prior documentation or treatment with anti-hyperglycemic medication or diagnosed according to the WHO criteria (random plasma glucose >11.1 mmol/L or fasting glucose >7.0 mmol/L or HbA1C ≥6.5%) and disease characteristics typical for SIDD or SIRD according to the ANDIS clustering

  • Ongoing metformin therapy with constant dose the last three months
  • Age 18 years or above
  • HbA1c ≥42 and <91 mmol/mol
  • Women who are not postmenopausal and who have not undergone surgical sterilization must have no current pregnancy, which will be assessed by pregnancy test, must take precautions to avoid pregnancy throughout the study and for 4 weeks after intake of the last dose and must be willing to use highly effective birth control methods. Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods.
  • Willingness to take injectable and oral medication
  • Written informed consent

Exclusion Criteria:

• • Type 1 diabetes, LADA, MODY, secondary diabetes or history of diabetic ketoacidosis

  • Anti-diabetic treatment other than metformin within 90 days prior to randomization or changed metformin dose within 90 days prior to randomization
  • Known acute cardiovascular event, e.g. transient ischemic attack, stroke, acute coronary syndrome, decompensated heart failure, coronary by-pass surgery or other coronary vessel intervention within 90 days prior to screening.
  • Heart failure NYHA class IV
  • History of acute or chronic pancreatitis
  • Known liver cirrhosis
  • Blood pressure above 170/110 mm Hg
  • A level of aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT), ALP or bilirubin of more than three times the upper limit of the normal range
  • Current chronic daily treatment with an oral steroid at a dose equivalent to oral prednisolone ≥10 mg (e.g., betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg)
  • Pregnancy or breast-feeding
  • Known galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
  • Estimated glomerular filtration rate <45 ml/min/1,73 m2 or unstable or rapidly progressing renal disease
  • Participant unable to understand the study information herself or himself
  • Involvement in the planning and/or conduct of the study
  • Participation in other clinical trial which may affect the outcome of the present study
  • Any condition or treatment that in the judgment of the investigator makes it difficult or unsafe to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: semaglutide; Patients randomized to add semaglutide (Ozempic) will receive injection training at the study site and inject 0.25 mg subcutaneously once weekly during the first four weeks, followed by 0.5 mg weekly for the subsequent four weeks and finally 1.0 mg weekly throughout the study.	Drug: Semaglutide; Ozempic s.c. once weekly for 6 months; Other Names: Ozempic
Active Comparator: dapagliflozin; Those randomized to dapagliflozin will receive 10 mg orally once daily in addition to metformin.	Drug: Dapagliflozin; Forxiga 10 mg p.o. once daily for 6 months; Other Names: Forxiga

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hba1c	The primary endpoint will be the intraindividual change of HbA1c in response to semaglutide or dapagliflozin relative to baseline in the two patient groups.	6 months

Collaborators and Investigators

• Sponsor: Region Skane
• Collaborators: Göteborg University

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2020
• Primary Completion (Actual): December 15, 2021
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: June 25, 2020
• First Submitted That Met QC Criteria: June 25, 2020
• First Posted (Actual): June 30, 2020

Study Record Updates

• Last Update Posted (Actual): October 21, 2022
• Last Update Submitted That Met QC Criteria: October 19, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: DIAB1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No