Oral Hypoglycemic Therapy for Monogenic Variant Carriers of the Joslin Medalist Study

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of adding oral hypoglycemic agents (OHA) to existing insulin treatment in monogenic variant carriers of the Joslin 50-Year Medalist Study (Medalists), who are characterized by ≥50 years of insulin-dependent diabetes. Our primary objective is to evaluate whether the presence of human leukocyte antigen (HLA) high-risk alleles for diabetes (DR3 and/or DR4) can affect the effectiveness of OHA in these subjects.

Official Title
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A Pilot Trial of Adding Oral Hypoglycemic Therapy to Insulin Treatment in Monogenic Variant Carriers of the Joslin 50-Year Medalist Study

Conditions
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Type 1 Diabetes, Monogenic Diabetes

Intervention / Treatment
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* Drug: Metformin Extended Release Oral Tablet
* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Existing participants in the Joslin 50-Year Medalist Study Residing in the United States Capable of giving informed consent Known detectable C-peptide >0.05 ng/mL Exclusion Criteria: Known diagnosis of cancer or active inflammatory disease such as rheumatoid arthritis, lupus, and inflammatory bowel disease Recent history of myocardial infarction, angioplasty, bypass surgery, heart failure, angina, stroke, or uncontrolled hypertension>160/100 during the past 3 months Known diagnosis of cognitive dysfunction, dementia or Alzheimer's disease Pre-existing liver disease or liver function tests (AST or ALT)>3x the upper limit of normal Pre-existing kidney disease (Chronic Kidney Disease Stage IV and below, or estimated glomerular filtration rate<45 mL/min/1.73 m2) Active use of immunosuppressants Recipients of prior islet cell or pancreas transplantation Inability to travel due to frailty or health reasons Donated blood within the previous two (2) months

Ages Eligible for Study
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Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: HLA+ Group<br>Participants who are high-risk HLA-DR3 and/or DR4 (+); monogenic variant (+) with rare exome variant ensemble learner (REVEL) score>0.75; and both glutamic acid decarboxylase (GAD65) and islet antigen (IA2) autoantibody (-) | Drug: Metformin Extended Release Oral Tablet<br>* Initial oral hypoglycemic agent added to existing insulin treatment<br>Drug: Sitagliptin<br>* Secondary oral hypoglycemic agent added to existing insulin treatment (for those who are intolerant to or unable to achieve glycemic targets with metformin)<br>|
| Other: HLA- Group<br>Participants who are high-risk HLA-DR3 and DR4 (-); with known or yet unknown monogenic variants with REVEL score>0.75; and either GAD65 and IA2 autoantibody (-), or autoantibody (+) with titers close to the cutoff | Drug: Metformin Extended Release Oral Tablet<br>* Initial oral hypoglycemic agent added to existing insulin treatment<br>Drug: Sitagliptin<br>* Secondary oral hypoglycemic agent added to existing insulin treatment (for those who are intolerant to or unable to achieve glycemic targets with metformin)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycated hemoglobin (HbA1c) | Change in HbA1c (%) between the two study groups | 3 months and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily insulin dose | Change in daily insulin dose (units/kg body weight) between the two study groups | 3 months and 6 months | 
| Body mass index (BMI) | Change in BMI between the two study groups. Weight and height will be combined to report BMI in kg/m^2. | 3 months and 6 months | 
| C-peptide | Change in C-peptide (ng/mL) between the two study groups | 3 months and 6 months | 
| Total cholesterol | Change in total cholesterol (mg/dL) between the two study groups | 3 months and 6 months | 
| Low density lipoprotein (LDL)-cholesterol | Change in LDL-cholesterol (mg/dL) between the two study groups | 3 months and 6 months | 
| High density lipoprotein (HDL)-cholesterol | Change in HDL-cholesterol (mg/dL) between the two study groups | 3 months and 6 months | 
| Triglycerides | Change in triglycerides (mg/dL) between the two study groups | 3 months and 6 months | 
| Area under the plasma concentration versus time curve (AUC) of C-peptide | Change in AUC of C-peptide between the two study groups, as measured by the hyperglycemic/arginine clamp, at the end of the study | 6 months |