Beta Cell Function in Type 2 Diabetes: Differential Effects of SGLT2 Inhibitors and GLIP-Receptor Agonists

MaryAnn Banerji

Status and phase: Active, not recruiting; Phase 4

Conditions: Type 2 Diabetes (T2DM)

Treatments: Drug: SGLT-2 inhibitor; Drug: GLP1-RA

Study type: Interventional

Funder types: Other

Identifiers

NCT07325435

1876088 SUNY Downstate Medical

New York Community Trust (Other Grant/Funding Number)

Details and patient eligibility

About

Minorities have higher rates of diabetes, poorer glucose control, and higher complications and mortality rates than white people. Several recently approved diabetes medicines improve cardiovascular and renal outcomes through two different mechanisms. This study will explore key determinants of blood glucose levels namely beta cell function after short-term randomized, parallel group treatment with FDA approved Glucagon-Like Peptide-1 Receptor Agonists¬ (GLP-1 RA), or FDA approved Sodium-Glucose co-Transporter-2 Inhibitor (SGLT-2i). Because diabetes in black people shows a unique ability to recover pancreatic insulin secretion, it is important to determine whether the effects of these drug classes differentially improve pancreatic beta cell function.

Full description

Approximately 200 black people with DM2 will be screened, then stabilized on diet and exercise alone, metformin alone or metformin plus a sulfonylurea. Following stabilization, those meeting study entry criteria will be offered the treatment study with 60 randomized to 4 months of treatment with GLP-1 RA or a SGLT-2i administered according to FDA approved guidelines. After an overnight fast, an oral glucose tolerance test (OGTT) will be completed prior to randomization and after 4 months, or at earlier study termination.

Screening Visit Screening consent, medical history and physical exam (including height and weight) will be obtained, as well as baseline blood work (complete blood count, fasting glucose, A1c, lipid profile, BUN, creatinine and thyroid panel), electrocardiogram (EKG) and pregnancy test (if capable of conception).

Post-screening Visits These will occur monthly with additional visits as needed and may be by telephone or in-person, as determined by patient and staff. Adverse events, report of finger stick glucose determinations will be obtained. If in-person, weight and blood glucose (optional) will be obtained.

Final Screening Visit (In-person) Once stabilized, participants will be evaluated for whether they meet all study Inclusion Criteria and none of the study Exclusion Criteria. Weight, finger stick report, and adverse events will be obtained. Laboratory specimens (as above), EKG and pregnancy test will also be obtained.

After explanation of the study, including its voluntary nature, those meeting study entry criteria will be asked to read and sign the study consent form and scheduled for their Randomization Visit and baseline OGTT.

Randomization Visit After an over-night fast, the study's Inclusion and Exclusion Criteria will be reassessed to confirm eligibility. The 60 eligible participants will have a standard 75 mg oral glucose tolerance test (OGTT). A catheter is inserted in the forearm for the 2-3 hours with blood withdrawn through the catheter at -10 and 0 and +10, + 20, +30, +45, +60, +90 and +120 minutes. Samples will be analyzed for glucose, insulin, and C-peptide; extra blood will be stored for possible later analyses of other blood elements, such as other hormones and metabalolomics.

Month 1, 2 and 3 Visits Logs of finger sticks and weight will be obtained, as well as specific queries about possible adverse events.

Final Study Visit (Month 4 or earlier for premature ending of study) Finger stick log, weight, adverse events and end-study OGTT will be obtained, as at the Randomization Visit.

Enrollment: 60 estimated patients

Sex: All

Ages: 24 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Agrees to participate (signs and dates the informed consent) and agrees to all study procedures and conditions of the protocol.
2. Black (self-identified) patients with relatively recent onset (< 15 years) DM2
3. aged >= 24 years of age (adults < age 24 years old need additional resources to consistently participate, and may have different metabolism)
4. HbA1c between 6.9% and 10%, inclusive
5. BMI > 23 and < 45 kg/m2, and stable body weight over 2 months
6. In good general health, as evidenced by medical history and physical examination. And not having any of the specific items of the exclusion criteria.
7. Currently taking no diabetes medication or on stable doses (2 months) of metformin or metformin plus sulfonylureas without additional diabetes medication(s).
8. Ability to take and agree to taking oral medication and to self-inject
9. For persons of reproductive potential: negative pregnancy test, use of effective contraception for at least 1 month prior to screening, and agreement to use such a method during study participation, and for an additional 4 weeks after completing the use of the study drug. They will be counseled that if they wish to become pregnant, they should follow the standard practice of optimizing their blood glucose in preparation for pregnancy. Use of these study drugs are not considered standard of care for diabetes during pregnancy. Effective contraception includes tubal ligation, hysterectomy, oral, implanted or injected contraceptives, mechanical (IUD) and barriers (diaphragm, condoms, spermicides) methods.
10. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout the study, including following a diabetic diet and maintaining a physical activity program

Exclusion criteria

1. Poor general health, low kidney function (eGFR < 45), abnormal liver blood tests (AST and ALT > 3 times the ULN, Bilirubin 2 x ULN), serious cardiovascular, liver or renal disease, known proliferative retinopathy, type 1 diabetes, pancreatitis or pancreas cancer, medullary thyroid cancer, MEN2 (or family history of MEN2), current low hematocrit (< 35% for men and 33% for women, frailty, at risk for falls, current (past six months) alcohol or substance use disorder, history of a non-traumatic bone fracture, amputation, organ transplant, HIV or COVID, or if the patient cannot complete study activities.
2. Current regular use of DDP-4 inhibitors, insulin or GLP-1 RA or SGLT2-inhibitors
3. Currently pregnant, planned pregnancy in the next 7 months or nursing/lactating.
4. Known allergic reactions to either the study medication
5. Treatment with another investigational drug or other intervention within 4 months, or plan to enroll in another interventional study during their participation in this study
6. Planned major surgery
7. Recent (within 6 months): MI, Stroke, Cerebrovascular accident or unstable angina or revascularization procedures, grade 3 or 4 heart failure
8. Use of weight loss medication, weight loss surgery.
9. Use of glucocorticoids for chronic illness within 8 weeks prior to screening or likely to begin glucocorticoids during study period
10. Study doctor considers subject a poor study candidate
11. Cancer - History of active or untreated malignancy or in remission from a clinically significant malignancy for < 5 years; exception: basal cell carcinoma of the skin.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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60 participants in 2 patient groups

GLP1-RA

Active Comparator group

Description:

We will examine the effect of GLP-1 RA on pancreatic beta cell function as measured by insulin, C-peptide and glucose serum concentrations during OGTT.

Treatment:

Drug: GLP1-RA

SGLT-2i

Active Comparator group

Description:

We will examine the effect of SGLT-2i on pancreatic beta cell function as measured by insulin, C-peptide and glucose serum concentrations during OGTT

Treatment:

Drug: SGLT-2 inhibitor