SGLT2 Inhibitors for Metabolic Diseases

(INFORM_2 Trial)

Overseen By Sarah Chu, NP

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: SGLT2 inhibitors, Steroids

Disqualifiers: Type 1 diabetes, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 24 weeks

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Women with HIV have an increased risk of having a myocardial infarction (heart attack) as compared to women without HIV. One of the mechanisms underlying the increased risk of myocardial infarction among women with HIV may involve reduced ability to increase blood flow through large and small coronary arteries at times when increased flow of oxygen-carrying blood is needed. We are conducting a study randomizing women with HIV and either diabetes, chronic kidney disease, or both to health education alone or to health education plus referral to see either an Endocrinologist or a Nephrologist in a subspecialty clinic for consideration of treatment with medication in a class known as sodium glucose transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors are clinically approved for use in patients with diabetes or chronic kidney disease but have been shown to be underutilized in people with HIV. One of our key analytic aims will be to test if SGLT2 inhibitor therapy results in improved blood flow through the large and small coronary arteries among women with HIV and either diabetes, chronic kidney disease, or both but who have no history of myocardial infarction. A second aim will be to test if subspecialty clinic referral (with or without SGLT2 inhibitor therapy prescription) results in improved blood flow through the large and small coronary arteries among the same group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using SGLT2 inhibitors or certain systemic steroids or immune suppressant therapies.

What is the safety profile of SGLT2 inhibitors in humans?

SGLT2 inhibitors, used mainly for type 2 diabetes, are generally safe but can cause side effects like genital infections, dehydration, and rare serious issues like diabetic ketoacidosis. They may also increase the risk of bone fractures and lower limb amputation, especially with canagliflozin, and should be used cautiously in people with certain conditions like bladder cancer. ^{1 2 3 4 5}

How do SGLT2 inhibitors differ from other drugs for metabolic diseases?

SGLT2 inhibitors are unique because they lower blood sugar by increasing glucose excretion in urine, independent of insulin, which helps avoid low blood sugar (hypoglycemia). They also offer additional benefits like weight loss, improved blood pressure, and better heart and kidney health, making them distinct from other treatments for metabolic diseases. ^{6 7 8 9 10}

What data supports the effectiveness of the drug SGLT2 inhibitors for metabolic diseases?

Research shows that SGLT2 inhibitors, like dapagliflozin and empagliflozin, help control blood sugar levels, reduce body weight, and lower blood pressure in people with type 2 diabetes. They also provide cardiovascular and kidney protection, reducing the risk of heart failure and kidney disease progression. ^{6 11 12 13 14}

Who Is on the Research Team?

Markella V Zanni, MD

Principal Investigator

MGH/HMS

Are You a Good Fit for This Trial?

This trial is for women with HIV and either diabetes, chronic kidney disease, or both. Participants should not have a history of heart attacks. The study aims to help those who may be underusing SGLT2 inhibitors—a medication that could improve their coronary blood flow.

Inclusion Criteria

I was born female.

Coronary flow reserve <2.5 on screening cardiac positron emission tomography/computed tomography

I am between 45 and 75 years old.

Exclusion Criteria

Uncontrolled hypertension at screen, defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg

Hemoglobin A1c ≥8.5% at screen

I have a history of heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive health education and may be referred to a subspecialty clinic for consideration of SGLT2 inhibitor therapy

24 weeks

Regular visits as per clinical care

Follow-up

Participants are monitored for changes in coronary flow reserve and other biomarkers

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• SGLT2 Inhibitors

Trial Overview The study tests if health education combined with referral to an Endocrinologist or Nephrologist and potential treatment with SGLT2 inhibitors can enhance coronary blood flow in women with HIV and metabolic disorders. It's a randomized trial comparing the effects of just health education versus additional specialist care.

How Is the Trial Designed?

Group I: Health education plus subspecialty clinic referral for consideration of SGLT2 inhibitor therapy Experimental Treatment 1 Intervention

Participants randomized to this study arm will receive health education and will be referred to establish clinical care in either the MGH Lipid and Metabolism Clinic or the MGH Renal Clinic for consideration of SGLT2 inhibitor therapy. By study design (inclusion criteria), participants will have a clinical indication for SGLT2 inhibitor therapy (either diabetes or chronic kidney disease). SGLT2 inhibitor therapy (e.g. empagliflozin 10 mg by mouth daily or dapagliflozin 10 mg by mouth daily) may or may not be prescribed by the subspecialty clinician as part of routine clinical care, according to the clinician's clinical judgement. Participants will also receive health education.

Group II: Health Education Experimental Treatment 2 Interventions

Participants randomized to this study arm will receive health education alone.

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

SGLT2 inhibitors, like dapagliflozin, help lower blood sugar levels by increasing glucose excretion in urine, working independently of insulin, which is a unique mechanism among diabetes medications.

Clinical trials and real-life studies show that dapagliflozin not only improves glycemic control by reducing glycosylated hemoglobin but also contributes to weight loss and lower blood pressure, offering additional metabolic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Impact of dapagliflozin on cardiovascular risk factors. Beyond glycemic control]. Pallarés, V., Escobar, C., Egocheaga, I., et al.[2021]

SGLT2 inhibitors, a new class of oral medications for type 2 diabetes, effectively lower blood glucose levels by preventing the reabsorption of glucose and sodium in the kidneys, and they also provide cardiovascular and renal protection.

While SGLT2 inhibitors are generally well-tolerated, they carry risks of serious side effects such as hypoglycemia, hypotension, and infections, necessitating careful patient monitoring to manage these potential complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary. Mascolo, A., Di Napoli, R., Balzano, N., et al.[2022]

A review of 47 systematic reviews on SGLT-2 inhibitors found that most had low methodological quality, leaving uncertainty about the risks of important side effects in patients with type 2 diabetes.

Canagliflozin and dapagliflozin were linked to an increased risk of genital infections and diabetic ketoacidosis, while dapagliflozin also showed a significant risk for urinary tract infections; however, no SGLT-2 inhibitors were associated with a significant increase in acute kidney injury or bone fractures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with sodium glucose co-transporter 2 inhibitors: an overview of quantitative systematic reviews. Pelletier, R., Ng, K., Alkabbani, W., et al.[2022]

Citations

1. Spain pubmed.ncbi.nlm.nih.gov

[Impact of dapagliflozin on cardiovascular risk factors. Beyond glycemic control]. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Evaluation of the pharmacokinetics, pharmacodynamics and clinical efficacy of empagliflozin for the treatment of type 2 diabetes. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Empagliflozin in South Asians with type 2 diabetes: Real world data on effects on cardiometabolic parameters, safety and determinants of response to therapy from a diabetes practice in Sri Lanka. [2023]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter 2 inhibitors: from apple tree to 'Sweet Pee'. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of SGLT2 Inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical adverse effects of sodium-glucose cotransporter 2 inhibitors: Protocol for a systematic review and meta-analysis. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Adverse events associated with sodium glucose co-transporter 2 inhibitors: an overview of quantitative systematic reviews. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Best practices for safe use of SGLT-2 inhibitors developed from an expert panel Delphi consensus process. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Safety of Sodium-Glucose Co-Transporter 2 Inhibitors. [2022]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Therapeutic Interventions of Novel SGLT2 Inhibitors Against Metabolic Disorders: Transforming the Association into Perspectives. [2022]

12. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Benefits of SGLT2 Inhibitors Beyond Glycemic Control - A Focus on Metabolic, Cardiovascular and Renal Outcomes. [2022]

13. Japan pubmed.ncbi.nlm.nih.gov

[Sodium-Glucose Transporters as a Therapeutic Target for Diabetes from the Viewpoint of Drug Discovery and Pharmacotherapy]. [2018]

14. Switzerland pubmed.ncbi.nlm.nih.gov

SGLT2 Inhibitors: the Star in the Treatment of Type 2 Diabetes? [2020]