SGLT2 Inhibitors for Type 1 Diabetes

(EmpaCKM Trial)

Overseen By Linden Perz, Bachelor of Medical Sciences

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: McGill University

Must be taking: Insulin

Must not be taking: GLP1-RA, Glucocorticoids

Disqualifiers: DKA, Severe hypoglycemia, others

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

Compensation: Varies

Number of Visits: 4

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how empagliflozin, a drug typically used for type 2 diabetes, can help people with type 1 diabetes manage blood sugar levels. Researchers are particularly interested in empagliflozin's effect on ketone levels, which can lead to diabetic ketoacidosis if they rise too high. Participants will continuously monitor their ketone levels, try different doses of the drug, and observe how exercise and diet changes impact results. This study is open to individuals who have managed type 1 diabetes with intensive insulin therapy for at least a year and who regularly monitor their blood sugar levels. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking diabetes research.

Will I have to stop taking my current medications?

The trial requires that participants continue their current intensive insulin therapy without changes during the study. However, if you are using any anti-hyperglycemic agents other than insulin, you must stop them at least one week before the trial starts.

Is there any evidence suggesting that empagliflozin is likely to be safe for humans?

Research has shown that empagliflozin, a drug commonly used for type 2 diabetes, has been studied in people with type 1 diabetes. Some studies have found that it can help lower blood sugar and body weight without increasing the risk of low blood sugar. However, there is a risk of diabetic ketoacidosis, a serious condition caused by high levels of ketones, which is important to recognize.

Large studies in type 2 diabetes have shown no increase in serious side effects like amputations or fractures, suggesting that empagliflozin is generally well-tolerated. For type 1 diabetes, the safety information is less clear, but some research indicates that the rate of ketoacidosis is similar to other treatments when used correctly.

Empagliflozin is already approved for type 2 diabetes, providing some confidence in its safety. However, the risk of ketoacidosis in type 1 diabetes necessitates careful monitoring. This trial aims to better understand how to use it safely for type 1 diabetes, especially with real-time ketone monitoring. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for type 1 diabetes?

Unlike the standard insulin therapy for Type 1 Diabetes, empagliflozin is unique because it targets the SGLT2 protein in the kidneys, which helps reduce blood sugar by preventing glucose reabsorption. This mechanism not only lowers blood sugar levels but also aids in weight management and reduces the risk of cardiovascular complications, which are common concerns for individuals with diabetes. Researchers are excited about empagliflozin because it offers a novel approach that could complement insulin therapy, providing a more comprehensive management strategy for Type 1 Diabetes.

What evidence suggests that empagliflozin might be an effective treatment for type 1 diabetes?

Research has shown that empagliflozin, a type of medication, can lower blood sugar levels in people with type 1 diabetes, although it is mainly approved for type 2 diabetes. Studies have found that empagliflozin improves blood sugar control and aids in weight loss for those with type 1 diabetes without increasing the risk of low blood sugar. It also benefits kidney health by reducing signs of kidney stress. However, it can raise the risk of diabetic ketoacidosis, a serious condition involving high levels of ketones. In this trial, participants will use continuous ketone monitoring to manage this risk while taking empagliflozin. ^{1 2 6 7 8}

Who Is on the Research Team?

Michael Tsoukas, M.D.

Principal Investigator

Clinique Medicale Hygea

Are You a Good Fit for This Trial?

This trial is for people with Type 1 Diabetes who are interested in using a drug called empagliflozin, which isn't typically used for their condition. It's to see if continuous monitoring of ketone levels can help prevent diabetic ketoacidosis, a serious complication. Participants should be willing to undergo an exercise study and possibly a low-carb diet.

Inclusion Criteria

HbA1c level of < 11% within the last six months

I have been diagnosed with Type 1 Diabetes for over a year.

Currently using CGM

Exclusion Criteria

I have had a severe low blood sugar or diabetic ketoacidosis in the past 6 months.

I have been taking high doses of steroids for a month or less.

Body mass index < 20 kg/m2

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

Participants use continuous ketone monitoring for a 4-week run-in period

4 weeks

1 visit (in-person)

Treatment with Empagliflozin 2.5 mg

Participants receive empagliflozin 2.5 mg for four weeks

4 weeks

1 visit (in-person)

Treatment with Empagliflozin 10 mg

Participants receive empagliflozin 10 mg for nine weeks, including exercise and low-carb diet sub-studies

9 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Empagliflozin

Trial Overview The trial tests how well continuous ketone monitoring works when participants with Type 1 Diabetes take empagliflozin. They'll start without the drug, then take a small dose, and finally a higher dose while their ketone levels are tracked during daily activities and exercise.

How Is the Trial Designed?

Group I: SGLT2 inhibitor dose scalation to maximum tolerated dose with Continuous Ketone Monitor Experimental Treatment 1 Intervention

This is a single arm study where 24 participants with T1D will use a CKM for a 4-week run-in followed by empagliflozin 2.5 mg for four weeks then empagliflozin 10 mg for nine weeks. Participants will perform an exercise sub-study during the fourth week of the CKM run-in and during the eighth week of empagliflozin 10 mg use. Certain participants will be invited to undergo a low-carb diet during the last week of empagliflozin 10 mg use.

Who Is Running the Clinical Trial?

McGill University

Lead Sponsor

Trials

421

Recruited

1,017,000+

Published Research Related to This Trial

In a study of 75 patients with type 1 diabetes, empagliflozin as an adjunct to insulin significantly reduced 24-hour glucose exposure and variability, particularly at doses of 10 mg and 25 mg, while increasing the time spent in the target glucose range.

Empagliflozin did not increase the risk of hypoglycemia compared to placebo, indicating it is a safe option for managing glucose levels in patients with type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucose Exposure and Variability with Empagliflozin as Adjunct to Insulin in Patients with Type 1 Diabetes: Continuous Glucose Monitoring Data from a 4-Week, Randomized, Placebo-Controlled Trial (EASE-1). Famulla, S., Pieber, TR., Eilbracht, J., et al.[2017]

In a 29-day study involving 33 patients with type 1 diabetes, sotagliflozin significantly reduced bolus insulin doses by 32.1% and improved glycemic control, as indicated by lower mean daily glucose levels and a decrease in HbA1c by 0.55%.

Sotagliflozin also increased the percentage of time patients spent in the target glucose range (70-180 mg/dL) to 68.2% and decreased time spent in the hyperglycemic range (>180 mg/dL) to 25%, all while promoting weight loss without increasing the risk of hypoglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Sands, AT., Zambrowicz, BP., Rosenstock, J., et al.[2022]

Empagliflozin, a newly approved SGLT2 inhibitor for type 2 diabetes, effectively lowers blood sugar levels, with an average reduction in HbA1c of about -0.8% and a decrease in fasting plasma glucose by approximately -2 mmol/L, as shown in multiple international studies.

The drug is generally safe, with a low risk of hypoglycemia and common side effects including urinary and genital tract infections, making it suitable as a first-line treatment or as an add-on therapy to other diabetes medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of empagliflozin in the management of type 2 diabetes by patient profile. Hedrington, MS., Davis, SN.[2020]

Sotagliflozin significantly improves glycemic control in adults with type 1 diabetes, reducing HbA1c levels and insulin requirements while also enhancing time in the target glucose range, based on a meta-analysis of six trials involving 3,238 participants over 4 to 52 weeks.

While sotagliflozin reduces the incidence of hypoglycemia, it does increase the risk of diabetic ketoacidosis and other side effects, indicating that careful patient management and insulin dose adjustments are necessary to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of dual SGLT 1/2 inhibitor sotagliflozin in type 1 diabetes: meta-analysis of randomised controlled trials. Musso, G., Gambino, R., Cassader, M., et al.[2022]

SGLT2 inhibitors, such as canagliflozin and dapagliflozin, show significant short-term efficacy in lowering HbA1c levels in patients with type 1 diabetes, particularly within the first 8-12 weeks of treatment, but this effect diminishes over longer durations (up to 52 weeks).

However, the use of SGLT2 inhibitors is associated with a significantly increased risk of serious adverse events, particularly diabetic ketoacidosis, with estimates suggesting one additional case for every 26 patient-years of treatment, raising concerns about their overall safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks. Taylor, SI., Blau, JE., Rother, KI., et al.[2020]

Empagliflozin is an effective oral medication for type 2 diabetes that works independently of insulin, showing improvements in blood glucose levels, body weight, and blood pressure across various patient populations.

It has been found to be well tolerated with no increased risk of hypoglycemia compared to placebo, making it a safe option for managing diabetes either alone or in combination with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. White, JR.[2018]

Dapagliflozin, a selective SGLT2 inhibitor, has been shown to improve glycaemic control in adults with type 1 diabetes (T1D) and a BMI of ≥27 kg/m2, allowing for reduced insulin doses and weight loss over 24 weeks, with effects maintained up to 52 weeks.

The drug has a favorable safety profile, with a lower incidence of diabetic ketoacidosis in patients with higher BMI compared to the overall population, making it a promising adjunct treatment for those not achieving adequate control with insulin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Review in Type 1 Diabetes. Paik, J., Blair, HA.[2021]

In a retrospective study of 37 Saudi patients with type 1 diabetes, empagliflozin as an adjunctive therapy led to a significant reduction in HbA1c levels by 0.82% after an average follow-up of 15.8 months, indicating improved glycemic control.

While there was a mild, non-significant weight reduction of 1.7 kg and a decrease in total daily insulin dose by 2.9 units, the treatment was associated with a slight increase in the risk of diabetic ketoacidosis (10.8%) and urinary tract infections (2.7%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of SGLT2 Inhibitors as Adjunctive Treatment in Type 1 Diabetes in a Tertiary Care Center in Saudi Arabia. Fallatah, W., Brema, I., Alobedallah, A., et al.[2022]

SGLT2 inhibitors (like dapagliflozin and empagliflozin) and the dual SGLT1/SGLT2 inhibitor (sotagliflozin) have been shown to improve blood sugar control and reduce body weight in type 1 diabetes without increasing the risk of hypoglycemia, based on recent phase 3 clinical trials.

To address the increased risk of diabetic ketoacidosis (DKA) associated with SGLT inhibitors in type 1 diabetes, a 'STOP DKA Protocol' has been developed as a practical strategy to minimize this risk while still benefiting from the medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter inhibitors, their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: The STOP DKA Protocol. Goldenberg, RM., Gilbert, JD., Hramiak, IM., et al.[2021]

SGLT-2 inhibitors and dual SGLT-1/2 inhibitors, when used alongside insulin, significantly improve glycaemic control in type 1 diabetes patients, leading to reductions in glycated hemoglobin and glucose variability over trials lasting up to 52 weeks.

While these medications can reduce body weight and insulin requirements, they are associated with a higher risk of genitourinary infections and a low incidence of diabetic ketoacidosis, necessitating careful monitoring and risk management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter inhibitors as adjunctive treatment to insulin in type 1 diabetes: A review of randomized controlled trials. Boeder, S., Edelman, SV.[2022]

In a study of 75 patients with type 1 diabetes, empagliflozin as an adjunct to insulin significantly increased urinary glucose excretion and improved HbA1c levels after 28 days, while also reducing the total daily insulin dose and body weight compared to placebo.

The treatment was found to be safe, as it did not increase the risk of hypoglycemic episodes, with low rates of symptomatic hypoglycemia reported across all empagliflozin doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Pieber, TR., Famulla, S., Eilbracht, J., et al.[2022]

Phase 3 trials of SGLT inhibitors (dapagliflozin, empagliflozin, and sotagliflozin) in adults with type 1 diabetes showed significant reductions in hemoglobin A1C, weight, and total daily insulin dose without increasing the risk of hypoglycemia over 52 weeks.

While SGLT inhibitors can provide meaningful benefits as adjuncts to insulin therapy, there is an increased risk of diabetic ketoacidosis (DKA), except for empagliflozin at 2.5 mg, which showed no increased DKA incidence and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-Glucose Cotransporters as Potential Therapeutic Targets in Patients With Type 1 Diabetes Mellitus: An Update on Phase 3 Clinical Trial Data. Patel, K., Carbone, A.[2022]

SGLT2 inhibitors significantly lower key diabetes markers in type 1 diabetes patients, including glycated hemoglobin (HbA1c) and fasting plasma glucose, while also reducing body weight and total insulin dosage, based on a meta-analysis of 16 randomized controlled trials involving 7192 patients.

Importantly, the use of SGLT2 inhibitors does not increase the risk of hypoglycemia, urinary tract infections, or diarrhea, suggesting they can be safely integrated into treatment regimens for type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium glucose cotransporter2 inhibitors for type 1 diabetes mellitus: A meta-analysis of randomized controlled trials. Nan, J., Wang, D., Zhong, R., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6709813/

Empagliflozin in type 1 diabetes - PMC In addition, treatment with empagliflozin resulted in a placebo-corrected reduction in body weight (up to −3.4 kg), systolic blood pressure (up ...

2. pro.boehringer-ingelheim.com pro.boehringer-ingelheim.com/us/products/jardiance/t2d/efficacy

T2D Efficacy Data | Jardiance® (empagliflozin) tablets JARDIANCE is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase their risk of diabetic ketoacidosis.

3. diabetesjournals.org diabetesjournals.org/care/article/41/12/2560/36495/Empagliflozin-as-Adjunctive-to-Insulin-Therapy-in

Empagliflozin as Adjunctive to Insulin Therapy in Type 1 ... Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between ...

4. journals.lww.com journals.lww.com/cjasn/fulltext/2021/11000/kidney_effects_of_empagliflozin_in_people_with.14.aspx

Kidney Effects of Empagliflozin in People with Type 1... Similar to observations in type 2 diabetes, in the pooled analysis in participants with baseline UACR ≥30 mg/g, UACR decreased by 55% with empagliflozin 25 mg ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11873775/

The effects of empagliflozin in patients with type 1 diabetes In this trial, empagliflozin 10 mg treatment for 12 weeks improved glycemic control and reduced total daily insulin doses and BMI in patients with T1D. The ...

6. boehringer-ingelheim.com boehringer-ingelheim.com/us/media/press-releases/jardiance-empagliflozin-analysis-reinforces-established-safety-profile

Jardiance® (empagliflozin) T2D Analysis on Safety Profile Analysis of 12,500 adults with type 2 diabetes from 19 studies showed amputations and fractures were not increased with Jardiance compared ...

7. endocrinolrespract.org endocrinolrespract.org/en/efficacy-and-safety-of-empagliflozin-in-type-1-diabetes-mellitus-patients-a-systematic-review-1317

Efficacy and Safety of Empagliflozin in Type 1 Diabetes ... As the efficacy and safety of empagliflozin remain poorly studied in Type 1 diabetes mellitus (T1DM) patients, this narrative-systematic review aims to review ...

8. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/jcpt.13521

Efficacy and safety of empagliflozin at different doses in ... High-daily doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the ...