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

Trial Summary

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.

What data supports the effectiveness of the drug Empagliflozin for type 1 diabetes?

Empagliflozin, when used alongside insulin, has been shown to help control blood sugar levels in people with type 1 diabetes, as seen in a study where it reduced glucose exposure and variability. However, while it can improve blood sugar control, it also increases the risk of serious side effects like diabetic ketoacidosis, a dangerous condition that can occur when the body starts breaking down fats too quickly. ^{1 2 3 4 5}

Is empagliflozin safe for use in humans?

Empagliflozin, a type of SGLT2 inhibitor, has been shown to be generally safe in humans, with common side effects including urinary and genital tract infections. In people with type 1 diabetes, there is a slight increase in the risk of diabetic ketoacidosis (a serious diabetes complication) and urinary tract infections. ^{6 7 8 9 10}

How does the drug Empagliflozin differ from other treatments for type 1 diabetes?

Empagliflozin is unique because it is an SGLT2 inhibitor that helps lower blood sugar levels by increasing glucose elimination through the kidneys, working independently of insulin. Unlike other SGLT2 inhibitors, Empagliflozin at a low dose of 2.5 mg has shown efficacy without increasing the risk of diabetic ketoacidosis, a serious complication, making it a potentially safer option as an add-on to insulin therapy. ^{4 10 11 12 13}

What is the purpose of this trial?

Type 1 diabetes is an autoimmune disease where the body attacks the insulin-producing cells in the pancreas. In the absence of insulin, the body is unable to effectively use glucose for energy, resulting in high blood sugar levels. This leads to a lifelong need for intensive insulin therapy to manage blood sugar and prevent complications arising from elevated blood glucose levels. When insulin is low, the body produces ketone bodies. If ketone levels rise too high, they can lead to the dangerous condition known as diabetic ketoacidosis. Diabetic ketoacidosis remains a leading cause of mortality in children and young adults with type 1 diabetes. Sodium/glucose cotransporter 2 inhibitors, such as empagliflozin, are effective in lowering blood sugar but can also increase ketone levels, raising the risk of diabetic ketoacidosis. Empagliflozin is approved for type 2 diabetes and has demonstrated benefits in type 1 diabetes, including improved blood sugar control at lower doses and reduced risks of chronic kidney disease and mortality at higher doses. However, its use in type 1 diabetes is still off-label due to the heightened risk of diabetic ketoacidosis. Using empagliflozin at a commercial dose safely is desirable to maximize its potential renal benefits in type 1 diabetes. While there are measures to monitor ketone levels, current methods, such as finger prick tests, often detect issues too late to prevent diabetic ketoacidosis. Continuous ketone monitoring offers real-time tracking of ketone levels, which could enable timely interventions to maintain safe levels. Moreover, there is currently no data on continuous ketone metrics in individuals with type 1 diabetes using sodium/glucose cotransporter 2 inhibitors. We aim to understand the dynamics of ketone levels in people with type 1 diabetes using empagliflozin, including in challenging situations such as during exercise and low-carbohydrate diets while on sodium/glucose cotransporter 2 inhibitors. To this end, we will conduct an open- label, single-arm, outpatient study where 24 participants with type 1 diabetes will use continuous ketone monitoring for a 4-week run-in, followed by empagliflozin 2.5 mg for four weeks and then empagliflozin 10 mg for nine weeks. Participants will perform an exercise sub-study during the fourth week of the continuous ketone monitoring run-in and during the eighth week of empagliflozin 10 mg use. Certain participants will be invited to undergo a low-carbohydrate diet during the last week of empagliflozin 10 mg use. The results, if positive, may lead to i) novel long-term (6 months) data on ketone levels in those with type 1 diabetes using empagliflozin, including individuals on multiple daily injections and closed-loop therapy across a wide range of body mass index, ii) data on the relationship between empagliflozin, exercise, low-carbohydrate diets, and type 1 diabetes, and iii) the creation of important metrics for ketone thresholds that have not yet been characterized. Furthermore, we hope this preliminary study will inform future research to investigate the use of continuous ketone monitoring to allow for the safe use of higher doses of sodium/glucose cotransporter 2 inhibitors in people with type 1 diabetes.

Research Team

Michael Tsoukas, M.D.

Principal Investigator

Clinique Medicale Hygea

Eligibility Criteria

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

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

HbA1c level of < 11% within the last six months

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 (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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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). [2017]

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

Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. [2022]

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

SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks. [2020]

4. England 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. [2022]

5. England 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. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Sodium glucose cotransporter2 inhibitors for type 1 diabetes mellitus: A meta-analysis of randomized controlled trials. [2023]

7. Germany 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. [2022]

8. England 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). [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

The role of empagliflozin in the management of type 2 diabetes by patient profile. [2020]

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

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

11. United States 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. [2022]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Review in Type 1 Diabetes. [2021]

13. England 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. [2022]