SGLT2 Inhibitors for Type 1 Diabetes
(EmpaCKM Trial)
Recruiting in Palo Alto (17 mi)
Overseen byMichael Tsoukas, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: McGill University
Must be taking: Insulin
Must not be taking: GLP1-RA, Glucocorticoids
Disqualifiers: DKA, Severe hypoglycemia, others
No Placebo Group
Trial Summary
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.
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.
12345Is 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.
678910How 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.
410111213Eligibility 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
+5 more
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
+2 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: SGLT2 inhibitor dose scalation to maximum tolerated dose with Continuous Ketone MonitorExperimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Hygea Medical ClinicMontreal, Canada
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Who Is Running the Clinical Trial?
McGill UniversityLead Sponsor
References
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]We evaluated the effect of empagliflozin as adjunct to insulin on 24-h glucose exposure and variability in patients with type 1 diabetes.
Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. [2022]To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes.
SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks. [2020]Sodium-glucose co-transporter-2 (SGLT2) inhibitors have several beneficial effects in patients with type 2 diabetes, including glucose lowering, weight loss, blood pressure lowering, and a reduced risk of major adverse cardiovascular events. To address high unmet medical need via improved glycaemic control, several clinical trials have been done to assess the efficacy and safety of SGLT2 inhibitors in combination with insulin therapy in patients with type 1 diabetes. In this Personal View, we summarise data from eight clinical trials of canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin in patients with type 1 diabetes. HbA1c-lowering efficacy was greatest at 8-12 weeks of therapy, but the magnitude of HbA1c lowering waned with longer duration of treatment (up to 52 weeks). Data are not yet available to establish for how long glycaemic efficacy could be sustained during long-term therapy in patients with type 1 diabetes. Moreover, SGLT2 inhibitor therapy induces serious adverse events, including a roughly six-times increased risk of diabetic ketoacidosis. The US Food and Drug Administration estimated that one additional case of ketoacidosis will occur for every 26 patient-years of exposure of patients with type 1 diabetes to sotagliflozin therapy. Assuming a case mortality of 0·4%, this estimate translates into 16 additional deaths per year per 100 000 patients with type 1 diabetes undergoing treatment. These considerations raise important questions about the risk-to-benefit profile of SGLT2 inhibitors when used as adjunctive therapy in patients with type 1 diabetes.
Efficacy and safety of dual SGLT 1/2 inhibitor sotagliflozin in type 1 diabetes: meta-analysis of randomised controlled trials. [2022]To assess the efficacy and safety of dual sodium glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin in type 1 diabetes mellitus.
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]Recent phase 3 clinical trials have evaluated the impact of adding sodium-glucose co-transporter (SGLT) inhibitors to the type 1 diabetes armamentarium. These trials studied SGLT2 inhibitors (dapagliflozin and empagliflozin) and a dual SGLT1 and SGLT2 inhibitor (sotagliflozin), and demonstrated that these oral non-insulin antihyperglycaemic medications are able not only to improve glycaemic control, but also to reduce body weight and extend time in range without increasing rates of hypoglycaemia in type 1 diabetes. Diabetic ketoacidosis (DKA) is a feature of type 1 diabetes and the risk is increased when SGLT inhibitors are used in type 1 diabetes. To minimize the risk of DKA and still gain the multiple benefits, we developed the "STOP DKA Protocol ", an easily accessible and practical tool, that provides a risk mitigation strategy for reducing DKA in patients with type 1 diabetes being treated with SGLT inhibitors.
Sodium glucose cotransporter2 inhibitors for type 1 diabetes mellitus: A meta-analysis of randomized controlled trials. [2023]Sodium glucose cotransporter2 (SGLT2) inhibitors are controversial in the treatment of type 1 diabetes mellitus (T1DM). This study is a systematic evaluation of the safety of SGLT2 inhibitors usage in T1DM.
Efficacy and Safety of SGLT2 Inhibitors as Adjunctive Treatment in Type 1 Diabetes in a Tertiary Care Center in Saudi Arabia. [2022]Background  Adjunctive treatment with sodium-glucose co-transporters 2 inhibitors (SGLT2- I) has been successfully used in patients with type 1 diabetes mellitus (T1DM) in recent years to improve glycemic control and reduce body weight without increasing the risk of hypoglycemia; however, there is a scarcity of evidence for real-world experience in their use in T1DM Saudi patients. The purpose of this study was to evaluate the efficacy and safety of empagliflozin as off-label adjunctive therapy in Saudi patients with T1DM. Methods  This study was a retrospective study for T1DM patients, who were prescribed empagliflozin as an adjunctive therapy. Baseline characteristics including age, changes in HbA1c, body weight, total daily insulin dose, lipid profile, and well as side effects such as urinary tract infections (UTIs) and diabetes ketoacidosis (DKA) were evaluated before and after initiation empagliflozin in 37 T1DM patients. Results  The mean age was 25.8 ± 8.0 years, mean weight was 75.3 ± 14.8 kg, mean body mass index (BMI) was 28.1 ± 6.7 kg/m 2 , mean duration of diabetes was 10.1 ± 6.5 years, and mean HbA1c was 9.4 ± 1.4%. After a mean follow-up duration of 15.8 ± 6.0 months, the mean reduction in the HbA1c% from baseline was 0.82% ( p  = 0.001) and mean weight reduction from baseline was 1.7 kg ( p  = 0.097). The total daily insulin dose was decreased by 2.9 units. UTIs and DKA episodes were reported among 2.7% and 10.8% of the participants, respectively. Conclusion  Empagliflozin in combination with insulin in overweight Saudi T1DM subjects resulted in a significant improvement in glycemic control, mild non-significant reduction in body weight, and a small but statistically significant reduction in the total daily insulin dose with a slight increase in the risk of DKA and UTIs. Further larger prospective studies are needed for better evaluation of the efficacy and safety of these agents in Saudi T1DM patients.
Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). [2022]To investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes.
The role of empagliflozin in the management of type 2 diabetes by patient profile. [2020]Current recommendations for the management of type 2 diabetes mellitus (T2DM) include patient-centered approach, ie, targeting glycemic control based on patient and disease characteristics. Ten different classes of oral and injectable anti-hyperglycemic agents have been developed for T2DM, including the newest class - sodium-glucose cotransporter 2 (SGLT2) inhibitors. Four members of the class with comparable glycemic efficacy and side effects have gained approval in the US and the rest of the world. This review covers empagliflozin - third approved SGLT2 inhibitor in the US. The drug has shown rapid absorption reaching peak levels in ~2 hours and an elimination half-life of ~13 hours. Empagliflozin is a highly selective SGLT2 inhibitor with 2600-fold higher affinity for SGLT2 compared with SGLT1. Oral administration results in a dose-dependent inhibition of the transporters with increased urinary glucose excretion and resultant reduction in plasma glucose. Its efficacy and safety have been shown in a number of studies conducted in many countries. Across the trials, significant improvements in primary and secondary efficacy end points have been demonstrated, including reductions in HbA1c (~-0.8%), fasting plasma glucose (~-2 mmol/L), body weight (~-2 kg), and blood pressure (systolic -4 mmHg and diastolic -2 mmHg). Similar to other SGLT2 inhibitors, empagliflozin does not increase the risk for hypoglycemia, and the most commonly reported side effects are urinary and genital tract infections. Although empagliflozin can be used as the first-line monotherapy, its current place in the treatment of T2DM appears to be as an add-on to other oral anti-hyperglycemic agent(s) or insulin at any stage of the disease.
Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. [2018]To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).
Sodium-Glucose Cotransporters as Potential Therapeutic Targets in Patients With Type 1 Diabetes Mellitus: An Update on Phase 3 Clinical Trial Data. [2022]Objective: To review phase 3 trials of sodium-glucose cotransporter (SGLT) inhibitors in type 1 diabetes mellitus (T1DM) patients. Data Sources: A literature search of Ovid MEDLINE databases (1946 through May 17, 2019) limited to English-language human clinical trials was conducted using the following terms: sodium-glucose transporter 2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, ipragliflozin, or remogliflozin combined with type 1 diabetes mellitus. Results were verified via Google Scholar and clinicaltrials.gov. Study Selection and Data Extraction: Articles were included if they were phase 3 trials in adults with T1DM. Data Synthesis: Phase 3 trials are available for dapagliflozin, empagliflozin, and sotagliflozin. All 3 drugs demonstrated statistically significant reductions in hemoglobin A1C, weight, and total daily insulin dose without an increased risk of hypoglycemia in up to 52 weeks of therapy. The incidence of diabetic ketoacidosis (DKA) was higher in patients on a SGLT inhibitor at all doses, with the exception of empagliflozin 2.5 mg (0.8% vs 1.2% with placebo). Relevance to Patient Care and Clinical Practice: SGLT inhibitors are potential adjuncts to insulin in T1DM patients, providing clinically meaningful benefits. Regulatory bodies have either approved or are reviewing these agents for use in T1DM. Clinicians should be familiar with the DKA risk associated with SGLT inhibitors and utilize DKA risk-mitigation strategies. Empagliflozin 2.5 mg warrants additional investigation given its efficacy without an increased incidence of DKA. Conclusions: Phase 3 trial data of SGLT inhibitors provide evidence for sustained efficacy in T1DM patients. Appropriate patient selection for therapy and routine monitoring are essential to minimize associated risks.
Dapagliflozin: A Review in Type 1 Diabetes. [2021]Oral dapagliflozin (Edistride®, Forxiga®) is approved in the EU at a dosage of 5 mg/day as an adjunct to insulin in adults with type 1 diabetes (T1D) and a body mass index (BMI) of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. As a highly selective SGLT2 inhibitor, dapagliflozin decreases plasma glucose levels independently of insulin action and enables glycaemic control improvement without increasing the risks associated with intensive insulin therapy. In the phase III DEPICT-1 and -2 trials, dapagliflozin 5 mg/day as an adjunct to insulin improved glycaemic control and reduced total daily insulin dose and bodyweight relative to placebo in adults with inadequately controlled T1D, including in patients with a BMI of ≥ 27 kg/m2, over 24 weeks of treatment. In extensions of these trials, these improvements were maintained up to 52 weeks. Dapagliflozin was generally well tolerated with a manageable safety profile and a hypoglycaemia profile generally similar to placebo. The incidence of diabetic ketoacidosis with dapagliflozin in patients with a BMI ≥ 27 kg/m2 was less than half that of the overall population who received dapagliflozin. Dapagliflozin is the first SGLT2 inhibitor to be approved for use in T1D and, while further clinical experience in T1D is required to more definitively establish its efficacy and safety profile, it provides a promising adjunctive treatment option for adults with T1D and a BMI of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.
Sodium-glucose co-transporter inhibitors as adjunctive treatment to insulin in type 1 diabetes: A review of randomized controlled trials. [2022]Many patients with type 1 diabetes (T1D) struggle to achieve glycaemic control and experience significant fluctuations in glucose concentrations, despite insulin treatment. Sodium-glucose co-transporter (SGLT)-2 inhibitors and dual SGLT-1/2 inhibitors increase glucose elimination via the kidneys and reduce hyperglycaemia via insulin-independent mechanisms. This review examines available efficacy and safety data for these agents under investigation as adjunctive therapy for T1D. Across randomized trials of up to 52 weeks, SGLT-2 inhibitors or SGLT-1/2 inhibitors as an adjunct to insulin demonstrated significant reductions in glycated haemoglobin, glucose exposure, and measures of glycaemic variability, as well as increased time in the target glycaemic range, compared with placebo. Non-glycaemic benefits included reductions in body weight and insulin doses, as well as improvements in some cardiovascular risk factors and treatment satisfaction. SGLT-2 inhibitors and SGLT-1/2 inhibitors were associated with similar rates of hypoglycaemia but a higher incidence of genitourinary infections, compared with placebo. Diabetic ketoacidosis occurred more often with SGLT-2 inhibitors and SGLT-1/2 inhibitors vs placebo, although the incidence was generally low. Risk mitigation strategies in light of clinical trial data are also discussed. Positive data from randomized controlled trials of the SGLT-2 inhibitor dapagliflozin have led to the approval of dapagliflozin as an adjunct to insulin in adults with T1D having body mass index ≥27 kg/m2 in whom insulin does not provide adequate glycaemic control in Europe and to approval as an adjunct to insulin for adults with T1D in Japan.