SGLT2 Inhibitors in the Management of Type 1 Diabetes (T1D): An Update on Current Evidence and Recommendations

Figures & data

Table 1 SGLT2 Inhibitors Chemical Structure and Main Pharmacokinetic Parameters

	Dapagliflozin	Canagliflozin	Empagliflozin	Ipragliflozin
Trade name	Forxiga (EU) Farxiga (US)	Invokana (EU + US)	Jardiance (EU +US)	Suglat (Japan)
Tablets doses (mg)	5, 10	100, 300	10, 25	25, 50
Chemical structure	C-glycosyl compound, an organochlorine compound and an aromatic ether	C-glycosyl compound, a member of thiophenes and an organofluorine compound	C-glycosyl compound, an aromatic ether, a tetrahydrofuryl ether and a member of monochlorobenzenes	C-glucoside derivatives with a terminal benzene ring with a fluorine atom substitution
Oral bioavailability (%)	78	≈ 65	>60	90
Food effect	-	-	-	NA
Dose dependent	+	+	+	+
Tmax (h)	1–2	1–2	1	1–2
Volume of distribution	118	119	74	NA
Plasma protein binding (%)	91	98	86	94.6–96.5
T1/2	12.2	11–13	12.4	10–15
Hepatic metabolism	Extensive glucuronidation to inactive conjugates	Extensive O-glucuronidation to two major inactive metabolites	Extensive glucuronidation and lesser oxidation to six inactive metabolites	Extensive glucuronidation to two inactive conjugates Suspected biliary excretion
Urinary elimination (%)	<2	<1	28.6	≤2
Drug interaction	-	-	-	-

Note: Data from these studies.^15–20

Abbreviations: EU, Europe; US, United States of America; NA, Not applicable.

Table 2 Clinical Characteristics of Dapagliflozin and Sotagliflozin

	Dapagliflozin	Sotagliflozin
Efficacy	Both T2D and T1D	Both T2D and T1D
Adverse events
Gastrointestinal events	√	√ common (diarrhoea and flatulence)
Volume depletion	√	√ common
Diabetic ketoacidosis	√ common	√ common
Genitourinary infections	√ common (female genital mycotic infections: very common)	√ common (female genital mycotic infections: very common)
Nasopharyngitis	√	–
Hypoglycemia	√	–
Renal injury	√	√ common
Fournier’s gangrene	√ rare	√ rare
Amputations	–	Under investigation
Serum lipids increased	√	Under investigation
Haematocrit increased	√	Under investigation
Regulatory decision	FDA: approval only for T2D EMA: approval only for T2D	FDA: approval only for T2D EMA: approval only for T2D

Abbreviations: T2D, Type 2 Diabetes mellitus; T1D, Type 1 Diabetes Mellitus; FDA, Food and Drug Administration; EMA, European Medicines Agency.

Table 3 Ongoing Clinical Trial on SGLT2 Inhibitors in T1D

Trial Title	Details	Trial status
Dapagliflozin in Physical Exercise in Type 1 Diabetes NCT04049110	SGLT-2 Inhibition Using Dapagliflozin During and After Physical Exercise - Effects on Glycemic Variability, Hormonal Regulators of Glucose Homeostasis and Ketone Body in Type 1 Diabetes - a Randomized, Placebo-controlled, Open-label, Cross-over Intervention Study. Two arms: 1) Dapagliflozin followed by placebo and 2) Placebo followed by Dapagliflozin Primary outcome measure: MAGE will be calculated via sensor glucose measurements obtained over 72 hours after physical exercise Secondary outcome measure: Glucagon-like peptide I, glucagon, Ketone bodies, Free fatty acids, Somatostatin	Recruiting
Dapagliflozin Plus Pioglitazone in T1DM NCT03878459	Aim: To examine the effect of addition of combination therapy with dapagliflozin plus pioglitazone to insulin on glucose control and plasma ketone concentration in patients with type 1 diabetes (T1D) After screening, eligible subjects will start 4 week run in. At week 4, subjects will receive dapagliflozin for 12 weeks. At week 16, subjects will be randomized to receive in a double blind fashion pioglitazone or placebo for 16 weeks. Two arms: Pioglitazone vs placebo Primary outcome measure: Hba1c Secondary outcome measure: Plasma ketones and insulin dose	Recruiting
Ketone Monitoring in T1D: Effect of SGLT2i During Usual Care and With Insulin Deficiency NCT05541484	This proposed study will test whether measurement of breath acetone (BrAce) can be used for the purpose of identifying ketosis (elevated ketones) in persons with T1D. This is important for the potential use of SGLT2i in persons with T1D. Two arms: 1) Participants will test the breath ketone analyzer under usual care conditions followed by usual care plus SGLT2i treatment and 2) Participants will test the breath ketone analyzer under usual care plus SGLT2i treatment followed by usual care. At the end of each segment, participants will undergo a one-day insulin withdrawal period with more intense monitoring. Primary outcome measure: ketone levels in blood and breath. Secondary outcome measure: Ketone levels in persons with T1D during usual care versus usual care plus SGLT2i treatment and Ketone levels in persons with T1D undergoing insulin withdrawal.	Recruiting
Triple Therapy in T1DM NCT03899402	To assess whether the addition of dapagliflozin to semaglutide and insulin (triple therapy) improves glycemic control in patients with T1D compared with semaglutide and insulin (dual therapy) and insulin only (standard) treatment. This will be a two-center, randomized, open-label then double-blind, parallel group, placebo and standard of care controlled prospective study in T1D. Four arms: 1) Controls patients treated with standard of care insulin, 2) dual therapy, patients treated with insulin and semaglutide, 3) triple therapy, patients treated with insulin, semaglutide and Dapagliflozin and 3) placebo comparator, patients treated with insulin, semaglutide and placebo. Primary outcome measure: Hba1c Secondary outcome measures: hyperglycemia, hypoglycemia, time in range, fructosamine, Weekly fasting glucose indices, insulin indexes, body weight, blood pressure and diabetic ketoacidosis.	Recruiting
Study to Explore the Effect of Dapagliflozin and Stress in Adolescent and Adults subjects With Type 1 Diabetes (T1D) (Dapa-Stress) NCT04234867	A Randomized, Double-Blinded, Placebo-controlled, Single-center Phase 1 Pilot Study to Explore the Effect of Dapagliflozin and Stress (i.v. ACTH) on the Development of DKA After Insulin Withdrawal in Adolescent and Adult Subjects With T1D Four arms: 1) Dapagliflozin – Stress Administration of 10mg dapagliflozin oral for 5 days and one i.v. administration of 250µg ACTH (Synacthen), 2) Dapagliflozin and Placebo Stress Administration of 10mg dapagliflozin oral for 5 days and one i.v. administration of Placebo matching Synacthen, 3) Administration of placebo oral for 5 days identical to dapagliflozin and one i.v. administration of 250µg ACTH and 4) Administration of placebo oral for 5 days identical to dapagliflozin and one i.v. administration of Placebo matching ACTH. Primary outcome measure: time to development of DKA Secondary outcome measure: time to decrease of pH level	Recruiting
Adolescent Type 1 Diabetes Treatment With SGLT2i for hyperglycEMia and hyPerfilTration Trial (ATTEMPT) NCT04333823	The ATTEMPT (Adolescent Type 1 diabetes Treatment with SGLT2i for hyperglycEMia and hyPerfilTration Trial) is a multi-center, double-blinded, randomized, placebo-controlled trial to evaluate the effect of treatment with Dapagliflozin when compared to placebo, in combination with adjustable insulin, on measured GFR in adolescents with T1D 12 to <19 years of age over a 16-week treatment period. Two arms: 1) Dapagliflozin 5mg tablet taken by mouth once daily for 16 weeks and 2) Placebo tablet taken by mouth once daily for 16 weeks. Primary outcome measure: Measured Glomerular Filtration Rate Secondary outcomes measures: HbA1c, Diabetes Ketoacidosis, Hypoglycemic events, Urinary and Genitourinary Tract Infections, ambulatory glucose profiles, time-in-range, body weight, body mass index, Tanner pubertal staging, Total Daily Insulin Dose, Flow-Mediated Dilation, Pulse Wave Velocity, Heart Rate Variability, Caloric Intake, Macronutrient Intake, Diabetes Treatment Satisfaction Questionnaire, Diabetes Management Questionnaire, functional renal imaging, Change in blood glucose levels from pre- to post-exercise and Change in TIR during a moderate activity exercise session.	Recruiting
Combination Adjunctive Therapy to Address Multiple Metabolic Imbalances in Type 1 Diabetes (SOTA) NCT05696366	This is a single site, double-blind, placebo-controlled, crossover trial to quantify the effects of combination adjunctive therapy on glycemic control, ketogenesis during insulinopenia, insulin resistance, and diabetes burden and quality of life. Three arms: 1) Active comparator sotagliflozin. Each participant will receive 12-week insulin-adjunctive treatment with both: (a) SGLT2i (sotagliflozin 200 mg PO each day) + Placebo and (b) SGLT2i + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods. 2) Active comparator volagidemab with previous therapeutic scheme. 3) Placebo Comparator: Placebo with previous therapeutic scheme. Primary outcome measure: HbA1c Secondary outcome measures: CGM provides much more granular data relating to glucose trends and time spent in target glucose range, above range (hyperglycemia), and below range (hypoglycemia). Change in ambulatory insulin dosing as shown through subject insulin diary.	Not yet recruiting

Note: Data from Clinicaltrial.gov. Available from: https://clinicaltrials.gov/search?cond=Type%201%20Diabetes%20Mellitus&term=SGLT2-Inhibitors.⁸⁵

Abbreviations: SGLT-2i, sodium glucose co-transport inhibitors; MAGE, mean of the amplitude of glucose excursions; T1D, type 1 diabetes; BrAce, measurement of breath acetone; Hba1c, hemoglobin A1C; ACTH, Adrenocorticotropic hormone; GFR, Glomerular Filtration Rate; TIR, Time in Range; GRA, glucose receptor antagonist; CGM, Continuous glucose monitoring; PO, per os.

Clinicaltrial.gov. Available from: https://clinicaltrials.gov/search?cond=Type%201%20Diabetes%20Mellitus&term=SGLT2-Inhibitors. Accessed 07 November 2023.

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