Sodium–glucose cotransporter 2 inhibitors as an add-on therapy to insulin for type 1 diabetes mellitus: Meta-analysis of randomized controlled trials

Abstract

Aims The aim was to systematically review the efficacy and safety of sodium–glucose cotransporter inhibitor (SGLT2i) as an adjunct to insulin at different follow-up durations in randomized, double-blind clinical trials in patients with type 1 diabetes. Methods We conducted a search on Medline, Embase, and the Cochrane Library for relevant studies published before May 2020. According to the duration of follow-up, the subgroup analysis included four periods: 1–4, 12–18, 24–26, and 52 weeks. In the five trials included both 24–26 and 52 weeks of follow-up, we compared the efficacy by the placebo-subtracted difference and changes in SGLT2i groups. Results Fifteen trials including 7109 participants were analyzed. The combination of SGLT2i and insulin improved hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), daily insulin dose, body weight, and blood pressure, which varied greatly by different follow-ups. Compared with %HbA1c at 24–26 weeks, placebo-subtracted differences and changes in the SGLT2i groups slightly increased. SGLT2i plus insulin treatment showed no difference in the occurrence of urinary tract infections (UTIs), hypoglycemia, or severe hypoglycemia but increased the risk of genital tract infections (GTIs) in a duration-dependent manner. SGLT2i treatment was associated with a significantly higher rate of ketone-related SAEs and diabetic ketoacidosis (DKA) at 52 weeks. Conclusion SGLT2i as an add-on therapy to insulin improved glycemic control and body weight and decreased the required dose of insulin without increasing the risk of hypoglycemia. However, after 6 months the benefits of SGLT2is on glycemic control may weaken and the risks of GTIs and DKA increased.

Real‐world data of 12‐month adjunct sodium‐glucose co‐transporter‐2 inhibitor treatment in type 1 diabetes from the German/Austrian DPV registry: Improved HbA1c without diabetic ketoacidosis

“…In the prospective randomized licensing trials for dapagliflozin in T1D, the major clinical outcomes were substantial reductions in HbA1c, BMI, insulin requirements, blood pressure, and glucose excursions. 5 Therefore, if healthcare providers in the real world may have chosen patients with T1D for SGLT2i treatment according to these results, it could be envisioned that the selection criteria would have been inadequate glycaemic control with high HbA1c, elevated BMI, high insulin requirements and large glucose excursions, and maybe also accompanying arterial hypertension. Indeed, in this observational trial in clinical practice, the selection of patients with T1D for SGLT2i treatment appears to be primarily triggered by the presence of higher HbA1c and BMI in combination with requirements of higher insulin doses, higher blood pressure, and the presence of microalbuminuria.…”

“…physiological glucose range, have been observed. 5 However, recognized as a rare side effect in T2D, SGLT2is significantly increased the risk for comparatively normoglycaemic diabetic ketoacidosis (DKA) in T1D trials. 5,6 In addition, no outcome trial results are available for the use of SGLT2is in T1D.…”

The Role of SGLT-2 Inhibitors as an Adjuvant to Insulin Therapy in Type-1 Diabetes Mellitus- Literature Review

“…Moreover, SGLT1 is expressed in the salivary glands, liver, lung, skeletal muscle, heart, pancreatic alpha cells, and brain, but their effect in these tissues is unknown [8]. Their combined inhibition leads to blunting and delaying glucose absorption from the gastrointestinal system and reducing the glucose reabsorption, respectively [8][9]. Additionally, sotagliflozin is 20-time more selective for SGLT2 compared to SGLT1 [8].…”

“…Further, SGLT2i alone was found to be effective in addition to insulin regimens in T1DM. In addition, osmotic diuresis and natriuresis lead to weight loss, which indirectly affects and improves blood pressure [9].…”

Effects of the SGLT2 Inhibition on Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats, a Model of Type 1 Diabetes Mellitus

“…Most studies have evaluated the effect of SGLT2 inhibitors on Type 2 DM but few have assessed their effects on Type 1 DM [14][15][16][17][18][19]; also, their effects on cardiovascular diseases are still unclear in Type 1 DM in both clinical and experimental scenarios. In Type 1 DM, the main mechanism responsible for cardiomyopathy is related to the decreased insulin signaling [20].…”