Improved Glucose Control With Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia With Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes

Abstract

OBJECTIVEWe investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODSPatients inadequately controlled on MDI insulin 6 metformin (mean HbA 1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m 2 ; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25 mg (n = 189), or placebo (n = 188) for 52 weeks. Insulin dose was to remain stable in weeks 1-18, adjusted to meet glucose targets in weeks 19-40, then stable in weeks 41-52. The primary end point was change from baseline in HbA 1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA 1c at week 52. RESULTSAdjusted mean 6 SE changes from baseline in HbA 1c were 20.50 6 0.05% (25.5 6 0.5 mmol/mol) for placebo versus 20.94 6 0.05% (210.3 6 0.5 mmol/mol) and 21.02 6 0.05% (211.1 6 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P < 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA 1c of 20.81 6 0.08% (28.9 6 0.9 mmol/mol), 21.18 6 0.08% (212.9 6 0.9 mmol/mol), and 21.27 6 0.08% (213.9 6 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA 1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA 1c <7% (<53 mmol/mol) with empagliflozin (31-42%) versus placebo (21%; both P < 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (29 to 211 international units/day) and weight (22.4 to 22.5 kg) versus placebo (all P < 0.01) at week 52. CONCLUSIONSIn obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4‐week, randomized, placebo‐controlled trial (EASE‐1)

“…Empagliflozin has consistently been shown to lead to sustained weight loss in patients with type 2 diabetes 13, 14, 15, 16, 17, 18, including those treated with a regimen of multiple daily injections of insulin, likely due to loss of calories in the urine. The majority of weight loss in patients with type 2 diabetes is attributable to a reduction in fat mass, including reductions in both trunk fat and limb fat and in both abdominal visceral and abdominal subcutaneous adipose tissue 23.…”

“…In patients with type 2 diabetes, empagliflozin given as monotherapy or as add‐on therapy (including as add‐on to basal insulin or multiple daily injections of insulin) has consistently been shown to improve glycaemic control and reduce blood pressure and weight, with a low risk of hypoglycaemia 13, 14, 15, 16, 17, 18.…”

Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials

“…1), totalling 15,309 unique participants [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin and ipragliflozin) were evaluated.…”

Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes

“…Moderate-quality evidence suggests that empagliflozin reduces all-cause mortality (7,11,40,44,46,47,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61) and increases the rates of diabetes control without increasing the risk of serious adverse effects and hypoglycemia when compared with placebo in adults with type 2 diabetes ( Table 1) (50,51,70). The increase in rates of glycemic improvement starts at the dose of 10 mg/day (150 attributable events per 1,000 treated, Figure 1) and increases to 210 attributable events per 1,000 treated after the larger dose of empagliflozin (25 mg/day, Figure 1).…”

“…The increase in rates of glycemic improvement starts at the dose of 10 mg/day (150 attributable events per 1,000 treated, Figure 1) and increases to 210 attributable events per 1,000 treated after the larger dose of empagliflozin (25 mg/day, Figure 1). Low-quality evidence suggests that empagliflozin reduces cardiovascular mortality, the risk of hospitalization for any cause (73), and hospitalizations for heart failure (59), as well as the risk of developing heart failure (73), developing or worsening of nephropathy (58), and the risk of treatment discontinuation due to lack of efficacy, at the expense of higher risk of adverse effects (Table 1) (7,11,40,44,46,47,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)70,(75)(76)(77). The observed improvement in patient outcomes is attributable to the largest RCT, EMPA-REG OUTCOME, which enrolled patients with established orally, once daily; comparator: placebo.…”