Sodium-Glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial

Perkins, Bruce A.; Cherney, David Z.I.; Partridge, Helen; Soleymanlou, Nima; Tschirhart, Holly; Zinman, Bernard; Fagan, Nora; Kaspers, Stefan; Woerle, Hans-Juergen; Broedl, Uli C.; Johansen, Odd-Erik

doi:10.2337/dc13-2338

Cited by 217 publications

(200 citation statements)

References 15 publications

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“…weight, insulin dose, and the incidence of hypoglycemia with canagliflozin treatment are consistent with the effects reported with other SGLT2 inhibitors added on to insulin therapy in patients with type 1 diabetes (17,18). Dose-related reductions in HbA 1c were seen with canagliflozin across phase 3 studies in patients with type 2 diabetes (10), but no dose response was observed in the current study.…”

Section: Discussionsupporting

confidence: 84%

“…In a 4-week study with sotagliflozin, 2 of 16 patients in the sotagliflozin arm had a serious AE of DKA compared with no patients in the placebo arm (19). In an 8-week openlabel study with empagliflozin, 2 of 40 patients experienced a DKA AE (18). These four reported DKA AEs occurred in the presence of other precipitating factors (e.g., insulin pump failure, gastroenteritis).…”

Section: Discussionmentioning

confidence: 99%

“…Several small pilot studies with SGLT2 inhibitors, ranging from 2 to 8 weeks, have been performed in patients with type 1 diabetes (17)(18)(19). These studies have generally shown that treatment with SGLT2 inhibitors provides improved glucose control and reductions in the insulin dose without increasing hypoglycemic events.…”

mentioning

confidence: 99%

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Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

et al. 2015

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OBJECTIVEThis study assessed the efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODSThis 18-week, double-blind, phase 2 study randomized 351 patients (HbA 1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion to canagliflozin 100 or 300 mg or placebo. The primary end point was the proportion of patients achieving at week 18 both HbA 1c reduction from baseline of ‡0.4% ( ‡4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA 1c , body weight, and insulin dose, as well as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTSMore patients had both HbA 1c reduction ‡0.4% and no increase in body weight with canagliflozin 100 and 300 mg versus placebo at week 18 (36.9%, 41.4%, 14.5%, respectively; P < 0.001). Both canagliflozin doses provided reductions in HbA 1c , body weight, and insulin dose versus placebo over 18 weeks. The incidence of hypoglycemia was similar across groups; severe hypoglycemia rates were low (1.7-6.8%). Overall incidence of AEs was 55.6%, 67.5%, and 54.7% with canagliflozin 100 and 300 mg and placebo; discontinuation rates were low (0.9-1.3%). Increased incidence of ketone-related AEs (5.1%, 9.4%, 0%), including the specific AE of diabetic ketoacidosis (DKA) (4.3%, 6.0%, 0%), was seen with canagliflozin 100 and 300 mg versus placebo. CONCLUSIONSCanagliflozin provided reductions in HbA 1c , body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin.Type 1 diabetes is an autoimmune disease characterized by progressive destruction of pancreatic b-cells, resulting in loss of endogenous insulin production and hyperglycemia (1). Consequently, treatment of type 1 diabetes requires lifelong insulin therapy to maintain normal blood glucose levels. Type 1 diabetes is associated with increased morbidity and mortality related to microvascular and macrovascular

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

et al. 2015

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“…This concern was initially raised about off‐label use of SGLT2 inhibitors in patients with type 1 DM 51, 52. Later in 2015, based on first‐year postmarketing surveillance reporting of 20 DKA cases, the FDA issued a statement warning that SGLT2 inhibitors might increase the risk of DKA 53.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

108

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BackgroundThe cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented.Methods and ResultsFor cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.

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“…In an 8‐week single‐arm pilot study in patients with type 1 diabetes, empagliflozin as adjunct to insulin led to significant reductions in glycated haemoglobin (HbA1c), fasting glucose, blood pressure, weight and the frequency of symptomatic hypoglycaemic events with plasma glucose <3.0 mmol/l 12.…”

Section: Introductionmentioning

confidence: 99%

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

Pieber

Famulla

Eilbracht

et al. 2015

Diabetes Obesity Metabolism

159

165

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AimsTo investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes.MethodsA total of 75 patients with glycated haemoglobin (HbA1c) concentrations of ≥7.5 to ≤10.5% (≥58 to ≤91 mmol/mol) were randomized to receive once‐daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as adjunct to insulin for 28 days. Insulin dose was to be kept as stable as possible for 7 days then adjusted, at the investigator's discretion, to achieve optimum glycaemic control. The primary exploratory endpoint was change from baseline in 24‐h urinary glucose excretion (UGE) on day 7.ResultsEmpagliflozin significantly increased 24‐h UGE versus placebo on days 7 and 28. On day 28, adjusted mean differences with empagliflozin versus placebo in changes from baseline in: HbA1c were −0.35 to −0.49% (−3.8 to −5.4 mmol/mol; all p < 0.05 vs. placebo); total daily insulin dose −0.07 to −0.09 U/kg (all p<0.05 vs placebo); and weight were −1.5 to −1.9 kg (all p < 0.001 vs. placebo). In the placebo, empagliflozin 2.5, 10 and 25 mg groups, respectively, adverse events were reported in 94.7, 89.5, 78.9 and 100.0% of patients, and the rate of symptomatic hypoglycaemic episodes with glucose ≤3.0 mmol/l not requiring assistance was 1.0, 0.4, 0.5 and 0.8 episodes per 30 days.ConclusionsIn patients with type 1 diabetes, empagliflozin for 28 days as adjunct to insulin increased UGE, improved HbA1c and reduced weight with lower insulin doses compared with placebo and without increasing hypoglycaemia.

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Sodium-Glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial

Cited by 217 publications

References 15 publications

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

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

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