Adding SGLT2 Inhibitors to Insulin

SGLT2 inhibitors added to insulin in individuals with T2DM may improve glycemic control and allow for reduction in insulin dose without significantly increasing hypoglycemia, according to a meta-analysis published online in Diabetes, Obesity and Metabolism.¹

 “[W]hen added to insulin therapy in patients with T2DM, SGLT2 inhibitors resulted in a greater reduction in HbA1c, fasting plasma glucose, and body weight without significantly increasing risk of hypoglycemia than placebo. However, this combination increased the risk of adverse events, [especially] genital infections,” wrote lead author Yiqing Song, MD, ScD, of Indiana University (Indianapolis, IN), and colleagues.

Recent reports of diabetic ketoacidosis (DKA) with SGLT2 inhibitors added to insulin have raised concerns about this combination.² Such reports influenced the US Food and Drug Administration (FDA) to issue a warning about increased risk for DKA with SGLT2 inhibitor use in May 2015.³ However, trials have shown inconsistent results about the benefits and risks of combined therapy with SGLT2 and insulin.

In the study, researchers searched four databases from inception to May 2016 for trials that lasted at least 12 weeks and compared the efficacy and safety of combined SGLT2 inhibitor and insulin therapy, vs placebo in individuals with T2DM. The meta-analysis included seven placebo-controlled trials covering 4235 patients, with a mean trial duration of 48 weeks.

Key results for SGLT2 inhibitors compared to placebo:

• Mean Hba1C: Significantly reduced by -0.56% (95%CI, -0.67 to -0.44%)

• Fasting plasma glucose: Significantly reduced by -0.95 mmol/L (95%CI, -1.21 to -0.70 mmol/l)

• Body weight: Significantly reduced by -2.63 kg (-3.10 to -2.16 kg)

• Insulin dose: Significantly reduced by -8.79 IU (95%CI -13.36 to -4.22 IU)

• Drug related adverse events: Significantly increased risk by 36% (RR 1.36; 95%CI, 1.17 to 1.59)

♦ Urinary tract Infections: Significantly increased risk by 29% (95%CI, 1.05 to 1.59)

♦ Genital mycotic infections: Significantly increased risk 457% (RR 4.57; 95%CI 3.47 to 6.02)

• Overall adverse events: No significantly increased risk (RR 1.00; 95%CI, 0.98 to 1.03)

• Serious adverse events: No significantly increased risk (RR 0.90; 95%CI, 0.80 to 1.02)

• Hypoglycemia: No significantly increased risk (RR 1.07; 95% CI, 0.99 to 1.15),

♦ Severe hypoglycemia: No significantly increased risk (RR, 1.24; 95%CI, 0.91 to 1.70)

• Diabetic ketoacidosis: None reported

• Risk of bias: Unclear or low.

The authors highlighted the lack of reported cases of DKA detected by the meta-analysis. However, they noted that only one trial reported this outcome.

Subgroup analyses by SGLT2 inhibitor dose showed only modest increases in efficacy for high compared to low doses. However, high doses were associated with increased risk for drug-related adverse events and urinary tract infections.

“The balance of risks and benefits associated with each dose need to be determined based on the individual patient by clinicians,” the authors noted.

Limitations include the small number of trials and small number of patients included in the meta-analysis.  Also, trials varied substantially in study populations, type of SGLT2 inhibitors, duration of treatment, and definitions of hypoglycemic events. The analysis pooled data from various SGLT2 inhibitors, though these drugs exhibit differences in treatment effect. Finally, the study could not compare SGLT2 inhibitors to other active antidiabetic agents added to insulin.

Nevertheless, the authors concluded, “Our metaanalysis indicated a greater reduction in HbA1c levels and body weight with SGLT2 inhibitors than placebo, despite a reduction in the dose of insulin by 8.79 IU. Therefore, to achieve HbA1c target levels and prevent the occurrence of hypoglycemic events, SGLT2 inhibitors may be considered as add-on to insulin therapy but clinicians are required to titrate the insulin doses for the individual patient.”

Take-home Points

• A meta-analysis of eight randomized clinical trials found that SGLT2 inhibitors added to insulin resulted in significant decreases in HbA1c, fasting plasma glucose, and body weight.

• Insulin dose was decreased by 8.79 IU.

• Overall adverse events, serious adverse events, hypoglycemia, and severe hypoglycemia were not significantly increased.

• No cases of diabetic ketoacidosis were detected, but only one study reported on this outcome.

• Drug-related adverse events were significantly increased, especially genital mycotic infections.

• SGLT2 inhibitors added to insulin may improve glycemic control and allow for a decrease in insulin dose, but insulin titration needs to be personalized for each patient.

The study was supported by the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative.

The authors report no conflicts of interest.

References:

1. Tang H, et al. Sodium-glucose cotransporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016 Sep 6.

2. Taylor SI, et al. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015 Aug; 100(8):2849-2852.

3. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Accessed September 6, 2016 at: http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm