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ADA 2014 UPDATE: SGLT2-Inhibitors

There was a lot of great information at this year’s ADA Scientific Sessions on the sodium glucose co-transporter 2 (SGLT2) inhibitors both alone and in combination with other medications, and we have a review for you.

Canagliflozin 

Canagliflozin has demonstrated improvement in glycemic control, body weight, and blood pressure across a broad population of patients with type 2 diabetes, including older individuals.

See more SGLT-2 Resources

The long-term efficacy and safety of canagliflozin were evaluated over a 104-week period in a randomized, double-blind, placebo-controlled study in patients 55-80 years of age with type 2 diabetes inadequately controlled on a stable anti-hyperglycemic agent regimen….

Efficacy endpoints at week 104 were changes from baseline in HbA1c, fasting plasma glucose, bodyweight, systolic blood pressure, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C).

Over 104 weeks, canagliflozin 100 mg and 300 mg reduced HbA1C, fasting plasma glucose, bodyweight, and systolic blood pressure. Small increases in HDL-C and LDL-C were observed in the 2 canagliflozin groups compared with those receiving placebo.

Regarding overall safety and tolerability, “Canagliflozin was associated with increased incidence of genital mycotic infections and adverse events related to osmotic diuresis compared with placebo but was overall generally well tolerated over 104 weeks. The incidence of documented hypoglycemia was higher with both canagliflozin doses than with placebo. There were few severe episodes of hypoglycemia in any of the groups.”

“In older patients with type 2 diabetes inadequately controlled by their current regimens, canagliflozin at the 100 mg and 300 mg doses improved glycemic control, reduced bodyweight, and lowered blood pressure compared with placebo over 104 weeks. Increases in HDL-C and LDL-C were observed with Canagliflozin compared with placebo at week 104. LDL-C levels plateaued after 26 weeks.”

There was also a poster showing that Canagliflozin Reduces Serum Uric Acid in Patients with Type 2 Diabetes Mellitus.

Empagliflozin

Empagliflozin used as monotherapy or as an add-on medication improved outcomes for patients with type 2 diabetes, according to new research. Roden and colleagues conducted a phase III, double-blind, 52-week extension trial comparing different doses of empagliflozin (EMPA) monotherapy against placebo and sitagliptin (SITA) in patients not already receiving treatment.

In drug-naive patients with type 2 diabetes, treatment with empagliflozin in 10 mg or 25 mg for 76 weeks led to sustained reductions in HbA1c vs. placebo, in body weight vs. placebo as well as sitagliptin and in systolic blood pressure vs. placebo as well as sitagliptin.

After 76 weeks, EMPA 10 mg and 25 mg had significantly reduced HbA1c compared with PBO (-0.89% and -0.66%) as well as body weight (-2 kg and .5 kg); clinically meaningful and sustained reductions in SBP were also observed with the EMPA treatments (-3.4 mmHg and 0.4 mmHg).

Adverse reactions including hypoglycemic events (glucose ≤70 mg/dL and/or requiring assistance) and urinary tract infection were similar with EMPA, PBO and SITA; more patients reported reactions consistent with genital infection with EMPA than PBO or SITA.

Add-on to metformin vs. glimepiride add-on

In another phase 3, double-blind study, Ridderstråle and colleagues compared EMPA with glimepiride (GLIM) as an add-on medication for patients with type 2 diabetes already receiving metformin; the 12-week study completed a 2-year trail.

Endpoints considered were changes from baseline in HbA1c, weight and systolic and diastolic blood pressure (SBP and DBP) and occurrence of hypoglycemic adverse events (glucose ≤70 mg/dL and/or requiring assistance).

“Empagliflozin, when added to metformin, provided a sustained reduction in HbA1c with a statistically significant difference compared with glimepiride and with a low risk of hypoglycemia,” Ridderstråle said during his presentation. “Treatment with empagliflozin as an add-on to metformin led to sustained body weight and blood pressure reductions compared with glimepiride and was well tolerated.”

At the end of the study, there was significant decrease in HbA1c with EMPA compared with GLIM (-.66% vs. -.55%). “This met the non-inferiority and also the superiority criteria,” Ridderstråle said.

Hypoglycemic events were reported in 2.5% of patients on EMPA and 24.2% on GLIM (RR=0.102; 95% CI, 0.065-0.162), with 2 patients on GLIM requiring assistance.

It is also of interest to note that BI/Lilly are working on a combination of the DPP-IV inhibitor Tradjenta (linagliptin) and empagliflozin and are starting phase 3 trials and they are also examining the use of empagliflozin with insulin.

Dapagliflozin

The researchers compared the efficacy and safety of dual add-on of saxagliptin (SAXA) and dapagliflozin (DAPA) to SAXA and DAPA alone in patients who were poorly controlled on metformin alone. The adjusted proportion achieving A1C <7% was 41% in SAXA+DAPA compared to 18% in SAXA+PBO (difference of 23%; 95% CI [15, 32]) and 22% in DAPA+PBO (difference of 19%; 95% CI [10, 28]). AEs occurred in 48.6%, 52.8% and 48.6% in SAXA+DAPA, SAXA+PBO and DAPA+PBO, respectively.

In conclusion, this first report of triple therapy adding a well-tolerated combination of DPP-4 and SGLT2 inhibitors to poorly controlled metformin-treated T2D demonstrated that the combination of SAXA and DAPA had greater improvements in glucose control than each component alone, bringing >40% of poorly controlled T2D to goal, with weight loss as DAPA alone and very low hypoglycemia risk.

In order to look at reducing hypoglycemia a phase 3, randomized, double-blind trial of DAPA (≤ 10 mg/d) vs glipizide (GLIP; ≤ 20 mg/d) in combination with metformin (MET; median 2000 mg/d) was conducted in 814 adults with type 2 diabetes mellitus inadequately controlled by MET alone,

DAPA reduced hypoglycemia events vs GLIP over 52 weeks and over 4 years of hypoglycemia data shows that 5.4% of patients in the DAPA group vs 51.5% in the GLIP group experienced ≥ 1 hypoglycemic event.

Since almost 56% of diabetes patients have hypertensive issues the value of an antidiabetic drug that can help reduce SBP would be valuable and the study entitled “Dapagliflozin Lowered Ambulatory Blood Pressure in Patients with T2DM and Hypertension Inadequately Controlled by a Renin-Angiotensin System Blocker With or Without Another Agent” it was found that At Week 12, mean 24-hour SBP was lower with DAPA vs PBO (-4.5 [1.37] mmHg, P=0.0012) and a drop in night time SBP was also evident vs PBO (-3.9 [1.51] mmHg). DAPA was well tolerated and heart rate showed no significant change from baseline. In conclusion, DAPA significantly reduced SBP vs PBO in pts with T2DM in combination with ACEI/ARB ± 1AHT.

Other potential candidates

There are currently 22 other SGLT2-Inhibitors in development and the following all had phase 3 trials going on: ipragliflozin, luseogliflozin, fogliflozin.