At 4 Years, Dapagliflozin Bests Glipizide as Add-on to Metformin

Results of a 4-year extension study of a phase 3 clinical trial of dapagliflozin vs glipizide as add-on therapy to metformin were published in February in Diabetes, Obesity and Metabolism. The study is the longest clinical trial to date comparing one of the new sodium glucose transporter 2 (SGLT2) inhibitors with a “commonly prescribed” oral antidiabetes drug (a sulfonylurea) as add-on therapy in patients with type 2 diabetes (T2DM).

First-line monotherapy for T2DM with metformin is standard as is erosion of the drug’s efficacy as β-cell failure progresses over time. Treatment intensification with a sulfonylurea (SU) is a common step but loss of efficacy is typically seen after 1 year. Insulin is also often initiated as add-on to metformin but both SU and insulin are associated with weight gain and hypoglycemia.  The present study sought to compare a traditional with a novel second-line treatment.

The randomized, controlled phase 3 trial took place in 10 countries and looked at long-term efficacy and tolerability of dapagliflozin vs glipizide given as add-on therapy to metformin in patients with inadequately controlled T2DM. 

Participants were randomized to receive dapagliflozin 2.5 mg, 5 mg, or 10 mg (n=406) or glipizide 5 mg, 10 mg, or 20 mg (n=408) combined with open-label metformin (1500-2500 mg/day) and lifestyle advice. Of these, 39.7% in the dapagliflozin groups and 34.6% in the glipizide groups completed the full 208-weeks (4 years) of follow-up. 

Key results at 4 years included:

A1c coefficient of failure: Significantly lower for dapagliflozin vs glipizide (difference -0.42; p=.0001)

Fasting plasma glucose: Sustained reductions with dapagliflozin vs glipizide, indicating a slower rate of rise in A1c with dapagliflozin (-13.3 mg/dL [95% CI -18.3 to -8.3] vs. -3.8 mg/dL [95% CI -9.0 to 1.4])

Glomerular filtration:  Deterioration seen more frequently with glipizide vs dapagliflozin

Volume depletion: No differences in rates of volume depletion AEs between the two groups

D/C for poor glycemic control: Probability of discontinuing treatment because of poor glycemic control was greater among glipizide- than dapagliflozin-treated subjects

Importantly, sustained reductions were seen in A1c, total body weight, and systolic blood pressure in dapagliflozin-treated patients. 

“Treatment [with dapagliflozin] was associated with a 10-fold lower incidence of hypoglycemia compared with glipizide add-on to metformin, with most episodes being minor in severity,” the authors wrote. “The 208-week coefficient of failure [a measure of deterioration in β-cell function] was lower with dapagliflozin than with glipizide… pointing to more sustained glycemic efficacy with dapagliflozin therapy.” 

“Overall,” the authors noted, “renal parameters showed no signs of decreased function associated with dapagliflozin treatment, but additional data to determine the clinical significance of these results is necessary.”

Table. Four-Year Results for Dapagliflozin and
Glipizide as add-on to Metformin

Dapagliflozin + MetforminN=204

Glipizide + Metformin
N=188

Fasting plasma glucose

-13.3 mg/dL
[95% CI -18.3 to -8.3]

-3.8 mg/dL
[95% CI -9.0 to 1.4])

A1c coefficient of failure

0.19
[95% CI 0.12-0.25]

0.61
[95% CI 0.49-0.72]

Weight

-4.38 kg

0.73 kg

Systolic blood pressure

-3.67 mmHg

-0.2 mmHg

D/C due to poor glycemic control

39.0%

45.4%

D/C due to AE

13.3%

11.3%

Hypoglycemic events

2.2%

28.4%

Genital mycotic infections

2.8%

1.9%

UTIs

6.7%

4.3%

Renal impairment^*

0.6%

1.2%

*Defined in terms of shift to a higher category of albuminuria

Disclosures:

The authors could not be reached for comment.

The study was sponsored by Bristol-Myers Squibb, the maker of glipizide, and AstraZeneca, the maker of dapagliflozin.  One or more of the authors has served on the advisory boards, speakers’ bureau, or is an employee of Astrazeneca.

References:

Del Prato S, Nauck M, Duran-Garcia S, et al.  Long-term glycemic response and tolerability of dapagliflozin versus a sulfonylurea as add-on therapy to metformin in type 2 diabetes patients: 4-year data. Diabetes Obes Metab. 2015 Mar 4. doi: 10.1111/dom.12459 http://www.ncbi.nlm.nih.gov/pubmed/25735400