Clinical Criterion

• Added on to metformin and a sulfonylurea for patients with inadequate glycemic control on metformin and a sulfonylurea and for whom insulin is not an option.

Condition

• The drug plan cost of treatment with empagliflozin should not exceed the drug plan cost of treatment with the least costly option from within the sodium glucose cotransporter-2 (SGLT-2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor classes.

Patient Input Information

The Canadian Diabetes Association responded to the CDR call for patient input. Surveys were used to collect perspectives of patients with type 2 diabetes. The following is a summary of information provided by the patients:

• Poorly controlled type 2 diabetes can result in serious long-term complications such as blindness, heart disease, kidney problems, nerve damage, and erectile dysfunction.
• Fluctuations in blood sugar can negatively affect patients’ ability to work and participate in social and family activities, and can interrupt their normal activities of daily living.
• Diabetes, and the related stigma, is associated with a psychological and emotional burden for patients.
• Many of the currently available therapies can cause significant weight gain and hypoglycemia.

Clinical Trials

The CDR systematic review included one 24-week double-blind RCT (study 23), as well as its 52-week double-blind extension phase (study 31). Study 23 was an international, multi-centre trial composed of two independent sub-studies of identical design. Patients with a stable dose regimen of metformin were entered in one sub-study (metformin background), and patients with a stable dose regimen of metformin plus a sulfonylurea were entered in the second sub-study (metformin plus sulfonylurea background [N = 668]). The CDR review and CDEC deliberations focused on the results of the metformin plus sulfonylurea sub-study. Patients were randomized (1:1:1) to either empagliflozin 10 mg, empagliflozin 25 mg, or placebo added on to their existing therapy. The planned treatment period was 24 weeks after an open-label placebo run-in period of two weeks.

Outcomes

Outcomes were defined a priori in the CDR systematic review protocol. Of these, CDEC discussed the following:

• Glycemic control — change from baseline in glycated hemoglobin (A1C), proportion of patients with A1C less than 7% at end point, and change from baseline in fasting plasma glucose
• Body weight — change from baseline in body weight
• Blood pressure — change from baseline in SBP and diastolic blood pressure (DBP)
• Hypoglycemia — events of severe hypoglycemia and any hypoglycemia
• Serious adverse events, total adverse events, and withdrawals due to adverse events.

The primary outcome of study 23 was the change from baseline to 24 weeks in A1C. No primary outcome was identified for the extension phase.

Efficacy

• There was a statistically significant reduction from baseline in A1C in both the empagliflozin 10 mg and 25 mg groups compared with placebo at both 24 weeks (study 23) and 76 weeks (study 31). The differences in adjusted mean change for 10 mg and 25 mg empagliflozin versus placebo, respectively, were:

  • 24 weeks: −0.64% (95% confidence interval [CI], −0.79 to −0.49) and −0.59% (95% CI, −0.74 to −0.44)
  • 76 weeks: −0.72% (95% CI, −0.93 to −0.52) and −0.72% (95% CI, −0.92 to −0.52).
• A greater proportion of empagliflozin-treated patients (31% with 10 mg and 34% with 25 mg) had A1C < 7.0% at 24 weeks compared with placebo (11%).
• Fasting plasma glucose was statistically significantly improved in patients treated with empagliflozin compared with placebo at 24 and 76 weeks. The differences in adjusted mean change for 10 mg and 25 mg empagliflozin versus placebo, respectively, were:

  • 24 weeks: −1.6 mmol/L (95% CI, −1.9 to −1.3) and −1.6 mmol/L (95% CI, −1.9 to −1.3)
  • 76 weeks: −1.8 mmol/L (95% CI, −2.3 to −1.4) and −1.8 mmol/L (95% CI, −2.3 to −1.4).
• Empagliflozin-treated patients demonstrated statistically significant weight loss compared with placebo-treated patients at 24 weeks. Although statistical analyses were not conducted, weight loss was also observed with empagliflozin in the 76-week extension phase. The differences in adjusted mean change for 10 mg and 25 mg empagliflozin versus placebo, respectively, were:

  • 24 weeks: −1.76 kg (95% CI, −2.25 to −1.28) and −1.99 kg (95% CI, −2.48 to −1.50)
  • 76 weeks: −1.88 kg (95% CI, −2.64 to −1.13) and −1.67 kg (95% CI, −2.42 to −0.91).
• There was a statistically significant reduction in SBP in the empagliflozin groups compared with the placebo group at 24 weeks; however, the reduction was not statistically significant at 76 weeks. The differences in adjusted mean change for 10 mg and 25 mg empagliflozin versus placebo, respectively, were:

  • 24 weeks: −2.7 mm Hg (95% CI, −4.6 to −0.8) and −2.1 mm Hg (95% CI, −4.0 to −0.2)
  • 76 weeks: −1.5 mm Hg (95% CI, −4.0 to 1.0) and −1.8 mm Hg (95% CI, −4.3 to 0.7).
• There were no statistically significant differences in DBP between the empagliflozin and placebo groups at either 24 or 76 weeks. The differences in adjusted mean change for 10 mg and 25 mg empagliflozin versus placebo, respectively, were:

  • 24 weeks: −0.4 mm Hg (95% CI, −1.6 to 0.9) and −0.4 mm Hg (95% CI, −1.6 to 0.8)
  • 76 weeks: −1.0 mm Hg (95% CI, −2.7 to 0.7) and −0.7 mm Hg (95% CI, −2.3 to 1.0).

Harms (Safety and Tolerability)

• The most commonly reported adverse events with empagliflozin were nasopharyngitis and urinary tract infections. The proportions of patients who experienced at least one adverse event were:

  • 24 weeks: 68% in the empagliflozin 10 mg group, 64% in the empagliflozin 25 mg group, and 63% in the placebo group
  • 76 weeks: 82% in both of the empagliflozin groups and 81% in the placebo group.
• The proportions of patients who experienced at least one serious adverse event were:

  • 24 weeks: 5% in the empagliflozin 10 mg group, < 1% in the empagliflozin 25 mg group, and 6% in the placebo group
  • 76 weeks: 13% in the empagliflozin 10 mg group, 11% in the empagliflozin 25 mg group, and 14% in the placebo group.
• The proportion of patients who discontinued the study as a result of adverse events was similar between the empagliflozin groups (3% in both) and the placebo group (4%). In the extension phase, the proportion of patients who withdrew due to an adverse event was also similar between empagliflozin groups (5% to 7%) and the placebo group (7%).
• Episodes of severe hypoglycemia were rare in both the core and extension phases of the study. Confirmed hypoglycemia was more frequently reported in the empagliflozin groups compared with the placebo group:

  • 24 weeks: 16% with empagliflozin 10 mg, 12% with empagliflozin 25 mg, and 8% with placebo
  • 76 weeks: 24% with empagliflozin 10 mg, 19% with empagliflozin 25 mg, and 16% with placebo.

Cost and Cost-Effectiveness

The manufacturer submitted a cost comparison of empagliflozin with other SGLT-2 inhibitors and DPP-4 inhibitors in patients with type 2 diabetes over a one-year time frame. The analysis was undertaken from the public-payer perspective. Prices from the Ontario Drug Benefit formulary (April 2015) were used to calculate the cost of comparator drugs. The assumption of similar treatment efficacy was based on a manufacturer-sponsored NMA, which suggested that empagliflozin (10 mg and 25 mg) is associated with similar changes in A1C and risk of hypoglycemic events compared with DPP-4 inhibitors and other SGLT-2 inhibitors.

CDR noted the following key limitations with the manufacturer’s analysis:

• The manufacturer’s NMA was limited by heterogeneity across the included studies.
• The manufacturer did not consider insulin as a relevant comparator in the cost comparison, despite including insulin studies in the NMA. In addition, other oral therapies used as third-line treatment of type 2 diabetes, such as alpha-glucosidase inhibitors (acarbose) and pioglitazone, were not considered.
• The savings reported by the manufacturer arising from the price differential between empagliflozin and the weighted average price of DPP-4 inhibitors will be realized only if empagliflozin replaces existing comparators in the proportion assumed by the manufacturer, which is unlikely.

At the submitted price of $2.62 daily, the cost of empagliflozin is the same as canagliflozin. Compared with the list prices of DPP-4 inhibitors, empagliflozin is less costly than sitagliptin ($2.98 daily), and the 5 mg dose of saxagliptin ($2.88 daily), but is more costly than linagliptin ($2.25 to $2.55 daily) and alogliptin ($2.10 daily, based on the Quebec Formulary price). Empagliflozin is more costly than pioglitazone, acarbose, and insulin.

Based on list prices, the daily cost of empagliflozin would need to be reduced by 14% to equal that of linagliptin ($2.25, based on the Nova Scotia Formulary price), the least costly DPP-4 inhibitor listed on a CDR-participating drug plan.