September 2017 Volume 42 Number 9

Indian Health Service National Pharmacy and Therapeutics Committee SGLT-2 inhibitors (Update) NPTC Formulary Brief August Meeting 2017

Background: The FDA has currently approved three SGLT-2 inhibitors, two of which have completed FDA-mandated cardiovascular outcomes trials. Last year, in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG), empagliflozin not only reduced cardiovascular events, but also mortality.1 This year, the Canagliflozin Cardiovascular Assessment Study (CANVAS) demonstrated equivocal cardiovascular benefits, no mortality benefit, and significant harms in those receiving canagliflozin.2 The DECLARE-TIMI 58 cardiovascular study of dapagliflozin will be completed in April 2019 (ClinicalTrials.gov Identifier: NCT01730534). Uncertainty remains regarding the current data, long- term benefits and harms, and differentiation among SGLT-2 inhibitors. Following a review of SGLT2 inhibitors at the August 2017 NPTC meeting on their cardiovascular outcomes, net benefit and place in therapy, no modifications were made to the National Core Formulary (NCF).

Discussion: EMPA-REG enrolled 7,020 patients with Type 2 diabetes mellitus (T2DM) and HgbA1c values between 7.0-10.0%. All patients had established cardiovascular disease (CVD) and were observed for a median duration of 3.1 years. Empagliflozin reduced the primary outcome of cardiovascular (CV) death, nonfatal myocardial infarction (MI), or nonfatal cardiovascular accident (CVA) by 6.5 events per 1000 patient-years (pt-yrs). Mortality decreased by 9.2 events per 1000 pt-yrs, primarily driven by a reduction in CV mortality of 7.8 events per 1000 pt-yrs. Heart failure hospitalization decreased by 5.1 events per 1000 pt-yrs. The number needed to treat (NNT) for the primary outcome was 63; for total mortality, the NNT was 38; and for cardiovascular mortality, the NNT was 45.1 Based on this evidence, the FDA approved empagliflozin for an additional indication to “reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.”

CANVAS enrolled 10,142 T2DM patients with HgbA1c values between 7.0-10.5%. Established CVD was not required in all In this Issue… patients at study enrollment; patients over 50 years old could be enrolled without established CVD if deemed at high risk (>2 risk 45 NPTC Formulary Brief: SGLT-2 inhibitors factors for CVD). As a result, the CANVAS population had lower (Update) overall CV risk than the EMPA-REG population. The results must therefore be compared with caution. Canagliflozin reduced the 48 NPTC Formulary Brief: New Long-Acting primary outcome of CV death, nonfatal MI, or nonfatal CVA by 4.6 Basal Insulins events per 1000 pt-yrs. Heart failure hospitalization declined by 3.2 49 Electronic Subscriptions Available events per 1000 pt-yrs however mortality did not decrease. Despite the improved time-to-event rate, patients treated with canagliflozin

September 2017 IHS PROVIDER 45 had absolute increases of 0.3% for the primary outcome, 0.4% for total mortality and 0.3% for CV mortality. This data was originally available in Table S6 of the Supplementary Appendix, but was later removed.2 It is plausible that canagliflozin decreases early events but increases later events, thereby increasing time-to-event while not decreasing total events.

Both empagliflozin and canagliflozin improved renal outcomes. Patient-oriented outcomes were only included in post hoc analyses, but the results were highly significant. The NNT for empagliflozin to prevent the composite endpoint of doubled creatinine/renal replacement/renal death was 71.3

Empagliflozin did not increase the rate of significant side effects, aside from the expected increase in genital mycosis. For women, the number needed to harm for genital mycosis was 14. Canagliflozin increased lower-limb amputations by nearly two-fold, from 3.4 events to 6.3 events per 1000 pt-yrs (p<0.001). The FDA has now required a boxed warning on the label for this adverse event. Fractures also significantly increased in canagliflozin patients by 3.5 events per 1000 pt-yrs, a 29% relative increase. Ketoacidosis, hypoglycemia, hypotension, hyperkalemia and UTIs were not significantly increased in either trial.1,2,6 There have been case reports published of euglycemic diabetic ketoacidosis (DKA) with these agents. A recent review by the American Association of Clinical Endocrinologists points out that euglycemic DKA occurred before these agents were initially administered, and it is not clear whether the frequency increased. They conclude that euglycemic DKA occurs infrequently and the risk-benefit ratio overwhelmingly favors continued use.7

Several meta-analyses note that SGLT-2 inhibitors decrease body weight by approximately 2 kilograms4, reduce systolic and diastolic blood pressures by about 2 mm Hg5, and cause trivial yet clinically insignificant changes in lipid parameters. In general, SGLT-2 inhibitors have few drug interactions, with dapagliflozin and empagliflozin having fewer than canagliflozin (Lexicomp, accessed 7/15/2017).

Findings: In CANVAS, canagliflozin reduced the incidence of CV death, nonfatal MI or nonfatal CVA, the primary outcome, however there was concern expressed by the NPTC that canagliflozin may actually increase risk over time (evidenced by increased total events with canagliflozin over study duration). There was also a trend, though non-significant, toward increased risk of mortality with canagliflozin. Renal outcomes are reassuring however, which seem to be a class effect. Risk of both amputations and fractures were increased.

EMPA-REG demonstrated that empagliflozin reduced the incidence rate of the primary outcome (CV death, nonfatal MI or nonfatal CVA), overall mortality, cardiovascular mortality, hospitalization for heart failure, and renal outcomes, without increasing adverse events beyond genital mycosis.

Conclusions: Despite positive outcomes for empagliflozin, the NPTC voted against NCF inclusion at this time for the following reasons: • Benefits are shown in only a single, drug manufacturer-funded study without independent oversight or analysis. • EMPA-REG included only patients with established cardiovascular disease. The impact of empagliflozin in T2DM patients outside this study population (without CVD) remains undefined. • Long-term effects are unknown. It is uncertain whether benefits outweigh harms for those without established cardiovascular disease. HgbA1c lowering is modest and may diminish significantly over time. • The CANVAS study demonstrated safety concerns (adverse effects) that may be class effects.

For questions about this document, please contact the NPTC at [email protected]. For more information about the NPTC, please visit the NPTC website.

References: 1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117–28. 2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Jun 12; DOI: 10.1056/NEJMoa1611925. Online only at the time of this analysis. 3. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jun 14;375(4):323–34. 4. Shyangdan DS, Uthman OA, Waugh N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open. 2016 Feb 24;6(2).

September 2017 IHS PROVIDER 46 5. Mazidi M, Rezaie P, Gao H, et al. Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients. J Am Heart Assoc. 2017 2017;6:e004007. DOI:10.1161/JAHA.116.004007 6. Kohler S, Zeller C, Iliev H, et al. Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes: Pooled Analysis of Phase I–III Clinical Trials. Adv Ther. 2017 Jul 1;34(7):1707–26. 7. Handelsman Y, Henry RR, Bloomgarden ZT, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF SGLT-2 INHIBITORS AND DIABETIC KETOACIDOSIS. Endocr Pract. 2016 Jun 1;22(6):753–62.

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Indian Health Service National Pharmacy and Therapeutics Committee New Long-Acting Basal Insulins NPTC Formulary Brief August Meeting 2017

Background: In August 2017, the Indian Health Service (IHS) National Pharmacy & Therapeutics Committee (NPTC) reviewed two newer, long-acting basal insulin therapies for the management of Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM) and evaluated their safety, efficacy and utilization within the agency. The NPTC last reviewed novel insulin delivery devices (including basal insulins) in August 2015 which resulted in the addition of pen devices to National Core Formulary (NCF) insulin products. Current insulins on the NCF include insulin aspart (NovoLog®), regular insulin (NovoLIN®), insulin NPH (NovoLIN® N), insulin detemir (Levemir®), and the combination products insulin aspart / insulin aspart protamine (NovoLog® 70/30 Mix) and insulin NPH / regular insulin (NovoLIN 70/30®). The 2017 NPTC review included the subcutaneous insulin products insulin degludec (Tresiba®) and insulin glargine (Basaglar®). Based on the NPTC review and committee discussion, no modifications were made to the NCF.

Discussion: Insulin therapy is the most effective treatment for lowering blood glucose for patients with type 2 diabetes mellitus (T2DM) and is the only treatment option for patients with type 1 diabetes mellitus (T1DM).1-3 The 2017 guidelines from the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) recommend starting insulin therapy with a basal insulin but offer no recommendations as to the selection of a specific insulin product upon initiation.2,3 The AACE recommends basal insulin analogs over neutral protamine Hagedorn (NPH) due to concerns for increased risk of hypoglycemia with NPH.3

In 2015, the FDA approved the ultra-long-acting insulin, Tresiba® (insulin degludec) in both 100 units/mL and 200 units/mL concentrations.4 The efficacy and safety of Tresiba® was studied in a series of open-labeled, randomized controlled trials that were designed to test for non-inferiority of Tresiba® versus insulin glargine or insulin detemir.5-11 The primary endpoint for each study was percent change in hemoglobin A1c from baseline, and secondary endpoints included reduction in fasting blood glucose (FBG) and achievement of an A1c less than 7%. The studies also observed episodes of hypoglycemia, including overall hypoglycemia and nocturnal hypoglycemia. Three studies were conducted in patients with T1DM, and four studies were conducted in patients with T2DM.

In terms of efficacy, all seven studies demonstrated non-inferiority between Tresiba® and insulin glargine or insulin detemir in reduction of A1c and FBG.4-11 The primary safety endpoint, overall episodes of hypoglycemia, was not significantly different, however four studies did report a statistically significant benefit with Tresiba® in episodes of nocturnal hypoglycemia. Despite absolute risk reductions (favoring Tresiba®) ranging from 0.1% to 7% in multiple studies5,7-9, the impact in improved patient safety is not likely to be deemed clinically significant.

Current data regarding the use of Tresiba® has focused primarily on benefits in terms of the efficacy and safety surrounding blood glucose management. The DEVOTE trial was a double-blinded, treat-to-target study of cardiovascular outcomes comparing Tresiba® to insulin glargine. The primary composite outcome included major cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) in patients with T2DM at high risk for cardiovascular events. Tresiba® was shown to be non-inferior to insulin glargine in the incidence of major cardiovascular events (HR, 0.91; 95% confidence interval, 0.78 to 1.06; p<0.001 for non-inferiority).12

In 2015, the FDA approved the long-acting insulin analog, Basaglar® (insulin glargine) as a “follow-on” product.13 Studies of Basaglar® demonstrated non-inferiority to insulin glargine (Lantus®) in A1c reduction, adverse events, allergic reactions, weight change, hypoglycemia and insulin antibodies in patients with T1DM and T2DM.14,15

September 2017 IHS PROVIDER 48 Findings: Insulin detemir is the most commonly prescribed basal insulin within IHS, representing approximately 76% of all prescribed long-acting basal insulins over the past 24 months. Currently, there is limited data comparing the efficacy of Tresiba® and Basaglar® beyond A1c reduction. Additionally, the majority of studies have targeted non-inferiority to the parent products and appear to offer little, if any, appreciable safety benefit over established products. Based on the available data, neither product demonstrated significant advantages over NCF insulins in terms of patient-specific clinical factors or cost-effectiveness to the IHS. For questions about this document, please contact the NPTC at [email protected]. For more information about the NPTC, please visit the NPTC website.

References: 1. Fridkin S., Baggs J., Fagan R., Magill S., Pollack LA, et al. (2014). "Vital signs: improving antibiotic use among hospitalized patients." MMWR Morb Mortal Wkly Rep 63(9): 194-200. 2. Hicks LA, Taylor TH, Hunkler R (2013). "U.S. outpatient antibiotic prescribing, 2010." N Engl J Med 368(15): 1461- 1462. 3. MacDougall C, Polk R. (2005). "Antibiotic stewardship programs in health care systems." Clin Microbiol Rev 18(4): 638-656. 4. Ohl CA, Dodds Ashley E. (2011). "Antibiotic stewardship programs in community hospitals: the evidence base and case studies." Clin Infect Dis 53 Suppl 1: S23-28; quiz S29-30. 5. Pollack LA, Srinivasan A. (2014). "Core Elements of Hospital Antibiotic Stewardship Programs From the Centers for Disease Control and Prevention." Clinical Infectious Diseases 59(suppl 3): S97-S100. 6. Septimus EJ, Owens, RC. (2011). "Need and potential of Antibiotic stewardship in community hospitals." Clin Infect Dis 53 Suppl 1: S8-S14 7. The White House. National Strategy for Combating Antibiotic Resistant Bacteria. September 2014. Available at: https://www.whitehouse.gov/sites/default/files/docs/carb_national_strategy.pdf. Accessed March 2015.

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