Drug Class Monograph

Drug Class Monograph Class: Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors Drugs: alogliptin, alogliptin/metformin, Januvia (sitagliptin), Janumet (sitagliptin/metformin), Janumet XR (sitagliptin/metformin), Jentadueto (linagliptin/metformin), Juvisync (sitagliptin/simvastatin), Kazano (alogliptin/metformin), Kombiglyze XR (saxagliptin/metformin), Nesina (alogliptin), Onglyza (saxagliptin), Oseni (alogliptin/pioglitazone), Tradjenta (linagliptin) Line of Business: Medi-Cal Effective Date: February 15, 2017 Revision Date: February 15, 2017 This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutic Subcommittee. Formulary Drugs: Drug Alogliptin Alogliptin/metformin Januvia (sitagliptin) Janumet (sitaliptin/metformin) Janumet XR (sitagliptin/metformin) Criteria Requirements Step Therapy: Trial of metformin or metformin containing products, unless contraindicated Non Formulary Drugs: Drug Jentadueto (linagliptin/metformin) Juvisync (sitagliptin/simvastatin) Nesina (alogliptin) Kazano (alogliptin/metformin) Kombiglyze XR (saxagliptin/metformin) Onglyza (saxagliptin) Oseni (alogliptin/pioglitazone) Tradjenta (linagliptin) Criteria Requirements Prior Authorization Criteria: a) Type II diabetes mellitus b) Failure or clinically significant adverse effects to metformin c) Failure or clinically significant adverse effects to alogliptin OR sitagliptin product d) One additional oral formulary alternative in a non-dpp-4 therapeutic class (e.g. sulfonylurea, pioglitazone, etc) e) HgA1C score of >7% after 3 months of optimal therapy can be considered as failure of therapy

Background: A significant advancement in the management of type 2 diabetes has been the development of numerous therapeutic classes in the past few years. Over the past 12 years, three new therapeutic classes were introduced in the management of diabetes. In 2005 the glucagon like peptide-1 (GLP1) class was introduced to the market. Followed by the dipeptidyl-4 inhibitors (DPP-4) class and the sodium glucose co-transporter 2 (SGLT2) class in 2013. Of these three new classes, DPP-4 inhibitors have been in the news due to the FDA warning of an increase risk of heart failure in patients. The DPP-4 inhibitors reversibly block the enzyme DPP-4, which is responsible for the rapid degradation of endogenous incretin hormones. These hormones are produced by the gastrointestinal tract in response to meals and are involved in the regulation of insulin. The antidiabetic actions of endogenous incretin hormones include the enhancement of meal stimulated insulin secretion, decreased glucagon secretion, improvements in β cell function, and slowing of gastric emptying. Through their effect on these hormones, the DPP-4 inhibitors primarily target post-prandial glucose and have also been shown to decrease fasting plasma glucose. In general, the DPP-4 inhibitors are associated with a favorable side effect profile and also have a weight neutral effect compared to other antidiabetic agents commonly used in the management of type 2 diabetes. Compared to sulfonylureas, the risk of hypoglycemia associated with the DPP-4 inhibitors is low due to the glucose-dependent nature of incretin hormone activity. In addition, the DPP-4 inhibitors have not been associated with the same increased risk of cardiovascular disease that has been observed with the use of thiazolidinediones (TZDs). In addition, as mentioned earlier the DPP-4 inhibitors improve the function of β cells and although TZDs and metformin treat insulin resistance, these agents do not address the progressive decline in β cell function that is observed in patients with type 2 diabetes. Overall, the DPP-4 inhibitors are significantly more effective compared to placebo in reducing glycosylated hemoglobin (HbA 1c ), fasting plasma glucose, and post-prandial glucose, with no major effect on body weight. Combination therapy with a DPP-4 inhibitor and metformin consistently demonstrates improved benefits in glycemic control over monotherapy with either a DPP-4 inhibitor or metformin, limited within class head-to-head trials have been conducted. Two meta-analyses revealed that DPP-4 inhibitors are not associated with an increased risk of cardiovascular events or cancer compared to placebo or other antidiabetic agents, respectively. However, recent findings suggested an increased risk of heart-failure with saxagliptin and alogliptin compared to placebo.

Januvia (sitagliptin) Nesina (alogliptin) Onglyza (saxagliptin) Tradjenta (linagliptin) MOA Inhibits DPP-4 activity resulting prolonged active incretin levels. Increasing postprandial incretin (GLP-1, GIP) concentrations Usual Dosing 100mg once daily 25mg once daily 2.5-5mg once daily 5mg once daily Administration Administer with or without food Dosage adjustment in renal impairment Yes, CrCl < 50 ml/min Yes, CrCl < 60 ml/min Yes, CrCl 50mL/min No PK/PD Drug-drug interaction Common Side effects Use with medications known to cause hypoglycemia (e.g. insulin, insulin secretagogues) Absorption: Rapid Distribution: ~198 L Protein binding: 38% Metabolism: Not extensively metabolized; minor metabolism via CYP3A4 and 2C8 Bioavailability: ~87% Half-life elimination: 12.4 Time to peak, plasma: 1 to 4 Excretion: Urine 87% (~79% as unchanged drug, 16% as metabolites); feces 13% Absorption: Extensive (~100%) regardless of food intake Distribution: 417 L Protein binding: 20% Metabolism: Not extensively metabolized; minor metabolism via CYP2D6 and CYP3A4 Bioavailability: ~100% Half-life elimination: ~21 Time to peak: ~1 to 2 Excretion: Urine 76% (60% to 71% as unchanged drug); feces 13% Protein binding: Negligible Metabolism:Hepatic via CYP3A4/5 Bioavailability: ~100% Half-life elimination: ~2.5 Time to peak: ~2 Excretion: Urine 75% (24% as unchanged drug); feces 22% No No Potent CYP 3A4/5 inhibitor: Use 2.5mg daily Diarrhea, Constipation, Nausea, Peripheral edema, Hypoglycemia, Osteoarthritis, Headache, Nasopharyngitis, Upper respiratory infection Headache, Nasopharyngitis, Upper respiratory infection, increased serum ALT Headache, hypoglycemia, urinary tract infection, peripheral edema, vomiting, abdominal pain Absorption: Rapid Distribution: Extensive Protein binding:70-80% concentration dependent Metabolism: Not extensively metabolized; minor metabolism via CYP2D6 and CYP3A4 Bioavailability: ~30% Half-life elimination: ~12 Time to peak: ~1.5 Excretion: 80% feces unchanged; 5% urine unchanged Avoid with CYP3A4 or P-gp inducers Hypoglycemia, headache, weight gain, hypertriglyceridemia, constipation, urinary tract infection, arthralgia, back pain, nasopharyngitis Yes Yes Yes Yes

Serious allergic and hypersensitivity Yes; Anaphylaxis, rash, Hypersensitivity reaction, Stevens- Johnson syndrome Yes; Anaphylaxis, Hypersensitivity reaction, Stevens- Johnson syndrome Yes; Anaphylaxis, Hypersensitivity reaction, Stevens- Johnson syndrome Acute Yes Yes Yes Yes pancreatitis Acute renal Yes No No No failure Hepatic failure No Yes No No Arthralgia Yes; severe arthralgia (FDA Safety Alert, Aug 28, 2015) Yes; severe arthralgia (FDA Safety Alert, Aug 28, 2015) Yes; severe arthralgia (FDA Safety Alert, Aug 28, 2015) Risk of heart failure Pregnancy Lactation No, but may exacerbate underlying myocardial dysfunction (AHA 2016) Particularly patients with pre-existing heart or kidney disease Particularly patients with pre-existing heart or kidney disease No Yes; severe arthralgia (FDA Safety Alert, Aug 28, 2015) Not recommended It is not known if DPP4 s are excreted in breast milk. The US labeling recommends that caution be exercised when administering to breast-feeding women. No Storage and stability How supplied Store at 25 C (77 F); excursions are permitted to 15 to 30 C (59 to 86 F). 25 mg 50 mg 100 mg 6.25 mg 12.5 mg 25 mg 2.5 mg 5 mg 5 mg

Clinical Justification: 2017 American Diabetes Association Guidelines: Recommend DPP-4 inhibitors as adjunctive therapy to first-line metformin based on patientspecific factors (e.g. weight gain, risk for hypoglycemia and ease of administration). Nevertheless, no one particular DPP-4 inhibitor was endorsed over another by ADA. 2017 ADA did not state any recommendations regarding DPP-4 inhibitors in patients at risk of heart failure. It addressed the recent FDA statement of discontinuing saxagliptin and alogliptin in people who develop heart failure and highlighted recent studies (SAVOR-TIMI 53, EXAMINE, and TECOS) that showed relationship between DPP-4 inhibitors and heart failure.

Clinical Trials: 1. Examine Trial: Heart Failure and Mortality Outcomes In Patients with Type 2 Diabetes Taking Alogliptin: EXAMINE trial (2013), Meta-Analysis (2014) and Systemic review and Meta-analysis (2016) The EXAMINE trial is a multicenter, randomized, double-blinded study that investigated safety of alogliptin in patients with type 2 diabetes and recent acute coronary syndrome and total 5,380 patients were followed up at a median of 533 days. The primary composite endpoint (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in a similar proportion of patients (11.3% and 11.8% in the alogliptin and placebo groups, respectively; HR 0.96, upper boundary of the one-sided CI 1.16). Hospitalization for heart failure occurred in 3.1% of patients receiving alogliptin and 2.9% of patients receiving placebo (HR 1.07; 95% CI 0.79-1.46; p=0.657). In a post-hoc analysis of the data, rate of hospital admission for heart failure showed no difference between alogliptin and placebo group (3.9% vs. 3.3%; HR: 1.19; CI: 0.90-1.58; p=0.220). However, there was greater number of hospitalization for heart failure in the alogliptin group than placebo group although the difference was not statistically significant. For patients with a history of heart failure at baseline, risk of hospital admission for heart failure was similar in the two treatment groups (alogliptin 13.9% vs. placebo 15.7%; HR 0.90; 95% CI 0.70-1.17). In those patients without a history of heart failure at baseline, the risk of cardiovascular death was similar but of hospital admission for heart rate was higher in the alogliptin group (alogliptin 4.9% vs. placebo 4.2%; HR 1.14; 95% CI 0.85-1.54). A meta-analysis done in 2014 included 82 studies in which patients receiving therapy with any DPP-4 inhibitor compared to either placebo or an alternative diabetes medication. The overall risk of acute heart failure was higher in patients treated with DPP-4 inhibitors compared to those treated with placebo/active comparators (MH OR: 1.19[1.03; 1.37]; p = 0.015). There was no difference seen between individual DPP-4 inhibitors compared to the other medications in the class. In 2016, a systemic review and meta-analysis of randomized and observational studies for risk of heart failure in patients taking DPP-4 inhibitors was done for 43 trials (n=68,775) and 12 observational studies (9 cohort, 3 nested case-control studies; n=1,777,358). The results showed increased risk of hospital admission for heart failure in patients treated with DPP-4 inhibitors compared to placebo group (42/15701 vs. 33/12591; odds ratio 0.97; 95% CI 0.61-1.56). However, the relative effect of DPP-4 inhibitors on the risk of heart failure in patients with T2DM is uncertain with relatively short follow-up and low quality of evidence. The baseline risk of patients was very low (under 1% per year) and small number of events with relatively wide confidence interval. 2. SAVOR TIMI Trial: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes- Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 7 examined the effect of saxagliptin compared to placebo on CV outcomes in patients with type 2 diabetes across 788 centers in 26 countries. The median follow-up for this study was 2.1 years. The primary CV endpoints was similar in the saxagliptin and placebo groups (7.5% vs 7.2%).

For the secondary endpoints, the saxagliptin group had higher rates of hospitalization for heart failure when compared with the placebo group (3.5% vs 2.8%, p< 0.007). 7 3. TECOS Trial: Heart Failure and Mortality Outcomes In Patients with Type 2 Diabetes Taking Sitagliptin: Stiagliptin Use in Patients With Diabetes and Heart Failure (2014) and TECOS trial (2015) No specific recommendations regarding patients with cardiovascular disease (including heart failure) are provided in the US labeling (Canadian labeling recommends against use in the heart failure population). Clinical trials included only a limited number of patients with heart failure. In a population-based restrospective cohort study of stiagliptin use in T2DM and heart failure, there was association between increased risk of heart failure-related hospitalization and patients with pre-existing heart failure who exposed to sitagliptin therapy (12.5% vs. 9.0%, adjusted odds ratio: 1.84, 95% CI: 1.16 to 2.92; p=0.01). In TECOS trial, 14,671 patients with type 2 diabetes and established cardiovascular disease were randomized, double-blinded to receive either sitagliptin or placebo to their existing therapy. For the primary and secondary composite CV outcome, sitagliptin has been shown to be noninferior to placebo (538 vs.525 events; HR 1.02, 95% CI 0.90-1.14) and there was no significant difference in the rate of hospitalization for heart failure (sitagliptin 3.1% (n=228) vs. placebo 3.1% (n=229); HR in the intention-to-treat analysis, 1.00; 95% CI 0.83 to 1.20; p=0.98). However, this study excluded patients with patients with severe renal insufficiency. FDA Drug Safety Communication: Diabetes Medications Containing Saxagliptin and Alogliptin - Risk of Heart Failure (April 2016) An FDA safety review has found that type 2 diabetes medicines containing saxagliptin and alogliptin may increase the risk of heart failure, particularly in patients who already have heart or kidney disease. As a result, FDA is adding new warnings to the drug labels about this safety issue FDA recommendation: Health care professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control. If a patient s blood sugar level is not well-controlled with their current treatment, other diabetes medicines may be required. References: 1. American Diabetes Association. Standards of Medical Care in Diabetes 2017. Diabetes Care Vol 40, supplement 1, January 2017. 2. Zannad F, Cannon CP, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015 May;385(9982):2067-76. Epub 2015 Mar 10. 3. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:689-697.

4. Li L, Li S, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systemic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610. 5. Weir DL, AcAlister FA, et al. Stiagliptin Use in Patients With Diabetes and Heart Failure. JACC: Heart Failure. 2014 December; 6(2):573-582. 6. Green JB, et al. "Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes". The New England Journal of Medicine. 2015. 373(3):232-242. 7. The FDA Safety Information and Adverse Event Reporting Program. Diabetes Medications Containing Saxagliptin and Alogliptin: Drug Safety Communication Risk of Heart Failure. Available at: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedical Products/ucm494252.htm. Accessed January 15, 2017. 8. Facts and Comparison, Dipeptidyl peptidase-4 inhibitors, http://online.factsandcomparisons.com. Accessed February 01, 2017. Change Control Date Change 02/15/2017 Add alogliptin to formulary with step therapy requirements