Breay W. Paty, MD, FRCPC (biography and disclosures)
Dr. Paty has received speaking fees and/or sat on advisory boards for Merck, Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi, Abbott, Tadeka and Boehringer Ingelheim.
Mitigating Potential Bias
A. Only published trial data is presented
B. Recommendations are consistent with published guidelines (CDA 2013, ADA 2015)
C. Recommendations are consistent with current practice patterns
Incretin agents have emerged as useful additions to the pharmacologic management of type 2 diabetes. This class of agents, including DPP-4 inhibitors (sitagliptin [Januvia®], saxagliptin [Onglyza®], linagliptin [Trajenta®]) and GLP-1 receptor agonists (RAs) (exenatide [Byetta®], liraglutide [Victoza®]) are based on the physiologic action of the gut peptide, GLP-1, which lowers blood glucose by augmenting glucose-stimulated insulin secretion among other actions. The average A1c lowering with DPP-4 inhibitors is between 0.5-1.0% (monotherapy) or 1.0-1.5% (in combination with metformin). These agents are considered weight neutral. Lower doses are recommended for sitagliptin and saxagliptin in moderate to severe renal dysfunction (sitagliptin 50 mg or 25 mg; saxagliptin 2.5 mg), but no dose reduction is needed for linagliptin because of hepatobiliary excretion. The GLP-1 receptor agonists are associated with an A1c lowering of between 1.0-1.5% (monotherapy) or 1.5-2.0% (in combination with metformin) and can be associated with weight loss, although this varies between patients. They are not currently recommended for patients with renal dysfunction. The cost of DPP-4 inhibitors in British Columbia ranges between $2-3 per daily dose ($73-$96 per month) and GLP-1 receptor agonists ranges between $8-9 per daily dose. DPP-4 inhibitors require special authority to be eligible for Pharmacare when insulin NPH is not an option and after inadequate glycemic control on maximum tolerated doses of dual therapy of metformin and a sulfonylurea. GLP-1 receptor agonists are not currently eligible for Pharmacare coverage.
What frequently asked questions I have noticed?
While these medications are generally well tolerated, some adverse effects are well known. Nausea can be a common side effect of GLP-1 receptor agonist, which can sometimes be dose limiting. However, this usually improves with time. As a new class of agents, evidence for the long-term safety of incretins is still emerging. Most of the safety questions involve cardiovascular (CV) risk, as well as pancreatitis and pancreatic cancer.
Data that answers these questions
Cardiovascular risk: Early clinical trials of incretins have shown no increased CV risk. Nevertheless, all the incretin agents have CV safety trials underway and the results of two of these trials are now available. SAVOR-TIMI53 compared the risk of CV events (composite of CV death, non-fatal MI, or non-fatal ischemic stroke) between subjects with type 2 diabetes (n=16,492) treated with saxagliptin versus placebo over 3.7 years. The results showed no difference in CV events between the two treatment groups (HR 1.00 [0.89 – 1.12]). Interestingly, there was an increased rate of hospitalization for heart failure in the saxagliptin group (HR 1.27 [1.07 – 1.51]), which has not been observed in other trials and has no clear explanation. The EXAMINE trial of the DPP-4 inhibitor, alogliptin (not currently available in Canada), compared similar endpoints between subjects with type 2 diabetes and acute coronary syndrome (n=5,380) treated with either alogliptin or placebo. The results also showed no difference in CV outcomes (HR 0.96 [upper CI ≤ 1.16]). Results from similar CV safety trials of the other DPP-4 inhibitors and GLP-1 RAs are expected over the next few years.
Pancreatitis and pancreatic cancer: A small number of cases of pancreatitis and pancreatic cancer were initially reported in the early clinical trials of incretins, but the incidence did not exceed that expected in people with type 2 diabetes. In 2013 the European Medicines Agency concluded that the data did not confirm concerns regarding a risk of pancreatic adverse events. Since then, subgroup analyses from the SAVOR-TIMI53 and EXAMINE trials have been published which also do not demonstrate an association between these DPP-4 inhibitors and pancreatic disease (SAVOR-TIMI53: pancreatitis – saxagliptin 24 cases [0.3%] vs. placebo 21 cases [0.3%], p=0.77; pancreatic cancer – saxagliptin 12 cases [0.1%] vs. placebo 5 cases [0.06%], p=0.095 favouring saxagliptin; EXAMINE: acute pancreatitis – alogliptin 12 cases [0.4%] vs. placebo 8 cases [0.3%], p=0.50; chronic pancreatitis – alogliptin 5 cases [0.2%] vs. placebo 4 cases [0.1%], p=1.00; pancreatic cancer – 0 cases in both groups).
What I recommend
The evidence available so far supports the safety of incretin agents, both in terms of CV risk and pancreatic safety. The increased rate of hospitalization for heart failure observed in the SAVOR-TIMI53 trial was unexpected and requires further examination. Results from ongoing CV safety trials will be available in the next few years, which will illuminate these and other questions regarding incretin safety. In the meantime, I use incretin agents when indicated for type 2 diabetes. Although the evidence is reassuring, I do not prescribe these agents for people with a history of pancreatitis or pancreatic cancer, but this may change if the evidence continues to support the safety of this pharmacologic class.
- Egan et al. Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment. N Engl J Med 2014; 370: 794-797. (Full free article) (View with UBC)
- Scirica et al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2013; 369: 1317-26. (SAVOR-TIMI53) (Full free article) (View with UBC)
- White et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013; 369: 1327-35. (EXAMINE) (Full free article) (View with UBC)
From BC Guidelines www.BCGuidelines.ca:
GPAC recommendation for the DPP4Is:
Dosage reduction required if eGFR < 50 mL/min (sitagliptin, saxagliptin).
Contraindicated: pregnancy, hepatic failure, previous lactic acidosis.
Both saxagliptin and sitagliptin are associated with increased heart-failure related hospitalizations and should be used cautiously in this population.
Pharmacare: $175 monthly for 1.2mg dose of Victoza (would be higher if using 1.8mg dose) and $150/month for Byetta (all doses). GPAC guideline lists these ranges for a year: $2120-$3183 victoza and $1817 byetta.
No coverage for sitagliptin. Limited coverage with special authority for saxagliptin and linagliptin.