Update on Diabetes Therapy

Germin FahimCurrently, about 29 million Americans have diabetes according to the CDC. Despite evidence that optimal glycemic control can help reduce disease progression and complications, most patients do not achieve recommended treatment goals.

 “Effective management of type 2 diabetes mellitus (T2DM) requires the use of combination therapy with different mechanisms of action,” said Germin Fahim, PharmD, BCPS, Clinical Assistant Professor at Ernest Mario School of Pharmacy and internal medicine clinical pharmacist at Monmouth Medical Center, Long Branch, N.J. The world of diabetes is rapidly evolving, and staying abreast of various treatment options enables pharmacists to provide optimal patient care.

SGLT2 inhibitors

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, unlike other available agents, decrease renal glucose reabsorption by promoting urinary glucose excretion. “This novel mechanism of action offers clinicians a different approach to individualize diabetes treatment and help patients control their blood sugar levels,” said Fahim.

The class is currently made up of 3 agents-canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim). Fahim pointed out that additional benefits of using SGLT2 inhibitors in individuals with T2DM include significant reductions in blood pressure and body weight.

Regulatory guidance specifies the need to establish cardiovascular (CV) safety of new diabetes therapies to rule out excess CV risk. According to a study published in the New England Journal of Medicine – involving more than 7,000 patients with T2DM – those receiving empagliflozin had significantly lower rates of death from CV events, hospitalization for heart failure, and death from any cause compared with placebo.¹ As reported in previous clinical trials, genital infection was more common in the empagliflozin group than placebo.

GLP-1 agonists

Fahim views glucagon-like-peptide-1 (GLP-1) receptor agonists as a welcome addition to the diabetes therapy armamentarium, because they effectively lower A_1C, weight, and blood pressure while posing a low risk of hypoglycemia.

The long-awaited, once-daily GLP-1 agent, lixisenatide (Adlyxin, Sanofi) received FDA approval for adults with T2DM in July, 2016, based on thirteen studies with more than 5,000 patients. Additionally, in a CV outcomes trial in patients with T2DM, lixisenatide did not increase the risk of CV adverse events. The drug’s availability also paves the way for approval of a combination product that incorporates lixisenatide with Sanofi’s basal insulin, Lantus (insulin glargine 100 U/mL).

Recently liraglutide (Victoza, Novo Nordisk) demonstrated improved CV outcomes in patients with T2DM who were at high risk for CV events. Published in the New England Journal of Medicine, the study followed 9,340 high-risk adults with T2DM for 3.5 to 5 years, who received either a subcutaneous injection of liraglutide or placebo along with standard therapy.² The primary endpoint was CV death, nonfatal myocardial infarction, or nonfatal stroke among T2DM patients. Liraglutide decreased the risk of CV death by 22% and overall heart risks by 13% compared with placebo.

Another GLP-1 analogue, semaglutide (Novo Nordisk), is currently in phase 3 development. In two studies, SUSTAIN 2 and SUSTAIN 3, presented at the American Diabetes Association 76^th Scientific Sessions in New Orleans, the once-weekly GLP-1 agent showed superior improvements in glycemic control compared with sitagliptin (Januvia, Merck) or exenatide extended-release (Bydureon, AstraZeneca). In the SUSTAIN 2 trial, semaglutide demonstrated superiority by a bigger margin, with reductions in A_1C of 1.3% for a 0.5-mg dose and 1.6% for a 1-mg dose compared with 0.5% with sitagliptin. In the SUSTAIN 3 trial, semaglutide lowered A_1C levels by 1.5% (1-mg dose) versus 0.9% with exenatide extended-release (2-mg dose). Fahim noted that in both trials, patients in the semaglutide group also achieved significantly greater reductions in body weight (up to 6.1 kg). The most common adverse events seen were GI, such as nausea and diarrhea.

Similar to liraglutide, semaglutide has been shown to reduce the rate of CV events in T2DM patients in a study published in the New England Journal of Medicine.³ In this CV outcomes study, patients were followed for 2.1 years.

Fahim cautioned that while the data on GLP-1 agonists are encouraging, all agents in this class carry an FDA warning for pancreatitis and thyroid cancer. According to the October 6, 2016 issue of ISMP Medication Safety Alert, what sets albiglutide (Tanzeum, GSK) apart from other GLP-1 agonists are more than 1,500 reports of patients having problems using the complex Tanzeum pen correctly. The ISMP newsletter advises that physicians should consider the ease of use when prescribing a GLP-agonist pen and ensure that patients know how to use the device if prescribing the Tanzeum pen.

Tresiba/Ryzodeg

Long-acting insulins are also effective for glycemic control in diabetic patients. The safety and efficacy of insulin degludec (Tresiba, Novo Nordisk), a long-acting insulin analog, was evaluated in three clinical trials involving 1,102 participants with type 1 and 2 diabetes. Treatment with Tresiba achieved levels of glycemic control similar to those achieved with Lantus and Levemir (insulin detemir), according to Tresiba’s package insert.

Ryzodeg 70/30 is a mixture of insulin degludec, a long-acting insulin analog, and insulin aspart, a rapid-acting human insulin analog. In clinical trials, treatment with Ryzodeg 70/30 provided reductions in A_1C equivalent to those achieved with other, previously approved long-acting or pre-mixed insulin. According to the drug labels, Tresiba and Ryzodeg should not be used in individuals with diabetic ketoacidosis.

References

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.

Marso SP, Daniels GH, Brown-Frandsen KB, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.

Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. September 16, 2016.

http://www.nejm.org/doi/full/10.1056/NEJMoa1607141#t=article