Armamentarium of Novel Diabetes Drugs Expanding
by David Wild
Austin, Texas—An unprecedented growth in treatment options for type 2 diabetes mellitus (DM) means more patients can achieve disease control, experts told attendees of the 2014 annual meeting of the American College of Clinical Pharmacy (ACCP).
Many patients have enthusiastically embraced the efficacy, convenience and added weight loss associated with sodium glucose co-transporter 2 (SGLT2) inhibitors and glucose-like peptide 1 receptor agonists (GLP-1 RAs), according to R. Keith Campbell, PharmD, CDE, Distinguished Professor in Diabetes Care and Pharmacotherapy at Washington State University College of Pharmacy, in Pullman. “The more patients use these agents, the more they like them,” said Dr. Campbell, who did not take part in the ACCP presentations.
New Oral Agents: SGLT2 Inhibitors
Because they can be used as monotherapy or as add-ons to other oral agents, SGLT2 inhibitors have proven versatile, said Matthew Strum, PharmD, clinical assistant professor in the Department of Pharmacy Practice, University of Mississippi School of Pharmacy, in Oxford. He pointed to data showing that the recently approved SGLT2 inhibitor, empagliflozin (Jardiance; Boehringer Ingelheim), which joins canagliflozin (Invokana, Janssen) and dapagliflozin (Farxiga, Bristol-Myers Squibb), is most effective in combination with metformin.
The data are from an open-label, 78-week extension study that compared empagliflozin (10 or 25 mg) with sitagliptin (Januvia, Merck), metformin alone, or metformin combined with one of these two agents (Diabetes Care 2013;36:4015-4021).
The results showed that after 78 weeks of treatment, empagliflozin 25 mg in combination with metformin led to a mean 0.77% reduction in hemoglobin A1c (HbA1c) and a mean 32 mg/dL reduction in fasting plasma glucose. In contrast, sitagliptin with metformin was associated with a mean 0.13% reduction in HbA1c and a decrease of 16 mg/dL in fasting plasma glucose.
Weight Loss Advantage
The combination of empagliflozin 25 mg with metformin also led to reductions in systolic blood pressure (mean 3 mm Hg) and significant weight loss (mean 2.5 kg), Dr. Strum noted. “The weight reduction we’ve seen with both SGLT2 inhibitors and GLP-1 RAs gives them a significant advantage over other agents,” he said.
CANTATA-SU, a randomized, double-blind, Phase III trial, included 1,450 patients with type 2 DM, who received metformin with once-daily canagliflozin 100 or 300 mg, or with glimepiride, a long-acting sulfonylurea antidiabetic drug (Lancet 2013;382:941-950). After 52 weeks of treatment, 300 mg of canagliflozin with metformin led to a mean 4 kg reduction in weight, compared with a mean 0.7 kg weight increase in the glimepiride with metformin group, Dr. Strum said.
Subjects receiving the combination therapy also experienced a mean 0.93% reduction in HbA1c and a mean 27 mg/dL decrease in fasting plasma glucose. In contrast, subjects administered glimepiride with metformin experienced a mean 0.81% reduction in HbA1c and a mean 18 mg/dL decrease in fasting plasma glucose.
“One striking finding from a study of dapaglifozin as an add-on to pioglitazone was that dapagliflozin mitigated the weight increases that occur with pioglitazone monotherapy,” said Dr. Strum, pointing to findings showing a mean 1.3-kg increase in weight in patients receiving 10 mg of dapaglifozin with at least 30 mg of pioglitazone daily, versus a mean 3 kg rise in weight in patients who took pioglitazone alone (Diabetes Care 2012;35:1473-1478). The greatest reductions in both HbA1c and fasting plasma glucose also occurred with a combination of the two agents, Dr. Strum said.
SGLT2 and Risk For Genitourinary Infections
A caveat to these positive findings is a risk for genital and urinary tract infections that accompanies all of the SGLT2 inhibitors, Dr. Strum noted. “The most common reason my patients have had to discontinue these agents is because they’ve developed a urinary tract infection, or in women, vulvovaginitis, or in uncircumcised men, balanitis [swelling of the head of the penis],” he said. The mechanism of action? “You are putting more glucose in the urine as a result of using these medications,” he explained. “A high-glucose environment is something that bacteria can thrive in; hence the increased risk for infection.”
GLP-1 Receptor Agonists
Two recent additions to the GLP-1 RA class of drugs, albiglutide (Tanzeum, GlaxoSmithKline) and exenatide synthetic (Bydureon, AstraZeneca), have the added convenience of once-weekly administration, said Krystal Edwards, PharmD, associate professor at Texas Tech University Health Sciences Center’s School of Pharmacy, in Dallas/Fort Worth. “There are also strong efficacy data supporting their use,” said Dr. Edwards, who spoke at the same ACCP session.
Such evidence is documented in the randomized, open-label DURATION-3 trial, which compared 2 mg of exenatide synthetic once weekly to glargine in 456 patients with type 2 DM who had not achieved adequate glycemic control with at least three months of treatment with oral glucose-lowering drugs at the maximum tolerated doses. Exenatide synthetic was found to effectively control hyperglycemia (Lancet Diabetes Endocrinol 2014;2:464-473). Some patients continued treatment with metformin or combined metformin and sulfonylurea during the trial.
After three years of treatment, the researchers found that HbA1c levels decreased by a mean 1.01% in patients receiving exenatide synthetic with or without the other oral agents, compared with a mean 0.81% reduction in those administered glargine, with or without the oral agents (P=0.03). Notably, rates of hypoglycemia were three times lower in patients treated with exenatide than in those given the other drug regimens (0.3 episodes per patient-year vs. 0.9 episodes with exenatide vs. glargine, respectively).
In contrast, safety data were less favorable: More exenatide synthetic recipients experienced gastrointestinal adverse events, including nausea (15% vs. 2% for exenatide synthetic vs. glargine, respectively), vomiting (6% vs. 3%) and diarrhea (14% vs. 7%).
“Although gastrointestinal adverse events with GLP-1 RAs are not uncommon, they are generally transient and do not require treatment discontinuation,” Dr. Edwards said.
Similar to the SGLT2 inhibitors, GLP-1 RAs are associated with weight loss, Dr. Edwards said, pointing to research demonstrating reductions of 1.5 to 4 kg after six to 18 months of type 2 DM treatment with exenatide or liraglutide (Diabetes Obes Metab 2014;16:9-21). In a trial of liraglutide in obese individuals, 64% of patients lost at least 5% of their body weight after a year of treatment with 2.4 or 3 mg of liraglutide (Int J Obes [Lond] 2012;36:843-854).
FDA Acts on Positive Data
Results like these were impressive enough to prompt an FDA advisory panel to recommend approval of liraglutide for use as a treatment for obesity.
GLP-1 RAs may have other non-endocrine benefits, Dr. Edwards said. Investigators are analyzing potential related improvements in blood pressure, total cholesterol, low-density lipoprotein and triglycerides (Diabetes Obes Metab 2014;129:2305-2312). “These effects are particularly useful in type 2 DM patients, since they frequently have these comorbidities,” Dr. Edwards said.
According to Dr. Edwards, a barrier to wider clinical adoption of GLP-1 RAs is the accompanying risk for pancreatitis and pancreatic duct metaplasia. “Given reports of these complications, I would not administer these agents in patients with a history of pancreatitis, alcohol abuse or pancreatic cancer,” she said.
But there’s a caveat: The extent of the risk for pancreatitis and pancreatic cancer is disputed, and the FDA said in February 2014 that studies suggest there aren’t enough data showing a direct link (N Engl J Med 2014;370:794-797). However, the adverse effect is listed in the Warnings and Precautions section of the prescribing information for exenatide, liraglutide and albiglutide. Moreover, in a population-based, case-control study use of GLP-1 RAs within the past 30 days increased the risk for acute pancreatitis by 2.24 times, and use for between 30 days and two years also doubled the risk (JAMA Intern Med 2013;173:534-539).
Despite the risk for pancreatitis, the American Association of Clinical Endocrinologists recommends GLP-1 RAs as a possible first-line monotherapy for patients with type 2 DM who have a HbA1c less than 7.5%, but as part of combination therapy if HbA1c is equal to or greater than 7.5%, Dr. Edwards said (http://bit.ly/1ARfQwo). “Nevertheless, GLP-1 RAs may or may not be available on all formularies.”
That lack of access may be a loss for patients, she suggested. “More and more data are coming out showing GLP-1 RAs have the potential to preserve β-cells” (Diabetes Obes Metab 2013;15:485-502).
Afrezza Approval Makes Splash
Although SGLT2 inhibitors and GLP-1 RAs are important additions to clinicians’ armamentarium, “the biggest news in diabetes treatment is the approval of the pulmonary insulin, Afrezza [MannKind],” Dr. Campbell said. “It begins working within minutes, peaks within 15 minutes, and is associated with few instances of hypoglycemia,” he said.
The failed launch of Pfizer’s Exubera, another inhaled insulin that was approved by the FDA in 2006 and quickly removed from the market due to low sales, may not bode well for Afrezza. But in Dr. Campbell’s view, differences between the two agents make it more likely that Afrezza will be widely adopted into clinical practice.
“Afrezza has greater pulmonary absorption and requires less patient education,” he said. “Patients needed half an hour of training to understand how to use Exubera. Afrezza, in contrast, requires one minute of training.”
