Tsunami of diabetes: Help is on the way

Issue focus: Diabetes

Given what pharmacists are seeing in clinics and medication therapy management sessions across America, the statistics are not surprising: diabetes prevalence up to 23% by 2025, from 14% now, and 439 million people worldwide with the disease by 2030.

In his presidential address at the 73rd Scientific Sessions of the American Diabetes Association (ADA), John Anderson, MD, asked whether the United States is prepared for this “tsunami of diabetes.”

Held in June, this year’s 73rd Scientific Sessions drew nearly 18,000 participants and included 2,500 abstracts, more than 2,000 research posters, and 92 symposia. The meeting was internationally attended. An estimated 60% of meeting attendees came to Chicago from countries outside of the United States.

This year’s program included presentations on treatment strategies for type 1 diabetes, as well as information on the efficacy of novel agents for diabetes and potential pathways for targeting better control of the disease. Key highlights from the meeting included a look back on important trials such as the Diabetes Control and Complications Trial (DCCT) and a glimpse into the future for the treatment of diabetes, including new drugs and formulations of antidiabetic agents.

DCCT and EDIC: Metabolic memory

Through long-term, intensive therapy, people with type 1 diabetes can achieve near-normal glucose levels and thereby reduce the frequency of severe eye disease, impaired kidney function, heart disease, and stroke. A special ADA symposium recognized this important information on tight glycemic control defined by DCCT, a landmark study launched 30 years ago. DCCT changed the face of the treatment of type 1 diabetes. A total of 1,441 volunteers with type 1 diabetes were enrolled at 29 medical centers in the United States and Canada between 1983 and 1989 and were followed until 1993. Each patient was randomly assigned to receive standard therapy of one or two daily insulin injections or intensive control therapy, which included frequently monitored blood glucose levels and at least three daily insulin injections or continuous subcutaneous insulin infusion.

New DCCT data presented at ADA came from a long-term follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, which began in 1994. Following the conclusion of DCCT, glycemic control in the standard versus intensive treatment groups converged to similar values after patients went back to their communities for care. EDIC, an ongoing study, measures the continued impact of glycemic control in patients originally enrolled in DCCT. Investigators dubbed a term—metabolic memory—to describe the glycemic phenomenon observed in EDIC.

Of the original 1,441 research patients enrolled in DCCT, more than 95% of the surviving members have been followed through the EDIC trial. After 18 years of EDIC follow-up, the overall prevalence of diabetic complications was 50% lower among the patients in the DCCT who were randomly assigned to intensive glucose control than among those who received conventional treatment.

Lloyd Aiello, MD, PhD, a DCCT/EDIC investigator at the Joslin Diabetes Center in Boston, reported new retinopathy findings from EDIC. After 18 years, patients in the intensive control group had a 46% reduction in retinopathy.

“Although we have means of treating severe eye disease to prevent vision loss, it is always better to reduce its development in the first place in order to avoid the need for expensive and only partly effective late-stage therapies,” Aiello said. “Intensive diabetes therapy effectively accomplishes this goal.” 

Updates on the long-term consequences of intensive therapy on kidney disease were summarized by Ian de Boer, a DCCT/EDIC investigator from the University of Washington. The 18-year update found a 39% reduction in risk of incident microalbuminuria and a 61% decrease. 

While it may be too soon to assess cardiovascular disease outcomes in the relatively young DCCT/EDIC population, positive benefits have already been seen. John Lachin, MD, principal investigator of the DCCT/EDIC Coordinating Center at George Washington University, reported that intensive glucose control resulted in a 42% decrease in any cardiovascular event and a nearly 60% reduction in nonfatal heart attack, stroke, or death at 9 years into EDIC follow-up. Extending these data into 2012, cardiac risk reductions are 33% and 35%, respectively.

“The long-term results of the DCCT/EDIC further reinforce the importance of early intensive therapy over the lifetime of people with type 1 diabetes,” said Judith Fradkin, MD, director of the Division of Diabetes, Endocrinology, and Metabolic Disease of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health. “Our challenge now is to ensure that all patients with type 1 diabetes are able to take advantage of these remarkable findings and to make intensive therapy as convenient and safe as possible.”

Dulaglutide shows promise as once-weekly GLP-1 agonist

Four abstracts and three oral presentations showcased the use of dulaglutide, a Phase III, investigational, once-weekly glucagon-like peptide (GLP-1) agonist in patients with type 2 diabetes. Results from three Lilly-sponsored AWARD (Assessment of Weekly Administration of LY2189265 in Diabetes) trials were presented at this year’s scientific sessions.  

This GLP-1 agonist exerts its effects by acting as an incretin mimetic, causing glucose-dependent insulin release while suppressing postprandial glucagon secretion. Gastric emptying is also delayed, which helps increase satiety. 

The AWARD-3 study—a randomized, double-blind, parallel-arm, monotherapy Phase III trial—compared the safety and efficacy of dulaglutide 0.75 mg or 1.5 mg once weekly to metformin 1,000 mg twice daily in 807 patients with early type 2 diabetes (A1C 6.5%–9.5%). After 26 weeks of therapy, both once-weekly doses of dulaglutide demonstrated superior glycemic control over metformin. After 52 weeks, the 1.5-mg dose of dulaglutide was found to be superior to metformin, reported Guillermo E. Umpierrez, MD, of the Emory University School of Medicine.

Results of the AWARD-1 and AWARD-5 trials supported these findings. AWARD-1 was a randomized, 52-week, placebo-controlled study comparing dulaglutide 0.75 mg or 1.5 mg once weekly and exenatide (Byetta—Amylin Pharmaceuticals) 10 mcg twice daily and placebo. Conducted in 978 patients, AWARD-1 enrolled participants with early type 2 diabetes who were already taking metformin and pioglitazone. Both doses of dulaglutide were superior to both placebo and twice-daily exenatide. 

The AWARD-5 study found that once-weekly dulaglutide 1.5 mg was superior to the oral dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia—Merck). More than 1,000 patients with type 2 diabetes who were treated with metformin were enrolled in the AWARD-5 study over a period of more than 100 weeks.  

Sustained weight loss was another important benefit of dulaglutide observed in the AWARD trials. In AWARD-5, patients taking dulaglutide 1.5 mg had significant weight loss compared with patients taking sitagliptin and similar weight loss to patients taking comparators in AWARD-1 and AWARD-3. The most commonly experienced adverse effect for all studies involving dulaglutide was mild to moderate nausea, and this was transient.

In terms of safety, rates for hypoglycemia (blood glucose level of 70 mg/dL or less) were low across all three AWARD trials. Documented cases of severe hypoglycemia were not seen in any of the trials.

Lilly expects to submit a new drug application for dulaglutide to regulatory authorities in 2013. Detailed results from two additional AWARD studies for presentation should follow at scientific meetings in 2014.

Insulin, metformin announcements

The combination of liraglutide (Victoza—Novo Nordisk) insulin degludec (Tresiba—Novo Nordisk)—which can be given daily or up to three times a week and has a duration of action that lasts up to 40 hours—was more effective than the component agents separately in a study of 1,663 patients with type 2 diabetes. The BEGIN Once trial compared the combination product, IDegLira (Nove Nordisk), with liraglutide 1.8 mg or titrated insulin degludec in patients who were not inadequately controlled on metformin with or without pioglitazone. The primary endpoint of the Phase III trial, A1C at 26 weeks, decreased from 8.3% to 6.4% with IDegLira, significantly greater than reductions seen with insulin degludec (1.4%) or liraglutide (1.3%) monotherapy.

“Our challenge now is to ensure that all patients with type 1 diabetes are able to take advantage of these remarkable findings and to make intensive therapy as convenient and safe as possible.”

Insulin degludec is available in the European Union. In February 2013, FDA declined to approve the agent and its companion agent Ryzodeg (Novo Nordisk), a combination product containing insulin degludec and insulin aspart. Instead, FDA issued a “complete response letter” in which it requested additional cardiovascular outcomes data. IDegLira is under review by the European Medicines Agency.

A novel formulation of metformin (NewMet—Elcelyx Therapeutics) was also unveiled at ADA. Targeted at patients who are unable to take metformin due to renal impairment, the delayed-release formulation may offer alternatives to help decrease the risk for lactic acidosis. The product bypasses the upper bowel and delivers metformin in the lower bowel, thus dramatically reducing circulating plasma metformin levels. 

Studies presented at ADA confirm this effect. If approved by FDA, this formulation of metformin could make a product once contraindicated in patients with renal insufficiency finally available—but at a cost that will no doubt be considerably greater than generic versions.