Antidiabetic agents: Efficacy, safety focus of ADA meeting

Canagliflozin, albiglutide, metformin, more


The American Diabetes Association’s (ADA) 72nd Scientific Sessions in Philadelphia drew nearly 18,000 participants from all 50 states and more than 100 countries. This year’s program included presentations on the efficacy of novel agents for the management of the disease and discussions about the safety of existing agents. Key highlights from the June meeting are discussed in this overview, and additional details about the information presented in Philadelphia can be accessed via ADA’s website at .

Canagliflozin, the first available SGLT-2 inhibitor?

Two late-breaking abstracts evaluated the efficacy and safety of canagliflozin, a sodium–glucose transport protein subtype 2 (SGLT-2) inhibitor currently being developed by Janssen. Canagliflozin exerts its mechanism of action by blocking the reabsorption of glucose by the kidneys, resulting in more glucose excretion in the urine.

In a randomized, double-blind, active-controlled Phase III trial, canagliflozin 100 mg and 300 mg were compared with glimepiride (mean dose 5.6 mg/d) in 1,450 patients with type 2 diabetes not controlled on metformin. The baseline mean age of patients was 56.2 years and glycosylated hemoglobin (A1C) was 7.8%.

After 52 weeks of therapy, all three treatments resulted in reductions in A1C (canagliflozin 100 mg –0.82%, canagliflozin 300 mg –0.93%, glimepiride –0.81%), with both doses of canagliflozin demonstrating noninferiority compared with glimepiride. The 300-mg dose of canagliflozin also demonstrated superiority to glimepiride. Over the 52-week treatment period, A1C reductions were consistently observed in the canagliflozin groups, whereas A1C began to rise after week 18 in the glimepiride group. In addition, weight loss was observed in both canagliflozin groups (approximately 4.5%), whereas patients in the glimepiride group gained weight (1.0%). In terms of safety, both canagliflozin groups were associated with fewer hypoglycemic episodes (canagliflozin 100 mg 5.6%, canagliflozin 300 mg 4.9% vs. glimepiride 34.2%), and fewer patients in the canagliflozin groups required glycemic rescue therapy. Although the total number of adverse events was similar between the three groups (approximately 66%), use of canagliflozin was associated with more events of superficial genital fungal infections in women and men, urinary tract infections, and osmotic diuresis–related events.

In another randomized, double-blind, active-controlled Phase III trial, canagliflozin 300 mg was compared with sitagliptin (Januvia—Merck) 100 mg/d in 755 patients with type 2 diabetes not controlled on metformin a sulfonylurea. The baseline mean age of patients was 56.7 years and A1C was 8.1%. After 52 weeks of therapy, reductions in A1C were greater in the canagliflozin group (–1.03%) than with sitagliptin (–0.66%). As with the glimepiride trial, A1C reductions were consistently observed over the 52-week treatment period in the canagliflozin group, whereas increases were observed after week 12 in the sitagliptin group. Other results were also similar, with patients in the canagliflozin group showing greater reductions in body weight and having more superficial genital fungal infections in women and men. However, a key difference between this trial and the other trial is that the incidence of urinary tract infections was similar between groups.

On May 31, Janssen announced that it submitted a New Drug Application to FDA seeking approval for the use of canagliflozin for the treatment of adult patients with type 2 diabetes. Janssen noted in the news release that the filing was supported by a comprehensive global Phase III clinical development program, which included nine multicenter, randomized clinical studies that enrolled approximately 10,300 patients. The clinical development program also included a dedicated cardiovascular study conducted in patients who have or are at high risk for developing cardiovascular disease.

Based on the positive data presented at the ADA meeting and the comprehensive filing a few months ago, clinicians may soon see this novel agent as another treatment option to help manage patients with type 2 diabetes who are inadequately controlled on other therapies. A big discussion point at the FDA Advisory Committee Meeting will most likely be the unique adverse event profile (e.g., increased risk for fungal infections, genital–urinary infections) associated with this agent.

Dapaglifozin, a similar agent developed by Bristol-Myers Squibb and AstraZeneca, failed to receive FDA approval earlier this year. The advisory committee expressed concerns about adverse effects associated with dapagliflozin such as genital–urinary infections, increased risk of breast and bladder cancer, liver injury, cardiovascular safety, and appropriate use in older patients and those with renal impairment.

Only time will tell if canagliflozin will be the first SGLT-2 inhibitor to reach the marketplace.

Long-acting GLP-1 agonist

Data on the efficacy and safety of albiglutide, a once-weekly investigational glucagon-like peptide-1 (GLP-1) receptor agonist, was also presented at the ADA meeting (abstract 945-P).

A 32-week, open-label, randomized, Phase III trial compared once-weekly albiglutide, manufactured by GlaxoSmithKline, with once-daily liraglutide (Victoza—Novo Nordisk) in patients with type 2 diabetes inadequately controlled on metformin, a thiazolidinedione, a sulfonylurea, or any combination of these agents. Patients were randomized to albiglutide 30 mg once weekly titrated to 50 mg once weekly at week 6 (n = 404) or liraglutide 0.6 mg once daily titrated to 1.8 mg once daily by week 3 (n = 408). The baseline mean age of patients was 55.6 years and A1C was 8.2%. After 32 weeks of treatment, changes in A1C from baseline were –0.78% with albiglutide compared with –0.99% with liraglutide, with albiglutide failing to meet the noninferiority criteria. Greater reductions in fasting plasma glucose were also observed in the liraglutide group (–30.4 mg/dL vs. –22.1 mg/dL).

Both GLP-1 agonists resulted in weight loss, with liraglutide outperforming albiglutide (–2.19 kg vs. –0.64 kg). Use of once-weekly albiglutide was associated with fewer gastrointestinal (GI) events (35.9% vs. 49.0%), with the difference between groups being particularly pronounced in the first 4 weeks of treatment (approximately 10% vs. 30%) and persisting for 12 weeks. Specifically, nausea and vomiting were reported by 9.9% and 5.0% of patients in the albiglutide group, respectively, compared with 29.2% and 9.3% in the liraglutide group, respectively.

The efficacy of once-daily liraglutide was slightly better than that of albiglutide, but the long-acting formulation was associated with fewer GI events, especially early in therapy. The reduced dosing demands of a once-weekly injection coupled with a better tolerability profile may result in improved adherence rates with albiglutide. Additional studies are needed to evaluate this endpoint to determine if this is truly the case. Glaxo-SmithKline plans to seek regulatory approval for albiglutide early next year based on positive data from numerous trials.

Metformin: Clinically relevent B12 deficiency?

Patients taking metformin therapy are known to have impaired vitamin B12 absorption, but the clinical relevance of this problem is unclear. Patients with vitamin B12 deficiency may present with peripheral neuropathy, which may be misdiagnosed as diabetic neuropathy.

A poster presentation at the ADA meeting assessed the effect of chronic metformin therapy on vitamin B12 levels and the degree of peripheral neuropathy seen in patients. A total of 84 patients (mean age 63 y) with type 2 diabetes who were receiving metformin for at least 4 years were included in the analysis. Serum concentrations of vitamin B12 were determined and all patients were assessed for the presence of peripheral neuropathy.

Of the 84 patients, serum vitamin B12 levels were low, defined as concentrations less than or equal to 150 pmol/L, in 15 (17.8%) and possibly low, defined as concentrations between 150 to 250 pmol/L, in an additional 22 (26%). The investigators reported that lower vitamin B12 levels were associated with a higher degree of peripheral neuropathy. They noted that older patients treated with chronic metformin therapy are more prone to this adverse event, as serum vitamin B12 levels were negatively associated with age and duration of metformin use. Clinicians should consider this possibility when evaluating patients with type 2 diabetes on long-term metformin and in those presenting with peripheral neuropathy. At the present time, however, if a vitamin B12 deficiency is found, it is unclear how much supplementation should be given and what the ideal route of administration should be.

Insulin glargine: Cancer risks

Patients’ cancer fears may be lessened after results from three epidemiologic studies concluded that insulin glargine (Lantus—Sanofi) is not associated with an increased cancer risk. The three insulin studies included the Northern European Database Study, the Kaiser Permanente Collaboration, and the MedAssurant Database.

The Northern European Database Study involved 447,821 patients using insulin for more than 1.5 million person-years of observation. After a mean follow-up time of 3.1 years for patients on glargine and 3.5 years for those on other insulins, no evidence for an increased risk of breast cancer in women, prostate cancer in men, or an increased risk for colorectal cancer in women or men was observed with use of insulin glargine versus other insulins.

The Kaiser Permanente Collaboration involved 115,000 patients with a median of 1.2 years of glargine use and 1.4 years of neutral protamine Hagedorn (NPH) insulin use. Results from this study revealed no evidence of an association between insulin glargine use and an increased risk for breast cancer, prostate cancer, colorectal cancer, or all cancers combined. The final epidemiological trial, the MedAssurant Database study, involving 43,306 patients on insulin glargine and 9,147 on NPH, also found no increased risk for a variety of cancers with glargine use.


The overview presented in this article is only a brief snapshot of information presented at this year’s ADA meeting, where much of the data focused on the efficacy and safety of treatments for diabetes.

The positive data for canagliflozin and albiglutide may result in the approval of these medications in the near future. If canagliflozin reaches the marketplace, this agent will offer patients with type 2 diabetes a new oral agent with a unique mechanism of action. In addition, if albiglutide reaches the marketplace, patients will have another long-acting GLP-1 agonist to use for the management of their disease. Based on data at the ADA meeting, patients can be reassured that use of insulin glargine is not associated with an increased cancer risk.

These results, along with other data presented at the meeting, can help clinicians anticipate future therapies, the agents’ place in diabetes therapy, and most importantly, the overall efficacy and safety.