Conference Coverage

Add-On Glargine Bests Sitagliptin for Regaining Glucose Control

Publish date: June 12, 2012
By
Miriam E. Tucker

View on the News

Long-Term Advantage of Early Insulin Still Unproven

In type 2 diabetes, progressive decline of beta-cell function leads to deterioration of glycemic control, necessitating intensification of blood glucose–lowering therapy during the course of the disease. Existing treatment algorithms advocate stepwise escalation of therapy, starting with metformin and subsequently adding other oral agents or insulin when glycated hemoglobin A1c exceeds the treatment target. To date, however, there is insufficient evidence to guide clinicians in choice of the second agent after metformin.


Dr. Michaela Diamant

An early start of insulin in type 2 diabetes has been advocated, because intensive insulin therapy immediately after diagnosis was shown to normalize blood glucose, preserve beta-cell function, and induce disease remission. In clinical practice, however, insulin treatment is often postponed because of barriers perceived by patients and health care providers to initiation of insulin. In these cases, various combinations of oral agents are prescribed, often at the cost of good glycemic control.

Since sulphonylurea use is associated with early treatment failure, weight gain, and hypoglycemia risk, dipeptidyl peptidase-4 (DPP-4) inhibitors are increasingly used. Presently, whether these agents can sustain glycemic control in the long term and improve outcomes in patients with type 2 diabetes is unknown.

In the current trial, insulin glargine resulted in a greater HbA1c reduction than did sitagliptin, with a mean adjusted difference of –0·59%. Significantly more patients in the insulin glargine group reached the prespecified HbA1c targets of both 7% and 6.5% than in the sitagliptin group.

A small increase in body weight was noted with insulin glargine use, whereas sitagliptin decreased body weight. The number of symptomatic as well as severe hypoglycemic episodes was greater with insulin glargine than with sitagliptin treatment.

With its very short duration and design, this study can only confirm the observations by others showing that addition of basal insulin, when dosed properly, to ongoing metformin monotherapy is more efficacious in lowering HbA1c than is any currently available oral agent.

Most patients and caregivers prefer to postpone insulin treatment as long as possible. At present, it is unclear whether initiation of basal insulin in the early stage of type 2 diabetes translates into longer term outcome benefits or whether its early use is ultimately offset by progressive weight gain and more hypoglycemic events, both of which could result in increased cardiovascular risk, higher cost, and poor quality of life.

The anticipated results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, comparing insulin glargine treatment in patients with dysglycemia and early type 2 diabetes with usual care for more than 7 years, will hopefully provide some answers to these questions.

Michaela Diamant, M.D., of the Diabetes Centre, VU University Medical Centre, Amsterdam, disclosed that she serves on advisory boards for Abbott, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk, and Poxel Pharma, is a consultant for Sanofi, and is a speaker for Eli Lilly, MSD, and Novo Nordisk. Through her, VU University Medical Centre receives research grants from Amylin/Eli Lilly, MSD, Novo Nordisk, and Sanofi, but she has received no personal payments in connection with any of these activities. The payments are transferred to an institutional research foundation.


 

FROM THE ANNUAL MEETING OF THE AMERICAN DIABETES ASSOCIATION

PHILADELPHIA – Introduction of basal insulin glargine for patients with type 2 diabetes who were uncontrolled on metformin was associated with improved glycemic control compared with the addition of sitagliptin in a 24-week, multicenter, open-label trial of more than 500 patients.

However, glargine was associated with a greater degree of weight gain and significantly greater rates of hypoglycemia, although severe hypoglycemia rates were rare, Dr. Pablo J. Aschner reported.

The study, funded by Sanofi, is the first randomized trial to compare two glucose-lowering treatment options that are often considered as second-line add-on treatment to metformin, in real-world conditions. "The results of this study support the option of introduction of basal insulin in patients with type 2 diabetes inadequately controlled by metformin, with the potential for long-term benefits arising from the achievement of optimum glycemic control early in the course of the disease," said Dr. Aschner, an endocrinologist and clinical epidemiologist, and professor of endocrinology and director of research at Javeriana University Hospital, Bogotá, Colombia.

The findings were simultaneously published online (Lancet 2012 June 9 [doi:10.1016/S0140-6736(12)60439-5]).

In the Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-Naive Patients (EASIE) study, 250 patients were randomized to glargine in doses starting at 0.2 units per kg of body weight injected at dinner or bedtime with a prefilled pen, and titrated up or down based on self-monitored blood glucose levels. The 265 patients in the sitagliptin group received a fixed oral dose of 100 mg once daily taken in the morning and no changes in dose were allowed during the trial. The patients, 480 of whom completed the trial (227 glargine/253 sitagliptin), were aged 35-70 years, diagnosed with type 2 diabetes for at least 6 months, and had hemoglobin A1c values between 7% and 11% while on metformin therapy.

HbA1c, 8.5% for both groups at baseline, was reduced to a significantly greater extent with insulin glargine than with sitagliptin throughout the study, with mean reductions of 1.72 versus 1.13 percentage points. At 24 weeks, more patients in the glargine group had achieved A1c levels below 7% (68% versus 42%) compared with those in the sitagliptin group. The story was similar for HbA1c levels of less than 6.5% (40% vs. 17%). Patients in the glargine group also had significantly greater reductions in self-monitored fasting plasma glucose, with an adjusted mean difference between groups of 41.2 mg/dL, Dr. Aschner reported.

Glargine doses increased throughout the study, from 0.19 units/kg at baseline to 0.45 units/kg at 12 weeks and then leveling off to 0.5 units/kg at 24 weeks, at which point patients were taking an average of 41.4 units/day.

Body weight increased by 0.44 kg in the insulin glargine group and decreased by 1.08 kg in the sitagliptin group, a significant difference. More patients in the glargine group had one or more episodes of symptomatic hypoglycemia (46% vs. 54%). Glargine was associated with 8.45 times more hypoglycemic events per patient-year than was sitagliptin (4.21 vs. 0.5 events/patient-year). Severe hypoglycemia was 3.4-fold more common with glargine, although it was rare in both groups (1% with glargine and less than 1% with sitagliptin). The incidence of other treatment-emergent adverse events did not differ between the groups.

In all, Dr. Aschner noted, these findings suggest that glycemic control can be achieved with an average supplementary dose of 0.5 units per kg of insulin glargine and a weight gain of less than 0.5 kg. The results of this study are in general agreement with previous results for both insulin glargine and sitagliptin, he added.

Intensive lowering of blood glucose should be accompanied by structured self-monitoring of blood glucose, especially in high-risk people with long disease duration, in an attempt to avoid hypoglycemia-related adverse effects such as cardiovascular disease and related death, Dr. Aschner advised.

"In view of the possible long-term benefits of intensive lowering of blood glucose and the superior efficacy of insulin to optimize glycemic control, strong arguments could be made to use insulin early when the dose is expected to be fairly low, with a reduced risk of hypoglycemia," he concluded.

This study was funded by Sanofi. Dr. Aschner has served on advisory boards for AstraZeneca, Eli Lilly & Co, GlaxoSmithKline, Janssen, Merck, Sharpe & Dohme, Novartis, and Sanofi and on speakers’ bureaus for AstraZeneca, Eli Lilly & Co, Merck, Sharpe & Dohme, Novartis, and Sanofi.

Next Article:

Three Glargine Studies Find No Link to Cancer