Reports

Update on HPV: Primary Care Providers Gatekeepers of Sexual Health for Mid-Life Women
Hamilton Health Sciences

Oral Therapies Realigned to Provide Improved Control and Reduced Risk in Type 2 Diabetes

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 74th Scientific Sessions of the American Diabetes Association (ADA)

San Francisco, California / June 13-17, 2014

San Francisco - New guidance for sustained glycemic control in type 2 diabetes mellitus (T2DM) has been derived from two studies of real-world therapy. Both studies, presented at the ADA, provided insight on long-term glycemic control in relation to decisions made when a second-line oral agent is added to metformin. Sustained glycemic control remains the largest single challenge to reducing the complications of T2DM. In one study, conducted in Europe, the limitations of a sulfonylurea were emphasized when this drug in combination with metformin failed to provide a similar degree of long-term control when compared to an oral incretin inhibitor plus metformin. In the other study, conducted in Canada, single combination pills of metformin and a second-line agent were shown to markedly improve the likelihood of achieving and maintaining glycemic targets relative to each drug taken separately. The advantages of each strategy inform patient care in those patients not sufficiently controlled on metformin alone.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

For selecting a second therapy to add to first-line metformin, the 2013 Canadian Diabetes Association (CDA) guidelines (Harper et al. Can J Diabetes 2013;37:S61-8), defer to physician decision based on patient characteristics and preferences. New data from the ADA provide practical guidance. While the CDA guidelines state that no goal may be more important than sustained glycemic control, the studies reveal important differences between strategies. In the larger of the two studies, conducted in France, metformin plus a dipeptidylpeptidase-4 (DPP-4) inhibitor was shown to provide a greater duration of control in a daily-practice, head-to-head comparison with metformin plus a sulfonylurea.

“In the primary efficacy analysis, the median treatment duration was 43.2 months on the combination with the DPP-4 inhibitor and 20.2 months [P<0.0001] on the combination with a sulfonylurea,” reported Dr. Paul Valesi, Director, Service d’Endocrinologie-Diabétologie-Nutrition, Hôpital Jean Verdier, Université de Paris Nord, Bondy, France. Regardless of the reason for treatment modification, “defined as any add-on therapy, withdrawal, or substitution,” initiating therapy with the DPP-4 inhibitor rather than a sulfonylurea more that doubled the time patients remained on treatment.

The study, called ODYSSEE, was conducted on the request of French health regulatory authorities, which sought data to determine whether DPP-4 inhibitors, which have demonstrated better tolerability than sulfonylureas in controlled studies, provided an adherence advantage in daily practice. In France, the two most widely used step-up regimens in patients on metformin monotherapy are the addition of a DPP-4 inhibitor, which accounts for 40% of prescriptions, and the addition of a sulfonylurea, which accounts for 38%.

The observational design of the study, which enlisted general practitioners throughout France, was straightforward. Adult patients with T2DM on metformin were enrolled within 8 weeks of initiating therapy with metformin and a sulfonylurea (MetSu) or metformin and sitagliptin (MetSita). The non-randomized groups were self-selected by the physician-based prescriptions. The data on the 2,607 participating patients were collected at standard visits over three years. In addition to the primary outcome of change in treatment, data were collected on adverse events, glucose control, and diabetic complications.

Comparable Efficacy

The efficacy of MetSu and MetSita did not differ significantly. Both combinations reduced HbA1c by approximately 0.6% over previous therapy. Overall, the greater risk of treatment modification on MetSu appeared to relate to tolerability. As expected, the incidence of hypoglycemia was higher in the MetSu than MetSita groups (21.0% vs. 9.7%). Hypoglycemia was also cited more often as a reason for treatment change in the MetSu than MetSita groups, but “other” reasons for a treatment change were also more common on MetSu, perhaps reflecting the greater overall acceptability of the MetSita regimen.

The data in this “naturalistic, real-life observational study are comparable to those described previously during the clinical development program for sitagliptin,” according to Dr. Valesi, but the study shows that these differences are relevant in routine daily practice. In particular, they suggest a greater likelihood of meeting guideline goals.

Treatment Considerations

In Canada, the CDA guidelines do not specify an order of second-line therapies but they do specify key properties to consider in the selection. The first and second of these, respectively, are durability of lowering blood glucose and relative risk of hypoglycemia. Efficacy for reducing complications of diabetes is also listed. Sulfonylureas, although inexpensive, are burdened not only by an appreciable risk of hypoglycemia but also by an adverse effect on long-term beta cell function, while observational data have raised concern about their cardiovascular safety. The ODYSSEE study suggests that second-line strategies are not interchangeable in regard to durable efficacy in the real-world setting.

Similar guidance was provided by another set of data presented at the ADA that also attempted to evaluate the impact of treatment decisions on real-world outcomes. In this Canadian study, called GIFT, the impact on adherence of a fixed-dose combination of metformin plus a DPP-4 inhibitor was compared to that of the drugs taken separately. These fixed-dose combinations have been approved in traditional randomized trials confirming efficacy and safety, but the goal of GIFT was to determine whether the convenience of a single pill altered efficacy in routine practice.

Evaluating Outcomes

Relative to separate prescriptions of metformin and a DPP-4 inhibitor, “we observed an improvement in measures of blood glucose control after the first fixed-dose combination was placed on the ODB [Ontario Drug Benefit], but we wanted to evaluate this systematically,” explained Dr. Harpreet S. Bajaj, LMC Diabetes and Endocrinology Center, Brampton, Ontario. The two co-primary outcomes of the study, HbA1c and fasting plasma glucose (FPG), were evaluated retrospectively at three time points: prior to the switch, three months or more after the switch, and at the most recent visit (typically >12 months).

“At both the first evaluation and the latter time point, we saw about a 22% reduction in both the HbA1c and the FPG over that observed with the drugs taken separately,” Dr. Bajaj reported. In absolute terms, the reductions were 0.2% for HbA1c and 0.6 mmol/L for FPG (both P<0.01). The reduction was slightly greater in those with an HbA1c between 7.0% and 10.0% at the time of the switch but similar for other stratifications, such as by ethnicity or age older or younger than 65 years.

The improvement was “probably related to better adherence,” observed Dr. Bajaj, noting that this would be consistent with fixed-dose combinations observed for other types of therapies, such as those used to control hypertension. In Canada, sitagliptin was the first DPP-4 inhibitor combined with metformin in a single pill. Two more DPP-4 inhibitors, saxagliptin and linagliptin, have since been combined with metformin for a one-dose combined therapy. Other combinations include metformin plus a sulfonylurea.

“There is a need for these kinds of real-world studies in order to identify better strategies to reach treatment targets,” Dr. Bajaj commented. He cited several recent studies, including one in Canada (Leiter et al. Can J Diabetes 2013;37:82-9) that suggest glycemic control rates are not improving despite a growing array of effective and well tolerated therapies.

One obstacle may be a delay among physicians to move to newer, better-tolerated therapies. In another study at the ADA, a survey of 1,498 patients on oral anti-diabetes drugs (OAD) in the U.S. found that sulfonylureas were still used in 52.4% of patients whether alone or in combination. According to the senior author of the study, Dr. Charles F. Shaefer, Jr., Medical College of Georgia, Augusta, Georgia, those taking a sulfonylurea tended to be older and to have a longer history of T2DM. Only 16% of the patients in this survey were at targets for HbA1c, blood lipids, and blood pressure.

“Established habits, insurance directives, and lower cost may drive sulfonylurea use,” Dr. Shaefer speculated. He suggested that the association between sulfonylurea and increased risk of hypoglycemia and CV complications suggest “education of healthcare providers is required to overcome the inertia” that appears to be an obstacle to selection of therapies with better safety and adherence profiles.

Conclusion

In the most recent CDA guidelines, sulfonylureas remain a viable second-line option, particularly when cost is a key consideration, but a real-world observational study suggests sustained glycemic control may be more often achieved when a DPP-4 inhibitor rather than a sulfonylurea is added to metformin. Another observational study suggested a further opportunity for improved glycemic control with fixed-dose combination pills for patients requiring two or more anti-diabetic therapies. In line with the overall goal of reaching treatment targets to prevent complications of diabetes, these data provide practical guidance for treatment selection. 

We Appreciate Your Feedback

Please take 30 seconds to help us better understand your educational needs.