Reports

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 - 20th World Diabetes Congress (IDF 2009)

Montreal, Quebec / October 18-22, 2009

The progressive nature of type 2 diabetes, marked by rising hemoglobin A_1C and fasting plasma glucose concentrations over time and the development of complications from chronic hyperglycemia, constitutes a strong argument for intensive blood glucose control very early on in the disease process. “There is a nice correlation between the increasing glucose concentration and the risk of microvascular complications; and the risk association between dysglycemia and cardiovascular [CV] events starts even earlier,” observed Dr. Stefano del Prato, Professor of Endocrinology and Internal Medicine, University of Pisa, Italy. Unfortunately, glycemic control may be hampered by several factors, including patients’ failure to recognize the gravity of diabetes and adhere to therapy, and inadequate adjustment of the treatment regimen when glucose targets are not met. In addition, evidence on the benefits of glycemic control has been overshadowed by findings from the ADVANCE, ACCORD and VADT trials that low A_1C levels were associated with adverse CV outcomes. However, according to a meta-analysis of several intervention trials, intensive treatment significantly decreases CV risk, Dr. del Prato confirmed (Turnbull et al. Diabetologia 2009;52(11)2288-98). Moreover, he contended, effective treatment must be instituted much earlier than was done in the three studies, in which the subjects’ baseline A_1C levels were often very elevated. “Ideally what we would like to do is make the diagnosis of the disease and then treat it in an appropriate manner to achieve and maintain good glycemic control from the very beginning,” Dr. del Prato commented. Table 1. UKPDS: Legacy Effect of Earlier Intensive Glucose Control

When treatment is delayed or is inadequate early on, he stated, “the glycemic control preceding the intensification of treatment may build up a negative legacy—a bad glycemic memory” that can influence later outcomes. In contrast, early glucose control may have a positive legacy. This notion is substantiated by long-term follow-up of the UK Prospective Diabetes Study group: those who were randomized to early intensive glucose control maintained a reduced risk of both micro- and macrovascular complications, even though within a year of the study’s end their A1C levels did not differ from patients with less optimal levels of blood glucose (Table 1) (Holman et al. N Engl J Med 2008;359(15):1577-89).

Proactive Approach

Most guidelines set an A_1C target of <7% or <6.5% for the majority of patients with type 2 diabetes. Attaining this target involves an uncompromising attitude and a proactive rather than conservative approach including sufficient medication doses and likely the earlier use of multiple pharmacologic therapies, indicated Dr. del Prato. In addition, the concomitant use of agents that act on different pathophysiologic defects, such as insulin resistance and beta cell dysfunction, is ideal. Therapy must be individualized to find the right balance of efficacy and safety and to promote long-term adherence. “Individualization may also mean a specific goal, so perhaps reducing the risk of hypoglycemia… We recognize that some treatments are associated with a higher risk and some with a lower risk,” Dr. del Prato remarked.

Individualization may also involve making the therapeutic regimen as simple as possible; the advent of fixed-dose combinations has been helpful in this regard, noted Dr. Bernard Zinman, Professor of Medicine, University of Toronto and Director, Leadership Sinai Centre for Diabetes, Ontario. “Fixed-dose combinations do have a particular value in the context of being able to initiate combination therapies early on. A fixed-dose combination reduces the number of tablets taken and may enhance convenience and improve compliance.”

Effective Combinations

There is now a plethora of therapeutic options, remarked Dr. Lawrence Leiter, Professor of Medicine, University of Toronto and Head, Endocrinology and Metabolism, St. Michael’s Hospital, Ontario. Among these are “incretin-based” agents that enhance the effects of the human gut hormone glucagon-like peptide (GLP)-1 to improve postprandial, glucose-dependent secretion and suppression of insulin and glucagon.

Two such agents, the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin and the GLP-1 analogue liraglutide, can be used in combination with metformin. Several trials have now confirmed the efficacy and safety of sitagliptin at various stages of the diabetes continuum and in different therapeutic combinations, noted Dr. Zinman. A recent study compared sitagliptin 100 mg q.d. and metformin 500 or 1000 mg b.i.d. and regimens combining both agents (sitagliptin 50 mg q.d./metformin 500 or 1000 mg b.i.d.) as initial therapy for patients with A_1C 7.5% to 11% (Williams-Herman et al. Curr Med Res Opin 2009;25(3):569-83). “The most robust drop in A_1C was with the maximum-dose combination… as you ratchet up the dose of each drug you get increasing effects,” Dr. Zinman commented. Among patients completing the study, 67% of the patients treated with the highest combination dose reached A_1C <7%. The incidence of GI adverse effects was similar with metformin alone or the combination therapy.

A 44-week trial assessed the efficacy and safety of a fixed-dose combination of sitagliptin/metformin (50/1000 mg b.i.d.) vs. metformin 1000 mg b.i.d. for 1250 adult patients with A_1C levels <u>></u>7.5% (mean about 9.8%). In the first phase in which the two regimens were compared as initial therapy over 18 weeks, “The combination… was more effective at achieving lower A_1C, with a difference of 0.6% which was statistically and clinically significant,” reported Dr. Leann Olansky, staff endocrinologist, Cleveland Clinic, Ohio.

In the 26-week second phase, the study subjects continued on their assigned regimen but investigators were encouraged to use additional agents to help patients attain glycemic control. Supplemental therapies were given to 16.7% of patients receiving metformin alone and 8.8% of patients assigned to sitagliptin/metformin. “The drop in A_1C with the combination was greater than the drop with metformin alone, the difference being 0.48 which was statistically significant. This is despite the opportunity for the physician to add other agents if appropriate,” Dr. Zinman commented. Mean A_1C reductions were 2.25% with the combination regimen and 1.77% with metformin alone; the greatest reductions were in patients with the highest baseline A_1C levels (Figure 1). A_1C <7% was also significantly more frequent with the sitagliptin/metformin combination (46% vs. 30% with metformin), as was A_1C <6.5% (28% vs. 17%, respectively, both P<0.001). The two treatment strategies were associated with weight loss of about 1 kg, a low incidence of hypoglycemia (3% with the combination vs. 3.7% with metformin) and similar tolerability. An intriguing finding, however, was that patients receiving the combination therapy reported less abdominal pain (3% vs. 5.3%) and diarrhea (13.8% vs. 18%) than those assigned to metformin alone.

Figure 1. A_1C Reduction by Ba
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Other studies have determined that sitagliptin combined with pioglitazone promotes a significantly better and more sustained drop in A_1C than occurs with the thiazolidinedione alone; and that triple oral therapy with sitagliptin/glimepiride/metformin is effective and safe. The addition of sitagliptin to insulin therapy (with or without metformin) decreases A_1C by about 0.6%, stated Dr. Zinman. Pooled study data have revealed no important safety issues or concerns with sitagliptin, although extensive, long-term studies must still be conducted, he remarked.

Although early combination therapy may be perceived as expensive, the highest costs of diabetes relate to its complications, the speakers here agreed. It is hoped that successful therapy initiated early will be a step toward improving outcomes.

Note: This report is based on the officially sanctioned International Diabetes Federation Accredited Satellite Symposium presented on Monday, October 19, 2009, Palais des Congrès de Montréal, Room 516abc, 17:30-19:30, and considered part of the whole meeting programme of the congress. The 20th World Diabetes Congress is accredited by the Royal College of Physicians and Surgeons of Canada for a maximum of 28 hours of CME credits.