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PRIORITY PRESS - Primary Care Today

Toronto, Ontario / May 7-9, 2009

Despite the wide range of medications available for the management of type 2 diabetes, an optimal glycated hemoglobin (A_1C) level of <u><</u>7% remains an elusive goal for many patients. Only about 50% of treated individuals achieve the recommended target. Even when glycemic control is achieved, it is seldom sustainable over the long term without increasingly intensive therapy, owing to progressive deterioration in pancreatic beta-cell function. This common clinical scenario, in tandem with the rising incidence and prevalence of type 2 diabetes, presages an epidemic of diabetic complications, remarked Dr. Diane Donat, Associate Professor of Medicine, University of Toronto, and staff endocrinologist, Toronto General Hospital, Ontario. “[Complications of diabetes constitute] one of the largest consumers of healthcare dollars. We have a responsibility to manage these patients aggressively.”

Targeting A_1C

Clinical practice guidelines issued by the Canadian Diabetes Association in 2008 direct physicians to tailor therapy according to the patient’s baseline level of A_1C: If it is <9%, a two- to three-month trial of lifestyle modification may be attempted before pharmacologic therapy is considered (Can J Diabetes 2008; 32(suppl 1):S1-S201). In patients with an A_1C of at least 9% at baseline, the guidelines suggest that antihyperglycemic medication or insulin should be instituted immediately in conjunction with a prescription for dietary changes and exercise. Typically, metformin is used as first-line therapy, although in patients whose A_1C is <u>></u>9%, a combination of two or more agents with differing but synergistic mechanisms of action is likely to be needed. The selection of therapies should be “based on the advantages and disadvantages of each specific drug and how they are best suited to the particular patient,” Dr. Donat summarized. Patients with symptomatic hyperglycemia and metabolic decompensation generally should be given insulin and metformin as initial therapy. “[Metformin] will mitigate the weight gain associated with insulin. Also, it will decrease insulin resistance and decrease the amount of insulin required,” she noted.

Medications currently available for the management of type 2 diabetes reduce A_1C by between 0.5% and 2%, with the alpha glucosidase inhibitors showing the lowest average potency and insulin, when titrated aggressively, the greatest. “But there are a couple of points to be aware of. The higher the starting A_1C, the greater the bang for the buck you are going to get from each therapy. Secondly, you are probably not going to get as much reduction when using a drug as add-on rather than initial therapy,” Dr. Donat told delegates.

Rationale for New Therapies

Long-term observational trials such as the UKPDS (UK Prospective Diabetes Study) (Lancet 1998;352(9131):854-65) and the ADOPT (A Diabetes Outcome Progression Trial) (Kahn et al. N Engl J Med 2006;355(23):2427-43) demonstrated that although increasingly intensive blood glucose-lowering therapy may be required to effect sustained control of A_1C, it also increases the likelihood of hypoglycemia. “So therapies that effectively control glycemia without increasing the risk of hypoglycemia are needed,” remarked Dr. Donat. Similarly, most established medications are associated with weight gain. “In the UKPDS trial, there was a gain of up to 8 kg in the 12 years that patients were followed, with the greatest gain being in those patients on insulin. And in the ADOPT study, we saw up to a 4.8-kg gain in five years,” she stated.

Reproducing the Incretin Effect

The newest additions to the array of agents for glycemic control potentiate the effects of the human gut hormone glucagon-like peptide (GLP)-1. Along with another incretin, glucose-dependent insulinotropic polypeptide (GIP), GLP-1 is secreted immediately upon food ingestion. Its release is largely responsible for postprandial, glucose-dependent regulation of insulin and glucagon. A key advantage of incretin-based agents is a very low potential for hypoglycemia, Dr. Donat indicated. Weight loss is a possibility. Clinical studies indicate they also preserve beta-cell function. The incretin-based agents display synergy with and are indicated (or, in the case of agents not yet approved in Canada, will likely be indicated) as adjuncts to metformin.

Natural GLP-1 has an extremely short half-life, as it is degraded within two minutes by the enzyme dipeptidyl peptidase (DPP)-4. As the first incretin-based therapy to be available in Canada, sitagliptin increases the plasma concentration and biological activity of GLP-1 by inhibiting DPP-4. Given in daily oral doses of 100 mg, it can reduce A_1C by approximately 0.8%. It has no effect on body weight and is well tolerated, although patients should be warned to stop taking it and seek immediate advice if they develop a rash, given a possible risk of Stevens-Johnson syndrome. Only a very few and as yet unproven cases have been reported among several million users of the medication, Dr. Donat stressed.

GLP-1 Receptor Agonist Studies

Two stable peptide preparations with actions similar to natural GLP-1 have also been developed. Both are administered by subcutaneous (s.c.) injection and appear to have a greater propensity than sitagliptin to induce insulin secretion, noted Dr. Donat. Formulated to be absorbed slowly from s.c. tissues and resist DPP-4 degradation, the GLP-1 analogue liraglutide has a half-life of 13 hours which allows for once-daily administration. In the LEAD (Liraglutide Effect and Action in Diabetes) study series, liraglutide monotherapy produced a decrease in A1C of up to 1.6% (from a baseline of 8.2%) which was sustained over 52 weeks; in contrast, the A_1C reduction in patients receiving a sulfonylurea was 0.9% and was not as likely to be maintained at one year (Garber et al. Lancet 2009;373(9662):473-81). When given in combination with metformin, liraglutide decreased A1C by 1.1% from baseline (Nauck et al. Diabetes Care 2009;32(1):84-90). Nausea was more likely to occur with liraglutide than placebo or active comparators but was usually mild and transient.

Two particularly interesting characteristics of liraglutide emerged in the LEAD studies. One was its ability to induce weight loss of approximately 2 to 2.5 kg and a decrease in waist circumference of about 3 cm. Weight loss was observed as early as two weeks after administration of the medication and, according to ongoing analysis, has been sustained for up to two years. In addition, liraglutide-treated patients experienced a reduction in systolic blood pressure (BP) of up to 3.6 mm Hg when treated with monotherapy and 2.8 mm Hg when treated with a combination of liraglutide and metformin. Both reductions were significant when compared with the patients’ baseline BP. An even larger decrease of up to 6.6 mmHg was observed in patients also receiving a thiazolidinedione (Colagiuri et al. Diabetes 2008;supp1:A16). Although patients with type 2 diabetes typically require several antihypertensive agents to achieve target BP of 130/80 mm Hg, “anything we can do to further reduce BP has a significant [cardiovascular] impact in our patients,” commented Dr. Donat.

A third incretin-based agent is the GLP-1 mimetic exenatide (not yet approved in Canada). Currently given by twice-daily injection, it may eventually be available in a long-acting preparation for weekly administration. In combination with metformin, exenatide lowers A_1C by as much as 0.8% from a baseline of 8.2% to 8.3%. Like liraglutide, it has been shown to induce weight loss. In clinical studies, exenatide-treated patients were significantly more likely than those receiving placebo to complain of gastrointestinal upset, notably mild to moderate nausea, although this problem appeared to resolve with time and seldom led to study dropout.

Welcome Addition

For many patients, the prospect of weight loss with liraglutide or exenatide, an effect likely related to delayed gastric emptying and increased satiety, may outweigh the perceived disadvantages of administration by injection and possible gastrointestinal side effects, Dr. Donat predicted. Overall, given their efficacy in lowering A1C with little risk of hypoglycemia and potential for ensuring weight stability or weight loss, the incretin-based therapies are a welcome addition to the list of second-line agents for type 2 diabetes, she affirmed.

Note: At press time, liraglutide is not available in Canada.