|Non-insulin therapies for type 2 diabetes|
Mona Ashiya1 & Richard E. T. Smith1
Non-insulin therapies for type 2 diabetes'Ishongololo' designed by Ryan Frank, www.ryanfrank.net
Sedentary lifestyles, dietary changes and genetics are some of the key factors that have conspired to create the current worldwide epidemic of type 2 diabetes (T2D), an acquired syndrome of elevated blood glucose. T2D is closely associated with obesity and is characterized by an initial phase of progressive insulin resistance and a subsequent phase of beta-cell (insulin-producing pancreatic islet cells) exhaustion. An estimated 246 million people worldwide (20.8 million in the US alone1) have T2D and this number is projected to grow to 366 million by 2030 (Ref. 2).
Oral drugs: first line of treatment
Treatment for T2D typically begins with oral antidiabetic agents and a reduction in glycated haemoglobin A1c (HbA1c) — a reflection of glucose levels over the preceding 3 months — to below 7% represents an elusive but key goal of therapy.
Metformin, a biguanide, and various sulphonylureas are two classes of oral drugs that are widely used and have robust single-agent potency (approx1.5% HbA1c reductions). Metformin is a safe, well-tolerated agent that inhibits gluconeogenesis; however, it carries a small risk of inducing lactic acidosis and is contraindicated in the setting of renal failure, a common complication of T2D. Sulphonylureas and the glinides sensitize pancreatic beta-cells to produce insulin. Both also cause weight gain, which is problematic in obese patients. Sulphonylureas can also produce hypoglycaemia, whereas glinides are modestly effective compounds principally used to reduce post-prandial glucose surge. The glucose surge can also be inhibited by alpha-glucosidase inhibitors, although gastrointestinal complaints are common with this class.
Thiazolidinediones (TZDs) achieve HbA1c reductions in the 0.5–1.5% range in monotherapy by activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma), which promotes adipocyte differentiation and improves insulin sensitivity. The principal liabilities of the two marketed TZDs, rosiglitazone (Avandia; GlaxoSmithKline) and pioglitazone (Actos; Takeda/Eli Lilly), both introduced in 1999, are oedema and weight gain. Increased circulatory volume, a consequence of PPARgamma activation, is a risk factor for cardiac failure and both agents, as highlighted in boxed warnings, are contraindicated in the setting of congestive heart disease. An FDA advisory committee recently concluded that rosiglitazone also increased cardiovascular ischaemic risk and, as of this writing, the agency's review continues. A similar increased heart attack risk has not emerged with pioglitazone but safety data is currently being reviewed by the FDA.
New entrants: incretin-based therapies
Incretins are peptide hormones that stimulate insulin secretion, inhibit glucagon secretion and promote satiety after nutrient ingestion. The short-lived activity of native incretins such as glucagon-like peptide 1 (GLP1) due to rapid degradation by the dipeptidyl peptidase 4 (DPP4) enzyme prompted the development of GLP1 analogues resistant to degradation and DPP4-selective inhibitors to address hyperglycaemia.
In April 2005, the FDA approved the first GLP1 analogue, exenatide (Byetta; Amylin/Eli Lilly). As monotherapy, it achieved HbA1c declines of approx1%, with modest progressive weight loss and a lower incidence of hypoglycaemia. Common side-effects were nausea and vomiting. However, exenatide has to be injected twice daily owing to its short half-life. An injectable long-acting release version, exenatide LAR, with a more convenient once-weekly dosing is currently being tested in a head-to-head Phase III trial against exenatide, with results expected later this year. Prior data suggest that the more even drug exposure with exenatide LAR may translate into an improved efficacy and side-effect profile. Liraglutide, an acylated GLP1 analogue that requires daily dosing, is another incretin mimetic in Phase III trials.
The chief advantage of small-molecule DPP4 inhibitors over injected GLP1 analogues is their oral availability. Sitagliptin (Januvia; Merck), the only marketed DPP4 inhibitor, was approved in October 2006. As a monotherapy, sitagliptin dosed daily achieved HbA1c reductions similar to those seen with the GLP1 analogues, with a weight-neutral profile and low risk of hypoglycaemia. Adverse effects observed so far have been mild but the role of DPP4 in lymphocytes has raised theoretical concerns about effects on immune function. Although not seen with sitagliptin, dermal necrosis has been observed in primate studies with high doses of other DPP4 inhibitors such as vildagliptin (Galvus; Novartis). Development of vildagliptin, which received an approvable letter from the FDA in February 2007, has been set back as trials determine whether skin toxicity also emerges with the higher drug levels expected in renally impaired T2D patients. To date, development of DPP4 inhibitors saxagliptin and alogliptin, both in Phase III testing, continues, and no trials in renally impaired patients have been announced.
In the development pipeline
With 394 candidates in development in 2006, (344 in 2005), diabetes is second only to cancer in R&D focus3. This is not surprising given the rising prevalence of T2D and the insufficiency of even combination therapy, on which approximately 36% of T2D patients in the US currently achieve target HbA1c levels4. Existing drugs lose their effectiveness over time, and side effects limit compliance.
Beyond the GLP1 analogues and DPP4 inhibitors, the diabetes pipeline includes compounds targeting sodium–glucose co-transporter 2 (SGLT2); hydroxysteroid (11-beta) dehydrogenase 1 (11BHSD1); G-protein-coupled receptors (GPCRs); and glucokinase. Dapagliflozin, which inhibits the SGLT2 channel, is now in Phase III testing. Despite the failures of dual PPARalpha/gamma agonists and challenges faced by the TZDs, PPAR targeting continues to attract substantial interest. In development are partial agonists of PPARgamma designed to retain potent antiglycaemic activity without the liabilities of full agonists, as well as selective PPARalpha/gamma modulators that may have favourable effects on atherogenic lipids. Broadly, there is heightened interest in developing therapies that not only improve glycaemic control but also address the micro and macrovascular complications that are associated with hyperglycaemia.
The US diabetes market generated US$11.2 billion sales in 2006 as compared to $9.6 billion in 2005. Metformin, the sulphonylureas and the TZDs were the most prescribed classes of non-insulin antidiabetic medications, accounting for 96% of all prescriptions in the US. However, with metformin and the sulphonylureas without patent protection, the TZDs captured close to 75% of the value of the non-insulin US diabetes market in 2006. Several factors are set to alter the picture for non-insulin antidiabetic therapies in 2007: heightened scrutiny is already having a negative impact on Avandia sales and although Actos sales have increased recently, the longer term prospects for this class appear uncertain at this time. Byetta, which achieved $430.2 million in wordwide net sales in its first full year after launch, now faces competition from Januvia, the first DPP4 inhibitor, which has the advantage of oral delivery but lacks the weight-loss properties of the GLP1 analogues. With Phase III data from exenatide LAR expected later in 2007, and the filing of saxagliptin anticipated in early 2008, the T2D market is certain to see more change in the coming years. See Fig. 1 & Table 1.
Vildagliptin (Galvus) Novartis Prereg* DPP4 inhibitor
Saxagliptin AstraZeneca/Bristol–Myers Squibb III DPP4 inhibitor
Alogliptin Takeda III DPP4 inhibitor
Liraglutide Novo Nordisk III GLP1 analogue
Exenatide LAR Amylin/Eli Lilly III GLP1 analogue
Dapagliflozin AstraZeneca/Bristol–Myers Squibb III SGLT2 inhibitor
GSK716155 GlaxoSmithKline II GLP1 analogue
AVE0010 Sanofi–Aventis II GLP1 analogue
R1583 Roche/Ipsen II GLP1 analogue
CJC-1134-PC Conjuchem II GLP1 analogue
AVE2268 Sanofi–Aventis II SGLT2 inhibitor
189075 GlaxoSmithKline II SGLT2 inhibitor
R1439 Roche II PPARalpha/gamma agonist
PLX204/PPM-204 Plexxikon/Wyeth II PPAR pan-agonist
PSN9301 OSI Pharmaceuticals II DPP4 inhibitor
INCB13739 Incyte II HSD11B1 inhibitor
R1440/GK3‡ Roche II Glucokinase inhibitor