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Promising late-stage candidates for type 2 diabetes

Diabetes was first treated in the 1920s, but ever since then the quest has continued to identify and manufacture the ideal anti-diabetic treatment
Promising late-stage candidates for T2DM

Type 2 diabetes mellitus (T2DM) is a complex heterogeneous endocrine and metabolic disorder that is characterised by insulin resistance and pancreatic ß–cell dysfunction. Both environmental and genetic factors contribute to the development of this disorder.

It is now well-recognised that the key contributors in modern times to the development of T2DM are being overweight and being obese. This explains in part the dramatic increase in the incidence of T2DM in the US, the European Union (EU) and many other countries worldwide. For example, the incidence of diabetes in the UK has more than doubled in the past 15 years. 

The Organisation for Economic Cooperation and Development (OECD) estimates the number of people with diabetes in the EU will increase from about 33 million in 2010 to 37 million in 2025. The costs of managing and treating people with diabetes will also grow, particularly because of the need to manage cardiovascular (CV) complications.  

While current treatments improve glycaemia, effects are not long-lasting because patients continue to have ß–cell dysfunction. Furthermore, current treatments have many side effects (eg, bodyweight gain, hypoglycaemia, gastrointestinal side effects, swelling of the extremities) that have potentially adverse CV effects.  

An ideal treatment would sustain glycaemic control, help weight loss, avoid hypoglycaemia, and have no adverse effect but a beneficial effect on CV outcomes.

Upcoming combination treatments
Several classes of diabetes treatments are well established, including insulins, sulphonylureas (eg, glimepiride), biguanides (eg, metformin), α - glucosidase inhibitors (eg, acarbose), meglitinides (eg, repaglinide), and thiazolidinediones (eg, pioglitazone). However, pharmacological therapy has changed in the last 10 years with new drug classes and drugs becoming available, allowing for combination regimens with improved glycaemic control. 

Newer drug classes include glucagon-like peptide-1 (GLP-1) mimetics (eg, exenatide and liraglutide), amylinomimetics (eg, pramlintide) and dipeptidyl-peptidase-4 (DPP-4) inhibitors (eg, sitagliptin, vildagliptin, saxagliptin). 

New glucose-lowering treatments in early development target the pancreas or liver, act by enhancing insulin, or act independently of insulin. However, many agents currently in phase III development are new agents within existing drug classes. Here we look at recent developments in late-stage drugs for T2DM.

Insulins
Patients with diabetes were first treated with insulin in the 1920s. Insulins act by directly activating the insulin receptor, decreasing liver glucose production, increasing peripheral use of insulin and reducing the breakdown of fats. 

Insulin degludec (Tresiba; Novo Nordisk), a long-acting insulin analogue injected subcutaneously, was approved in Japan for T2DM in September 2012. In October, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended it for approval in the EU. Then in November 2012, the US FDA's Endocrinologic and Metabolic Drugs Advisory Committee recommended approval of both insulin degludec monotherapy and insulin degludec/insulin aspart combination therapy, on the proviso that a post-approval CV outcomes trial should also be conducted. 

There are several insulin analogues currently in phase III development, such as insulin peglispro, insulin degludec/liraglutide and other oral and inhaled insulins. 

SGLT inhibitors
This novel class of anti-diabetic therapies significantly increases urine glucose excretion and lowers blood glucose levels via an insulin-independent mechanism in the kidney. Sodium-glucose-cotransporter-2 (SGLT2) inhibitors also have some weight-loss properties and might reduce blood pressure (BP). SGLT2 inhibitors may cause genital and urinary tract infections, but these adverse effects are generally of mild severity and can be managed with standard therapies.

Dapagliflozin (Forxiga; Bristol-Myers Squibb/AstraZeneca) was approved in the EU in November 2012 for the once-daily treatment of adult patients with T2DM as an adjunct to diet and exercise in combination with other glucose-lowering treatments, including insulin, or as a monotherapy in metformin-intolerant patients. The drug is also under regulatory review in the US.  

Canagliflozin (Mitsubishi Tanabe; Johnson & Johnson) has been investigated in over 10,300 patients in placebo- and active comparator-controlled trials. Results of a phase III trial presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension in early November 2012 showed that canagliflozin 100mg or 300mg administered once daily in combination with metformin or pioglitazone produced greater glycaemic control, compared with placebo. Reductions in body weight and BP were also observed with canagliflozin. 

These results were in line with phase III results announced earlier in 2012 at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes, which showed that canagliflozin can help control blood glucose levels in a wide variety of patients with T2DM. Regulatory applications were submitted in both the US and EU during the first half of 2012. Mitsubishi Tanabe also expects to seek Japanese approval during 2013.

An ideal treatment would sustain glycaemic control, help weight loss, avoid hypoglycaemic events and have no adverse effect

Other SGLT2 inhibitors that are in phase III development include: ipragliflozin (Japan, South Korea, Taiwan), luseogliflozin (Japan), tofogliflozin (Japan) and empagliflozin (worldwide).

GLP-1 mimetics
GLP-1 receptor agonists mimic the endogenous hormone GLP-1 (an incretin) that is released in response to food intake, resulting in insulin secretion. In fact, at least half of meal-related insulin secretion is induced by incretins. GLP-1 not only stimulates insulin secretion, but reduces food intake and slows gastric emptying, and in so doing may aid weight loss.  Exenatide (Byetta; Eli Lilly) and liraglutide (Victoza; Novo Nordisk) are two agents that are already approved in this drug class, but there is some question over their long-term safety profile and association with pancreatitis and a type of kidney cancer (medullary cell carcinoma). 

Three GLP-1 mimetics are in late-stage development (lixisenatide, dulaglutide, albiglutide), of which the most advanced is lixisenatide (Lyxumia; Sanofi). 

In November 2012, the EMA recommended approval of lixisenatide as a once-daily therapy for the treatment of adults with T2DM. The recommendation is based on results from the phase III GetGoal programme, and covers the use of lixisenatide to achieve glycaemic control in combination with oral glucose-lowering agents and/or basal insulin, when these have been ineffective. 

In contrast, dulaglutide is a once-weekly therapy (administered by subcutaneous injection), and Eli Lilly expects that regulatory submission could be made in 2013. This is likely because of positive top-line results from three completed active-comparator phase III trials (AWARD-1, AWARD-3 and AWARD-5), and the expectation that two other AWARD trials (AWARD-2 and AWARD-3) will conclude in early 2013. 

DPP-4 inhibitors
Another mechanism for increasing endogenous GLP-1 is to inhibit DPP-4 (CD26), a widely expressed enzyme that inactivates incretins like GLP-1. Several are already approved for the treatment of T2DM, the most recent approvals being for linagliptin (Trajenta; Boehringer Ingelheim/Eli Lilly) in the US and EU as add-on therapy to insulin in adults with T2DM and alogliptin (Nesina; Syrrx Inc) in Japan as a once-daily treatment for T2DM for use alone or in combination with thiazolidinediones, sulphonylureas or biguanides. 

Two are in phase III development – omarigliptin (Merck & Co), trelagliptin (Takeda) – and several combination therapies are also in late-stage development. Unlike other orally-administered DPP-4 inhibitors that are given once daily, trelagliptin is administered once a week. It is being evaluated in a phase III double-blind trial in patients with diabetes in Japan, comparing its efficacy and safety at a dose of 100 mg/day with that of alogliptin 25 mg/day and placebo. 

Thiazolidinediones (TZDs)
TZDs activate peroxisome-proliferator-activated-receptor-ɣ, which reduces insulin resistance in the periphery (meaning TZDs make muscles and fat sensitive to the actions of insulin). These are the most expensive of the oral agents for T2DM. 

Pioglitazone and rosiglitazone are already marketed, although rosiglitazone was discontinued in Europe and is available in the US only through a restricted access programme because of concerns of increased risk of myocardial infarction (heart attack). Despite these potential cardiovascular safety issues, two TZDs have reached phase III development in selected Asian countries: DLBS 3233 (Dexam Medica) and lobeglitazone (Chong Kun Dang).

More treatment choices but less risk
While standard therapies (eg, metformin) with an established long-term safety profile are likely to remain the cornerstone of first-line pharmacological therapy for patients with T2DM, the introduction of newer agents such as incretin-based treatments (GLP-1 mimetics and DPP-4 inhibitors) and insulin-independent therapies (eg, SGLT-2 inhibitors) provide clinicians with more treatment choices. However, the long-term safety of these newer agents remains to be established. 

Potential new anti-diabetic treatments and novel drug combinations continue to be investigated in an effort to achieve the ideal anti-diabetic treatment. It is with hope that the challenge of treating the T2DM epidemic can be met head-on.

Article by
Tracy Harrison

Adis International (Springer Healthcare), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact
Daniela Ranzani on
+39 02 423 4562 or email her

22nd March 2013

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