The diabetes mellitus type 2 is a metabolic disorder, primarily characterized by hyperglycemia, (after meal). According to estimation by the World Health Organization, over 170 million people are suffering from diabetes mellitus out of which type 2 accounts for 90 per cent of the cases. Long term uncontrolled diabetes can lead to nerve degeneration, diabetic coma, renal damage, gangrene of limbs, elevated blood lipid levels and related heart diseases.

Management of diabetes type 2 includes – management of blood sugar levels, lipid level in blood as well as blood pressure. The drugs used include apart from insulin, oral hypoglycemic agents such as Sulfonyl ureas (Glimepiride), Biguanides (Metformin), Thiazolidinediones (Pioglitazone), α-glucosidase inhibitors (Miglitol) and Phenylalanine analogues(Nateglinide). In spite of recent advances in therapies for the management of type 2 diabetes, the search for safe and effective anti-diabetic medication has not yet ended.

Incretin mimetic
Incretins are hormones released from the gut, after intake of food. Incretin mimetics are agents, which promote the release of insulin, quantitative to the ingested glucose. They are also known as Glucagon like peptide-1 (GLP-1) drugs. Usually following intake of food, there is release of incretins from the intestine, proportional to the glucose ingested. These incretins are responsible for regulating the blood sugar level by modulating the insulin release from the ß-cells of the Pancreatic Acini. The enzyme DPP IV limits the activities of incretins by metabolizing the incretins. Hence, DPP IV inhibitors can also be used as anti diabetics.

In a diabetic individual, there is a derangement in post-meal incretin release from the intestine, which affects the circulating blood sugar levels. Incretin mimetics increase the amount of incretin available in the body, thereby enhancing insulin release, post-meal. The main enzyme involved in the metabolism of incretins is Dipeptidyl Phosphatase IV (DPP IV). The DPP IV inhibitors (like Sitagliptin, Saxagliptin etc.) prevent the degradation of Incretins and thereby increasing the levels of available incretins in the body.

Commercially available incretins are originally discovered from the saliva of the lizard Gila Monster. The recently approved analogues of GLP-1 are Exenatide (synthetic) and Liraglutide (recombinant) which being used as adjuvants in therapy with Metformin and Sulfonyl ureas. Prominent side effects of these drugs include nausea, vomiting, diarrhea, while more serious side effects include - hypoglycemia (especially when used in combination with Sulfonyl ureas), dizziness, headache etc. Acute pancreatitis, is a very serious side effect of these drugs and discontinuation of therapy, is advised if any symptoms for the same appear. They are contraindicated in patients with known drug allergies and history of acute pancreatitis.

Exenatide is a drug marketed under the brand name Byetta. It is marketed as prefilled pens. This medication is advised to be used regularly for maximum benefits. The drug should be taken by the patient 60 minutes before a meal and in case of a missed dose, the patient should not take it after the meal, instead he should wait till his next dose. The time gap between two doses of Byetta should be minimum 6 hours. Byetta shows effectiveness in decreasing HbA1c levels to 0.4-0.8 per cent. Use of Byetta is not advised in case of type 1 diabetes mellitus and diabetic Ketoacidosis. It falls under the FDA pregnancy category C, i.e. It is not known whether Byetta passes into foetal circulation from maternal circulation or whether it gets excreted in breast milk. However, the major drawback associated with this class of drugs is that they are very expensive (approximmately Rs.9000/- per month).

 Liraglutide

Liraglutide was first developed by Novo Nordisk, and marketed under the brand name Victoza in Europe, Japan and USA. From the data received from LEAD phase III trials (Liraglutide effects and action in diabetes), the following observations were made:

·         In LEAD 1 - After assessing 1026 patients under therapy with maximal dose of Glimepiride, who were randomized to therapy with Liraglutide, Rosiglitazone and Placebo, treatment with Liraglutide achieved the best results (HbA1c- 7%).

·         In LEAD 2 - After assessing 1026 patients under therapy with maximal dose of Metformin, who were randomized to therapy with Liraglutide, Glimepiride and Placebo, treatment with Liraglutide achieved the best results.

·         In LEAD 5 - After assessing 581 patients combination of Liraglutide with Metformin and Glimepiride showed good results in 50% of the patients with over 35% achieving an HbA1c of 6.5%.

·         In LEAD 6 - A comparative study between Liraglutide and Exenatide showed Liraglutide as a better oral hypoglycemic agent than Exenatide.

These findings suggest that Liraglutide is as effective or in some cases even better than the standard drugs for therapy of diabetes type 2. Lead findings suggest that GLP-1 analogues aid in weight loss in obese patients. There was an average weight loss of 2 kg after 30 weeks of treatment. This is a significant advantage because the major drawback of most of the other anti diabetic medication is weight gain. The use of Liraglutide to treat obesity is of interest and has been supported by preclinical findings.

DPP IV inhibitors
Dipeptidyl phosphatase IV inhibitors are a class of drugs that inhibit the action of the enzyme dipeptidyl phosphatase IV which breaks down incretin and other related molecules. Currently approved DPP IV inhibitors include: Sitagliptin and Saxagliptin. These drugs are effective in lowering fasting glucose levels as well as post-meal rise in blood glucose, by maintaining the levels of circulating incretins in the body. Its side effects include - hypersensitivity reactions (anaphylaxis), angioedema, and rash. Sitagliptin is associated with side effects like acute pancreatitis, elevation of liver enzymes, hypoglycemic episodes (rare). Saxaglitpin is associated with upper respiratory tract infection, urinary tract infection and headache. These drugs are contraindicated in patients with known drug allergies, type 1 diabetes, and diabetic ketoacidosis.

Incretin mimetics are administered by injection whereas DPP IV inhibitors are administered orally. Effects on circulating levels of GLP-1: Incretin mimetics cause a sustained increase of GLP-1 in the patients circulation whereas DPP IV inhibitors increases GLP-1 only after a meal. Both incretin mimetic and DPP IV inhibitors have similar effects on the reduction of HbA1c levels. Incretin mimetic cause weight loss whereas DPP IV inhibitors don’t affect the weight. Incretin mimetics have the disadvantage of causing nausea especially when the treatment is started, whereas DPP IV inhibitors don’t cause nausea. Although the patient can control diabetes mellitus type 2 by regulating his/her diet and by exercise. Drugs can further benefit the patient but are ineffective alone. They have a marginal effect on the elevated blood glucose level in a diabetic individual. Hence, lifestyle management and drug therapy go hand in hand in effective management of diabetes.

(The authors are with Manipal College of Pharmaceutical Sciences, Manipal 576104)