The prevalence of diabetes mellitus is increasing rapidly worldwide. At present, there are approximately 35 million people affected with diabetes in India of the 150 million in the world. This figure will rise several folds by 2030 to reach about 80 million in India. This makes India the "Diabetic Capital of the World". The treatment of Type 2 diabetes is through lifestyle, diet, exercise and oral hypoglycemic agent. However, whenever indicated, insulin is to be considered to improve glycemic control.
Anti hyperglycemic agents
The appropriate treatment of any disease is based on the understanding of its pathophysiology. The mechanisms responsible for Type 2 diabetes are impaired insulin secretion and insulin resistance. The latter occurs in the adipocyte, skeletal muscle and liver. Recently, it has been identified that a defect in entero insular axis plays a role in Type 2 diabetes mellitus. Figure 1 depicts the various pathogenesis of Type 2 diabetes mellitus and various sites of action of different oral hypoglycemic agents.
Figure 1
Various classes of anti-diabetic agents are given below:
i. Insulin Secretogogues -- Sulfonylureas --
Non-sulfonylureas Increase the insulin secretion
ii. Insulin sensitizers -- Metformin --
TZD Reduce the peripheral insulin resistance
iii. Glucosidase Inhibitor -- Acarbose --
Miglitol
Voglibose
Delays the gastric emptying
iv. Insulin and Insulin
analogues
Insulin secretagogues
This group of drugs act on the beta islet cells of pancreas and stimulate these to release insulin by binding with ATP sensitive K+ channel located over the cell membrane of beta cells. Sulfonylureas bind to a specific site on the beta cell membrane called Sulphonylurea receptor (SUR receptor) and close the ATP sensitive K+ channel and thereby inhibiting the K+ efflux, which leads to opening of L-voltage gated Ca+ ion channel. This increases the intracytoplasmic calcium levels that stimulate exocytosis of both mature and immature insulin granules. There are different binding sites described for sulfonylureas and meglitinides. The sulfonylureas are classified as following:
a) First generation drugs like chlorpropamide and tolbutamide, which are not in use or preferred currently.
b) Second generation drugs like Glibenclamide, Gliclazide, Glipizide.
c) Third generation drug: Glimipiride.
Presently only the second and third generation drugs are used in India.
Table 1: Various sulfonylureas and their doses
Name of drug Dosage Commonly used drugs Remarks
Glibenclamide 2.5 - 15 mg Daonil
Euglucon
Glyboral Because of its prolonged action, hypoglycemia is
common in old people
Gliclazide 40 - 320 mg Reclide, Diamicron
Diamicron MR Inhibit platelet aggregation
Glipizide 2.5 - 40 mg Glynase, Glide
Glynase XL Can be given in mild renal
insufficiency
Glimipiride 1 - 6 mg Amaryl 1,2
Zoryl 1,2
Glimi 1,2
GP1 2,3 Ischaemic preconditioning
effect is an advantage
As the sulfonylureas act on the beta islets of pancreas, they require some amount of beta cells for their antihyperglycemic activity. Sulphonylurea as monotherapy reduce the HbA1c levels by 1.5-2.0%. They can be combined with Metformin and Glitazone. Side effects of sulphonylurea includes mild weight gain, high risk of hypoglycemia, hypersensitivity reactions, transient rashes, erythema multiforme, jaundice and chlorpropamide induced alcohol flushing.
Meglitinide
There are two molecules available in this group i.e. Repaglinide and Nateglinide. These drugs are absorbed more rapidly and attained its peak plasma level very quickly within 10-15 minutes. They bind with SUR receptor and disassociate very rapidly hence, it can be used to reduce the postprandial glucose excursions.
These molecules are metabolized in liver and excreted through urine, which are useful in mild and moderate renal insufficiency. As a monotherapy, they are weaker than sulfonylureas and the HbA1c reduction was 0.8%-1.0%. These drugs are commonly used in the following dose.
1) Repaglinide (Novonorm) - 0.5 to 4.0 mg
2) Nagaglide (Glinate) - 60 to 180 mg
Both sulfonylureas and meglitinides are contraindicated in Type 1 diabetes, hepatic impairment, allergic to sulphonylurea and severe infection. Pregnancy is relatively contraindication for sulfonylureas but these drugs are increasingly being used in pregnancy.
Insulin sensitizers
Biguanides (Metformin) and Thiazolidinediones (Pioglitazone and Rosiglitazone) reduce the insulin resistance by acting in the peripheral tissues such as skeletal muscle, adipose tissue and liver.
Biguanides
These are derivatives of gunanidine - the active ingredient of goats rue. Metformin is absorbed mainly from the small intestine with oral bioavailability of 50-60%. The mechanism of action of metformin is not fully understood. It enhances sensitivity of both hepatic and skeletal muscle to the insulin. It inhibits the hepatic glucose output (20-30%), decreasing intestinal absorption of glucose. It also increases the muscle AMPK activity leading to enhanced insulin mediated glucose disposal. It also decreases triglyceride synthesis in the liver and facilitates the conversion of atherogenic LDL to the less atherogenic LDL (5,6). Metformin has no effect on the beta cells, so it produces hypoglycemia only very rarely.
Metformin is available in different formulations like extended release and sustained release which increases its bio availability and duration of action. Usually Metformin is started in 500 mg then gradually increased up to maximum of 3000 mg/day in divided doses. It reduces the HbA1c by 1-2% as a monotherapy.
Metformin produces gastro intestinal side effects like nausea, abdominal discomfort and diarrhea. It can also interfere with vitamin B12 absorption. Lactic acidosis, although uncommon should be kept in mind and therefore the drug is to be avoided if renal insufficiency, tissue hypoperfusion, stroke, pulmonary insufficiency or liver disease. Metformin is also contraindicated in heart failure, hepatic and in renal failure if the serum creatinine >1.5 mg/dl. Metformin is used in PCOS (polycystc ovary syndrome) as it reduces the hyperinsulinemia and induces the ovulation. It can be continued in PCOS women becoming pregnant, up to first trimester although more studies were needed for its safety during pregnancy.
Thiazolidinedione (TZD)
The TZDs are a class of insulin sensitizing agents, which act as synthetic ligands of the intra cellular Peroxisome Proliferator Activator Receptor (PPAR) gamma and bind to PPAR gamma, which are located on adipocytes and vascular endothelial cells. PPAR gamma is complexed with retinoid alpha receptor and activation of PPAR gamma - RXR complex will result, activation of regulatory sequence of DNA that controls the expression of specific genes, including lipoprotein lipase, fatty acid transport protein, fatty acylcoA synthase and GLUT - 4.
The main effect of TZD on adipocytes is to increase fatty acid uptake, lowering triglycerides and NEFA levels, adipocyte differentiation and prevention of apoptosis of beta cells. TZD's reduces the HbA1c level by about 1-1.6% as a monotherapy. It can be combined with Sulphonylurea and Metformin. Although the usage of TZD along with insulin is also widely done, the risk of weight gain and fluid retention are high.
Pioglitazone is used in 15,30,45 mg once daily and rosiglitazone 2, 4, 8 mg in divided doses. The most common side effects of TZDs are weight gain and pedal odema. While prescribing TZDs, the liver function tests are monitored periodically. It should be avoided in class III, IV - heart failure as there is a slight increase in risk of heart failure. In renal insufficiency creatinine, clearance up to 30 ml, TZDs can be given. In the recent DREAM trial, Rosiglitazone prevented new onset diabetes by 62% in people with pre-diabetes.
Alpha glucosidase inhibitors
Alpha glucosidase inhibitors, competitively inhibit the ability of enzymes in the small intestinal brush border, which is breaking down oligo saccarides and dissacarides into mono saccarides. Under this class, there are three molecules available in India, which include acarbose, voglibose and miglitol. Acarbose is a complex carbohydrate, that reversibly inhibit alpha glucosidase enzymes, results in delayed absorption of carbohydrate and thereby reduces the postprandial glucose excursion.
Acarbose : 50-150 mg
Miglitol: 25-50 mg
Voglibose: 0.2 mg / 0.3 mg
All these can be given up to three times daily along with first bite of food.
Like Metformin, alpha glucosidase inhibitors also produce gastro intestinal system symptoms such as bloating, belching, flatulence and diarrhea. Acarbose may mildly increase serum transaminase level. The GIT symptoms can be avoided by starting with low doses and if titration is done in due course. The subject who is taking alpha glucosidase inhibitors has to be corrected by glucose for hypoglycemic episodes.
Combination therapy
We are living in poly pharmacy era. To reduce the number of pills and achieve the HbA1c target of < 7%, the combination of drugs is required. In India, various combination of anti-diabetic agents is available. Some of them are as follows:
" SU + Metformin
" SU + Glitazone
" Metformin + Glitazone
" SU + Metformin + Glitazone
Mechanism of Action Metformin TZD SU Meglniitide Acarbose
Glycosylated Haemoglobin reduction 1.5 - 2.0% 1.3 - mg 1.5 - 2.0 0.8 - 1.8 0.6 - 1.0
Triglycerides --- --- ---
HDL cholesterol --- --- ---
Body weight ---
Plasma insulin
Table 2: Comparison of different anti-diabetic agents
Insulin
In Type 2 diabetes, as the disease duration advances, the beta cell reserve is decreasing and the glycemic control is difficult to maintain with a single or multiple oral hypoglycemic agents. Meanwhile exogenous insulin is needed to maintain the glycemic control. In India both animal and human recombinant insulins are available. The human insulin is different from porcine and bovine insulin by one and three amino-acids in their primary sequences correspondingly. Bovine insulins are cheaper and have longer-duration by action, but have a greater immunogenecity potential. By the mode of action, the insulin is divided in to short, intermediate and long acting. In Table 3, various types of insulin, its onset and duration of action are given in detail.
Insulin analogues
By altering the amino-acid sequence of the insulin molecule, in the specific sites like B chain 28, 29, the action of insulin can be modified on rapid or long acting. These insulins are known as insulin analogues.
Insulin Onset of action Peak action Duration of action
Rapidly acting
Lispro
Aspart
5-15 minutes
1-2 hr
4 hr
Regular 30-45 minutes 2-3 hr 5-8 hr
Intermediate acting
Neutral Protamine Haggord
2-4 hr
4-8 hr
10-12 hr
Long acting
Glargine
Detemir
2 hr
No peak
24 hr
16-18 hr
Premixed
25/75 Lispro
5-15 minutes 1-2 hr 10-16 hr
Aspart 30/70
5-15 minutes 1-2 hr 10-16 hr
30/70 Regular
30-45 minutes 2-3 hr 10-16 hr
Future directions
There are a number of ongoing trials to identify the ideal molecule for Type 2 diabetes. Recently in the USA, the Food and Drug Administration approved the inhaled insulin and DPP-IV inhibitors (Sitagliptin). Several more drugs are under phase III clinical trials, the results of which are awaited. Screening for diabetes in the adulthood and by achieving the good glycemic control from the initial stage with appropriate use of drugs would help reduce the prevalence of cardiovascular and renal diseases.
(The authors are with Dr Mohan's Diabetes Specialities Centre & Madras Diabetes Research Foundation, Chennai)