These drugs are taken just before or with a meal. The drug is avoided if a meal is skipped. They are mainly useful in postprandial blood glucose control. They are useful in elderly and those with irregular eating patterns. They can be used in patients with moderate renal impairment but not with hepatic failure. The anti-hyperglycaemic effectiveness of repaglinide is comparable to that of sulphonylureas, while nateglinide is less efficacious.
   These agents have not specifically been assessed for their long term efficacy in reducing micro- or macrovascular complications. They have been approved for monotherapy or in combination with metformin.

INSULIN SENSITIZERS
Insulin resistance, at the level of liver, adipose tissue and skeletal muscle, plays a major role in the pathophysiology of type 2 DM. Biguanides and thiazolidinediones are the currently used insulin sensitizers.

Biguanides
Metformin is the only agent approved for use in this category, since phenformin was banned due to an excess risk of lactic acidosis.
   Mechanism of action. Metformin activates adenosine monophosphate-activated protein kinase (AMPK) resulting in decreased hepatic gluconeogenesis, glycogenolysis and lipogenesis with increased fatty acid oxidation. The net result of this is decreased hepatic glucose output along with increased hepatic insulin sensitivity. Metformin has also been shown to increase peripheral glucose disposal, though this effect may be mediated by reduced glucotoxicity and not through a direct drug effect. It does not cause any stimulation of insulin secretion.
   Properties. Metformin is absorbed rapidly after oral administration. It does not bind to plasma proteins and it is not metabolized. It has a plasma half-life (t1/2) of 2–5 hours. It is excreted unchanged in urine mainly by tubular secretion. Cimetidine may interfere with this process. More than 90% of the absorbed drug is excreted in 12 hours.
   The beneficial effects of metformin include weight loss besides improvement in glycaemia. In placebo-controlled trials, metformin monotherapy reduces HbA1c by 1%–2%, similar to that reported with sulphonylureas. This has also been confirmed in head-to-head comparisons between sulphonylureas and metformin. Improvement in lipid profile (reduced low density lipoprotein cholesterol and triglycerides) and plasminoger activator inhibitor (PAI)-1 levels has also been described with metformin. Reports also suggest a reduction in vascular reactivity, which, in conjunction with lowered circulating insulin levels, possibly contributes to the cardiovascular benefits attributed to metformin therapy.
   Acute gastrointestinal side-effects including anorexia, metallic taste, abdominal discomfort, bloating and diarrhoea are seen in 10%–20% of patients. This may be due to decreased intestinal glucose absorption by metformin. It can be reduced by starting the drug in low doses and slowly increasing the dose. Around 5%–10% of patients cannot tolerate the drug and require its discontinuation. Chronic use decreases intestinal vitamin B12 and folate absorption.
   Lactic acidosis is the most dreaded complication though the likelihood is 100 times less than that with phenformin. Contraindications and precautions to use of metformin include:

1. Moderate-to-severe renal failure: Serum creatinine >1.4 mg/dl in women and 1.5 mg/dl in men.

2. Previous history of lactic acidosis.

3. Gastrointestinal disorders and alcohol abuse.

4. Other conditions predisposing to lactic acidosis: hepatic disease, cardiac failure, chronic hypoxic lung disease.

5. It should be stopped 48 hours before the administration of intravenous contrast media or a surgical procedure and restarted later, not earlier than 48 hours, after renal functions are confirmed to be normal.

6. Metformin should also be stopped immediately in the presence of any acute illness predisposing to tissue hypoxia. A very low calorie diet or fast mandates stoppage of metformin.

   If these precautions and cointraindications are observed, the likelihood of lactic acidosis is nearly abolished.
   Metformin is used in daily doses of 500–2500 mg. Sustained release preparations of metformin for once daily use are also available.
   Intensive therapy with metformin has been shown to reduce the incidence of micro- and macrovascular complications. A significant reduction in the risk of cardiovascular events, not reported for intensive therapy with sulphonylureas, has been reported with metformin therapy. These agents are approved for use as monotherapy and in combination with insulin and all other oral agents.

Thiazolidinediones
These agents reduce insulin resistance at skeletal muscle and adipose tissue. Pioglitazone and rosiglitazone are the two agents in clinical use. Troglitazone, an earlier thiazolidinedione, was removed from the market due to a rare idiosyncratic hepatocellular injury.
   Mechanism of action. They act by stimulation of PPARa, a nuclear receptor expressed predominantly in adipose tissue and to a lesser extent in liver and muscle. Thiazolidinediones promote differentiation of pre-adipocyte to adipocyte with accompanying lipogenesis, increase glucose transporter (GLUT-4) expression in adipose tissue leading to increased glucose uptake and
promote shift of fat from visceral to subcutaneous depots. Thiazolidinediones also decrease tumour necrosis factor and increase adiponectin production by adipocytes, thereby contributing to the increase in insulin sensitivity and decrease in plasma glucose. Recent evidence suggests that thiazolidinediones also reduce cell apoptosis and preserve cell function. Similar to biguanides, these agents do not act as insulin secretagogues.
   Properties. Both agents are rapidly and completely absorbed with peak plasma levels achieved within 2 hours. Absorption is delayed by food. The metabolites of pioglitazone are active and excreted in bile while those of rosiglitazone are weakly active and are excreted in urine. Other metabolic actions reported for thiazolidinediones include reduction in urinary albumin excretion, blood pressure and PAI-1 level. Rosiglitazone increases total cholesterol by increasing low density and high density lipoprotein cholesterol, while pioglitazone decreases triglyceride levels. Reduction in blood pressure, increased fibrinolysis and improved endothelial function has also been documented with the use of thiazolidinediones, though the clinical relevance of these observations is yet unclear.
   Used as monotherapy, thiazolidinediones decrease HbA1c by 1%–2%, a range similar to that seen with sulphonylurea and metformin therapy. Head-to-head studies with metformin and sulphonylureas have confirmed that the anti-hyperglycaemic efficacy of these agents is similar.
   Adverse effects include weight gain of around 1–4 kg due to a combination of increased peripheral fat and fluid retention; this stabilizes in 6–12 months. Fluid retention causing peripheral oedema, pulmonary oedema and congestive cardiac failure are major concerns with thiazolidinediones. Peripheral oedema occurs in 3%–5% of patients using thiazolidinediones as monotherapy. Congestive cardiac failure is reported in 1% of cases with monotherapy and in 2%–3% of cases on combination therapy. Fluid retention can cause dilutional anaemia. The initial concern about the potential hepatotoxicity of the currently marketed agents has abated, and the advisory regarding mandatory periodic liver function testing has been withdrawn. The contraindications and caution for therapy with thiazolidinediones include:

1. Congestive heart failure: New York Heart Association (NYHA) classes II, III and IV.

2. Liver dysfunction with transaminase levels >2.5 times upper limit of normal.

3. Caution is needed in patients with mild renal failure and anaemia in view of fluid retention. Haemoglobin should be checked before starting thiazolidinediones.

   Recent concerns. A recent meta-analysis has suggested that patients on rosiglitazone have a 43% excess risk of myocardial infarction and 64% excess risk of cardiovascular death. A recent interim analysis showed a non-significant increase in hospitali-zation and death from cardiovascular causes, which has not alleviated the concerns raised by the meta-analysis. A similar meta-analysis indicates that, unlike rosiglitazone, pioglitazone is not associated with any excess cardiovascular risk, and may even be protective. In response, the US Food and Drug Administration (FDA) will probably advise thiazolidinedione manufacturers to carry a warning with details of increased cardiovascular risk while marketing these agents. Recent evidence also suggests that both agents reduce bone mineral density and pose an increased risk of fractures in post-menopausal women.
   Pioglitazone is started at a dose of 15 mg once a day and increased to a maximum of 45 mg once a day. Rosiglitazone is started at 2–4 mg once a day and increased to 8 mg/day in 1 or 2 divided doses. Its full effect is seen in 2–3 months. The long term efficacy of these agents in reducing diabetic complications has not been proven in clinical trials. Thiazolidinediones can be used as monotherapy, and also in combination with secretagogues and insulin sensitizers. Combination with insulin should be prescribed with caution due to the increased risk of weight gain and fluid retention.

1. AGIs are contraindicated in chronic intestinal diseases such as irritable bowel syndrome, inflammatory bowel disease and others where gaseous distension can aggravate symptoms.

2. Severe renal and liver failure.

3. Pregnancy and lactation.

   With AGIs, one has to ensure dietary compliance with no simple sugars and more of complex carbohydrates. The drug is taken with the first bite of the meal so that it remains in the intestine during digestion of food. Table IV lists some salient features of AGIs.

AGENTS TARGETING THE ENTERO-INSULAR AXIS AND THE INCRETINS
These agents are not yet available for clinical use in India. The presence of an entero-insular axis was made apparent by the fact that using equivalent glucose loads, oral glucose tolerance tests resulted in a higher insulin peak than the intravenous glucose tolerance test. Gut hormones contributing to incremental insulin release were called ‘incretins’. GLP-1 is the major incretin and is secreted by the ileum and, to some extent the colon, with levels rising within 15 minutes of ingesting a meal. Following ingestion of a meal, GLP-1 levels increase within 15 minutes. It has a half-life of 1–2 minutes as it is degraded by DPP IV to GLP-1 (9–36) amide. The GLP-1 receptor is expressed on pancreatic cells, lung, brain, liver, skeletal muscle and adipose tissue among others. The actions of GLP-1 include:

1. Insulinotropic actions: GLP-1 stimulates glucose-dependent insulin secretion; with eugylcaemia there is no stimulation.

2. Glucagonostatic effect: suppresses glucagon secretion in a glucose-dependent manner.

3. Proliferative and anti-apoptotic effect: GLP-1 may stimulate proliferation and neogenesis of cells while inhibiting apoptosis.

4. On gastrointestinal tract: GLP-1 inhibits gastric emptying thereby delaying postprandial plasma glucose rise and also causing satiety.

5. On central nervous system: GLP-1 promotes satiety and weight loss.

   Impaired glucose tolerance and type 2 DM are characterized by low levels of GLP-1 with normal sensitivity. Clinical use of GLP-1 needs continuous infusion as it is rapidly degraded. This is overcome using enzyme resistant analogues (Exendin 4, Liraglutide) or with DPP IV inhibitors (sitagliptin and

Table IV. Salient features of a-glucosidase inhibitors

vildagliptin). Preclinical studies suggest that these agents may also promote cell neogenesis and proliferation.

Exendin 4 (Exenatide). It is obtained from the saliva of the Gila monster, Heloderma suspectum. Synthetic exendin 4 is also available. It is resistant to DPP IV and following subcutaneous injection has a plasma half-life of about 26 minutes. The usual dose is 5–10 mg subcutaneously taken twice a day, up to
60 minutes before each meal. Nausea and vomiting may be related to delayed gastric emptying or central effects. It can be used in combination with sulphonylureas, metformin or thiazolidinediones, and the dose of sulphonylureas may need to be reduced if hypoglycaemic symptoms appear. With exenatide therapy, patients may report a reduction in appetite and most of them also have weight loss. Exenatide has only recently become available in India and its precise place in the management of type 2 diabetes in India is still to be established.

Liraglutide, a synthetic GLP-1 analogue, has an acyl side chain attached that results in non-covalent binding to albumin. The half-life is about 15 hours allowing once daily injection. The dose is up to 2 mg/day. This agent also suppresses glucagons, reduces fasting blood glucose and causes weight loss.

Sitagliptin and vildagliptin, both inhibit DPP IV activity by 100% within 15–30 minutes of their oral ingestion, and more than 80% inhibition lasts for 16 hours or more. This allows both agents to
be given as a once daily dose of 100 mg. While sitagliptin has received FDA approval, vildagliptin is awaiting regulatory approval.

Sitagliptin. Monotherapy with once daily dose results in a reduction in HbA1c by 0.8%–1%, and is associated with either weight neutrality or weight loss. This agent has also been studied in combination therapy with metformin and thiazolidinediones and leads to an additional decline in HbA1c of approximately 0.75%. A concern with use of DPP IV inhibitors is that these agents may also cleave other bioactive molecules involved in the immunoinflammatory pathway. This has not been borne out by clinical studies till date. Current data suggest that DPP IV inhibitors are best positioned as therapy early in the course of type 2 DM either as monotherapy or in combination with metformin and thiazolidinediones.

USES OF OADs

Diet, exercise and weight loss are the key non-pharmacological interventions for the management of type 2 DM (details provided in an earlier article in the series). Over a period of time, these lifestyle interventions alone are not adequate to attain optimal glycaemic control, necessitating the introduction of OADs. However, it must be emphasized that continuing lifestyle modification is a critical requirement to ensure target blood glucose levels and ameliorate cardiovascular risk factors even

when the patient is concurrently on pharmacological therapy.

How does a physician choose the most appropriate agent for monotherapy for a particular patient? The preceding discussion makes it clear that except for AGI, nateglinide and the newer agents, all other drugs currently in clinical use cause comparable reduction in HbA1c. Table V provides a synopsis of the relative merits and concerns for individual agents.

Recent guidelines from the American Diabetes Association and European Association for the Study of Diabetes, recommend metformin to be the best first-line agent, especially in obese patients, because of the weight loss/weight neutrality associated with this agent. The long term benefits in reducing micro- and macrovascular complications as demonstrated by the UKPDS and the near absence of hypoglycaemia make this drug an attractive choice for initiating pharmacotherapy.

Insulin secretagogues are currently preferred less than metformin while starting monotherapy because of the concern regarding weight gain and hypoglycaemia. Additional unresolved issues are the possible adverse cardiovascular implications of hyperglycaemia. However, they remain an important part of combination treatment. They are also appropriate for monotherapy if fasting blood glucose levels are high (about 250–300 mg/dl) and in non-obese patients. Like metformin therapy, long term therapy with these agents has been associated with reduction in microvascular complications, though benefits with regards to macrovascular complications are equivocal.

Non-insulin secretagogues are best considered as ‘niche’ agents, to be used in special situations, e.g. patients with irregular meal timings. They do not provide any advantage over conventional sulphonylureas, other than shorter duration of action. While this results in better postprandial control it may be associated with preprandial hyperglycaemia.

Thiazolidinediones are an important group of insulin sensitizers for whom the entire spectrum of metabolic effects and side-effects still need to be elucidated. They are slow in

Table V. Currently available oral hypoglycaemic agents for type 2 diabetes mellitus

onset of action taking up to 8–12 weeks to manifest their full hypoglycaemic effect. This makes them less attractive if the patient has symptomatic hyper-glycaemia and needs prompt reduction in blood glucose. Similarly, the significant weight gain and fluid retention with resultant pedal oedema and likelihood of precipitating congestive cardiac failure remain a matter of concern. The recent literature suggesting an excess risk of cardiovascular events and mortality also needs to be resolved. At present, there is limited evidence to strongly recommend thiazolidinediones as first-line agents for monotherapy.
   In summary, while there may be no compelling reason to recommend any one group of agents, metformin is possibly the most appropriate drug for monotherapy especially in the overweight patient. Patient factors such as age, weight, co-morbid conditions, regularity of meals and interaction with other medication must be considered before making a decision.

Combination therapy
Since a combination of insulin deficiency and insulin resistance are responsible for type 2 DM, combination therapy with insulin sensitizers and insulin secretagogues becomes logical, especially as the disease progresses. The most commonly prescribed combination is metformin and sulphonylurea, though sulphonyl-urea with thiazolidinediones and metformin with thiazolidinediones have their proponents in specific clinical situations. There is no evidence to show that given a comparable reduction in HbA1c, any one combination is superior to the other, underlining the primacy of glycaemic control and not the means to attain target blood glucose levels.
   When a two-drug combination is not adequate to meet glycaemic targets, triple drug combination (sulphonylurea, metformin and thiazolidinediones) can be considered. Data suggest that adding a third drug to a 2-drug combination is unlikely to reduce the HbA1c by more than 1%. The inference thereby is that if HbA1c exceeds the target for control by >1% while on optimal doses of 2 agents, adding a third drug is unlikely to help achieve the target; and it may be advisable to consider insulin therapy at this juncture.