• Mild gastrointestinal upset;

• Skin reactions: rashes, purpura, pruritus;

• Weight gain (this effect can be minimized or prevented by increasing emphasis on dietary habits). Glimepiride appears to cause less weight gain than all the others, which is most likely due to its insulin-sparing effect;

• Hyponatremia, fluid retention, and the Antabuse reaction have also been reported with the use of chlorpropamide, but may occur with any sulfonylurea especially when taken in large doses;

• The major complication of sulfonylurea therapy is severe or recurrent mild episodes of hypoglycemia. Severe, longlasting hypoglycemia is seen more often with chlorpropamide than with any other agent because of its long half-life and duration of action, although severe hypoglycemia can occur with the use of any sulfonylurea. Glipizide is reported to have a lower risk of hypoglycemia because it is metabolized to inactive by-products that do not have hypoglycemic activity;

• Hematologic reactions: leukopenia, thrombocytopenia, hemolytic anemia;

• Cholestasis (with and without jaundice).

Biguanides

The adverse effects of metformin include gastrointestinal (GI) complaints (eg, diarrhea, bloating), metallic taste, and effect on vitamin B12 levels. The GI adverse effects are self-limited and can be managed by starting with a low dose and increasing in an every 2- to 4-week regimen. Taking the drug along with meals also helps in reducing this side effect.
Some patients complain of a decrease in appetite.

The major complication of metformin is a low, but significant, risk for fatal lactic acidosis. Because the kidneys excrete metformin, any agent that affects renal function increases the risk of lactic acidosis. Patients receiving metformin should have their serum creatinine monitored periodically. Patients with serum creatinine above 1.4mg% (women) and 1.5 mg% (men) should be taken off the medication.

Metformin is also contraindicated in patients with significant hepatic disease, cardiac insufficiency, alcohol abuse, and any hypoxic condition or history of lactic acidosis. Metformin should be temporarily discontinued 1 to 2 days before any dye studies so that serum metformin levels are low if the patient develops renal failure from the dye. In any patient who is hospitalized with an acute severe illness, metformin should be temporarily discontinued.

Alpha-Glucosidase Inhibitors

The main side effect of acarbose is flatulence. Soft stools or diarrhea and mild abdominal pain have also been reported. Many of the symptoms are dose related and transient, occurring with the highest frequency during the first 8 weeks of therapy. The symptoms are probably caused by the osmotic effect of undigested carbohydrates in the distal bowel. The most important factor in avoiding side effects is to titrate acarbose slowly.

Meglitinides

The most common adverse effect of repaglinide is hypoglycemia, although at a lower incidence than that of the SUs. Other adverse effects that occasionally occur include headaches, upper respiratory infection symptoms, arthralgia, and back and chest pain.

Other, minor side effects which may be seen include nausea, diarrhea, constipation, vomiting and dyspepsia;

Thiazolidinediones

Most side effects reported are mild. Commonly reported ones included upper respiratory tract infections, headaches, sinusitis, muscle pain, tooth disorders, and sore throats.

Weight gain of about 4 to 7 lbs. occurs with all the glitazones. This is of some concern because weight gain increases insulin resistance.

Pioglitazone and rosiglitazone both appear to cause fluid retention, which can make the effects of congestive heart failure or other fluid overload diseases worse.

Unlike troglitazone, statistically both pioglitazone and rosiglitazone do not have hepatic toxic effects. Only 2 cases of hepatic toxicity have been reported with rosiglitazone use during the past 2 years, and both cases had many other risk factors. To date, pioglitazone has had no reported cases of hepatic toxicity.

Liver functions must be monitored every two months in the first year of therapy and regularly thereafter.

Any person using the glitazones who presents with symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and dark urine or jaundice must have the glitazone stopped immediately and the person investigated for a liver disorder.