Safety concerns and troublesome side effects have significantly reduced the use of this class of drugs. A meta-analysis of 42 randomized clinical trials with rosiglitazone suggested that this drug increased the risk of angina pectoris or myocardial infarction. As a result, its use was suspended in Europe and severely restricted in the United States. A subsequent large prospective clinical trial (the RECORD study) failed to confirm the meta-analysis finding and so the United States restrictions have been lifted. The drug remains unavailable in Europe.
Fluid retention occurs in about 3–4 % patients on thiazolidinedione monotherapy and occurs more frequently (10–15%) in patients on concomitant insulin therapy. Heart failure can occur, and the drugs are contraindicated in patients with New York Heart Association class III and IV cardiac status (see Chapter 13). Macular edema is a rare adverse effect that improves when the drug is discontinued. Loss of bone mineral density and increased atypical extremity bone fractures in women are described for both compounds; this is postulated to be due to decreased osteoblast formation. Other adverse effects include anemia, which might be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs, especially when used in combination with a sulfonylurea or insulin. Some of the weight gain is fluid retention but there is also an increase in total fat mass. In preclinical trials, bladder tumors were observed in male rats on pioglitazone. Initial clinical reports indicated that this might also be true in humans. A 10-year observational cohort study of patients taking pioglitazone, however, failed to find an association with bladder cancer. A large multi-population pooled analysis (1.01 million persons over 5.9 million person-years) also failed to find an association between cumulative exposure of pioglitazone or rosiglitazone and incidence of bladder cancer. Another population based study generating 689,616 person-years of follow-up did find that pioglitazone but not rosiglitazone was associated with an increased risk of bladder cancer.
Troglitazone, the first medication in this class, was withdrawn because of cases of fatal liver failure. Although rosiglitazone and pioglitazone have not been reported to cause liver injury, the drugs are not recommended for use in patients with active liver disease or pretreatment elevation of alanine aminotransferase (ALT) 2.5 times greater than normal. Liver function tests should be performed prior to initiation of treatment and periodically thereafter.
The `-glucosidase inhibitors competitively inhibit the intestinal α-glucosidase enzymes and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides.
Acarbose and miglitol are available in the United States. Voglibose is available in Japan, Korea, and India. Acarbose and miglitol are potent inhibitors of glucoamylase, α-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase.
Acarbose has the molecular mass and structural features of a tet rasaccharide and very little is absorbed. In contrast, miglitol has structural similarity to glucose and is absorbed.
Acarbose treatment is initiated at a dosage of 50 mg twice daily with gradual increase to 100 mg three times a day. It lowers post prandial glucose levels by 30–50%. Miglitol therapy is initiated at a dosage of 25 mg three times a day. The usual maintenance dosage is 50 mg three times a day, but some patients may need 100 mg three times a day. The drug is not metabolized and is cleared by the kidney. It should not be used in renal failure.