PROBLEMS OF GLITAZONE THERAPY

PROBLEMS OF GLITAZONE THERAPY

1. It is recommended that glitazone not to be given to individuals with baseline ALT level >2.5 times the upper limit of the normal range. Patients on thiazolidinedions should have LFT at base line and periodically thereafter. It is drug related hepatotoxicity.
2. Weight Gain: Weight gain has been a constant factor of therapy with all of the thiazolidinedions. The weight gain is due to both an increase in body fat and fluid retention. During treatment of II DM patient, thiazolidinedions increase subcutaneous adiposity but cause no significant change in visceral adiposity. The increase in total body fat averages ~1.5kg at low doses and 3.5 – 4 kg at maximal doses. The weight gain is somewhat greater than thiazolidinidions are combined with sulfonylurea and greatest with combination therapy with insulin (~4-5.4 kg). The increase in weight reflects increase in subcutaneous fat because visceral fat mass is generally unchanged or slightly reduced. A rare individual can gain as much as 5-30kg.
3. Fluid retention: Fluid retention is also seen during treatment with all thiazolidinedions. Haemoglobin and hematocrit are decreased on average ≤ 1gm/dl ≤3.3% respectively. These changes occur during the first 12 weeks of therapy and reflect increase in plasma volume because RBC mass is unchanged. Mild to moderate peripheral edema in 4-5% of patient on thiazolidinedions monotherapy. This increase to 6-8% thiazolidinedions and sulfonylurea combination therapy and 15% on thiazolidinedions and insulin combination treatment. The fluid retention is mediated by activation of PPAR-g receptor in proximal tubule of the nephron, which facilitates increase reabsorbtion of sodium in proximal convaluted tubule. The fluid retention is poorly response to loop diuretics because they act predominantly at DCT. Aldosterone antagonist may be the best agents with which to attempt to treat the thiazolidinidione mediated fluid retention which is modest in magnitude. Discontinuation of the thiazolididione in such patient results in excretion of retained fluid.
4. Congestive Cardiac Failure: The development of CCF in type II diabetic patients treated with thiazolidinedions. This is likely a manifestation of excess fluid retention in individuals who have an increased susceptibility to develop heart failure (5-7%) in individuals given the maximum dose of thiazolidinedions risk factors include a) Combination therapy with insulin, b) Female sex c)Predisposing condition such as CRF/poor cardio vascular disease

            Heart failure attributed to thiazolidinedions therapy usually occurs within the first several months of treatment. In patients at risk, therapy with thiazolidinedions should be initiated with lowest dose (15mg Pioglitazone) and gradually titrated up with careful observation of weight gain and evidence of fluid retention. The maximal dose of the thiazolidinedions is to be avoided if possible, particularly when combined with insulin. Excessive weight gain during first several weeks of thiazolidinedions therapy is indicative extreme fluid retention and if not reduced by diuretic therapy, indicates that thiazolidinedions therapy should be discontinued.

            Thiazolidinedions cause or exacerbate CCF in some patients. If symptoms and signs  of heart failure (including excessive, rapid weight gain, dyspnea and or edema) develop, the heart failure should be managed.

5. Bone Fracture: In women, bone fracture had occurred in 9.3% of patients on rosiglitazone, 5.1% of those on metformin, and 3.5% of those on glyburide. The increase in fracture with rosiglitazone occurred in pre and post menopausal women and is occurred predominantly in lower and upper extremities. Increased fractured risk has been noted with pioglitazone and in PCOD. Both chronic rosiglitazone and pioglitazone treatment. (>8 prescription corresponding to 12-18 months of therapy) increased the occurrence of bone fractures 2.43 fold compared with not using the treatment. Fractures were predominantly in the hip and wrist and were independent of sex and age. Patient taking other antidiabetic agents had no increase in fracture. The mechanism for the thiazolidinedions associated increase risk of bone fractures appears to be an increase in bone marrow stem cells differentiating into adipocytes and a decrease in bone formation from osteoblast. Contra indicated in type I diabetes, pregnancy, active liver disease, III/IV CCF.

Note: Patients who are potentially at high risk CCF or bone fracture should be carefully evaluated before initiating thiazolidinedione therapy and should receive periodic careful followup while on therapy.

REFERENCE:  Therapy for DM and Related Disorders, ADA