Concomitant therapy with pioglitazone and insulin for the treatment of type 2 diabetes

To prevent hyperinsulinemia, which may cause atherosclerosis, thiazolidinediones (TZDs), also known as insulin sensitizers, are often added to the therapeutic regimen of patients with type 2 diabetes who are receiving insulin. The combination of insulin with pioglitazone, a TZD, reduces glycoated hemoglobin (HbA(1c)) by 0.6%–2.1%. The higher the HbA(1c) baseline the larger the therapeutic reduction of HbA(1c). This combination therapy has been shown to be beneficial even in lean Japanese patients with diabetes. It should be noted that such combination therapy is much more useful when the main clinical aim is lowering not postprandial, but fasting and nocturnal glycemia. The glycemic-lowering effects of pioglitazone alone occur slowly, whereas the addition of insulin to pioglitazone often shows a dramatic glucose-lowering effect. Thus, such combination therapy increases the possibility of frequent hypoglycemia within 1 to 2 months of combining the drugs. Severe hypoglycemia in patients using this therapy is rare. Patients treated with combination therapy who show a predominant reduction of glycemia often have severe edema; in 10%–20% of patients, combination therapy leads to drug-related congestive heart failure (CHF). However, this phenomenon is usually weakened if low doses of pioglitazone which are added to insulin therapy (ie, 15 mg/day or even 7.5 mg/day for women). It is well known that pioglitazone has an anti-atherosclerotic effect, although it is unclear if hyperinsulinemia induces atherogenic changes, either directly or indirectly, by the promotion of obesity. Until now, we have not confirmed whether the anti-atherosclerotic effects of pioglitazone exceed the supposed disadvantageous action of insulin when used in combination therapy. The addition of pioglitazone tends to reduce daily insulin dosages, but study findings have not been consistent. Improvement of lipid profiles has also been weak with this combination therapy. Long-term trials are needed before any conclusions can be reached concerning atherogenic effects of treatment for type 2 diabetes. Combination therapy of even small doses of pioglitazone with insulin should be primarily used for patients who achieve insufficient reduction in glycemia with insulin monotherapy.