Concomitant Use of TZDs and Insulin
The thiazolidinedione (TZD) class of antidiabetic agents, improve glycemic control while reducing circulating insulin levels. This class of agents improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. They are not chemically or functionally related to the sulfonylureas, the biguanides or the alpha-glucosidase inhibitors. Rosiglitazone (Avandia) is a highly selective and potent agonist for the peroxisome proliferator- activated receptor- gamma (PPARγ). Pioglitazone (Actos) has both PPAR gamma and PPAR alpha agonist activity. In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism and in the maturation of preadipocytes, predominantly of subcutaneous origin.

Insulin resistance is a primary feature characterizing the pathogenesis of type 2 diabetes. TZD results in increased responsiveness of insulin-dependent tissues and significantly improves hepatic and peripheral (muscle) tissue sensitivity to insulin in patients with type 2 diabetes. Clinical studies in patients with type 2 diabetes treated with Rosiglitazone or Pioglitazone either as monotherapy or in combination with metformin or sulfonylureas showed improved beta-cell function and decreased fasting plasma glucose, insulin and C-peptide values following 26 weeks of treatment. A homeostasis model assessment (HOMA) was conducted using fasting plasma glucose and insulin or C-peptide levels as a measure of insulin sensitivity and beta-cell function. In these studies, reductions in mean plasma pro-insulin and pro-insulin split product concentrations were also observed.

These medications significantly reduce hemoglobin A1C (A1C, a marker for long term glycemic control), and fasting blood glucose (FBG) in patients with type 2 diabetes. Inadequately controlled hyperglycemia is associated with an increased risk of diabetic complications, including cardiovascular disorders and diabetic nephropathy, retinopathy and neuropathy.

Studies between 8 and 26 weeks with rosiglitazone have shown a statistically significant reduction in markers of inflammation, C-reactive protein (CRP) and matrix metalloproteinase-9 (MMP-9).

Thiazolidenediones (TZD) are active only in the presence of insulin due to their mechanism of action. Therefore members of this class should not be used in the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. Close monitoring of glycemic control and dose adjustment may be needed when TZD is co-administered with CYP2C8 inhibitors or inducers


Thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which can exacerbate or lead to congestive heart failure. The fluid retention may very rarely present as rapid and excessive weight gain. All patients should be monitored for signs and symptoms of adverse reactions relating to fluid retention and heart failure. In particular, patients who are at risk for heart failure including those receiving concurrent therapy which increases insulin levels (i.e. sulfonylureas), and those patients with mild to moderate heart failure (NYHA Class I and II) should be closely monitored, TZD is contraindicated in patients with NYHA Class III and IV cardiac status. TZD should be used with caution in patients with edema because they may induce fluid retention by increasing sodium resorption. In healthy volunteers who received a TZD as monotherapy for 8 weeks, there was a statistically significant increase in median plasma volume (1.8 mL/kg) compared to placebo. In controlled clinical trials of patients with Type 2 diabetes, mild to moderate edema was observed at a greater frequency in patients treated with AVANDIA and may be dose related. There have also been reported incidents of macular edema.

Use with Insulin

Both TZD and insulin may cause fluid retention by increasing sodium resorption, thus the use of both agents together increases risk of increased fluid retention, edema and potentially heart failure. The indication for combined use of insulin & TZD has not been applied for in Canada although in other jurisdictions it is approved and concomitant use is common particularly by diabetes specialists under certain circumstances. In the very insulin resistant diabetic, the use of a TZD along with insulin may improve insulin sensitivity and decrease the doses of insulin required. The risk of edema is increased so close monitoring should be done. TZD induced edema may be difficult to treat, loop diuretics such as furosemide may be only modestly effective. The most effective diuretics are amiloride (usual dose 5 mg/day) or spironolactone (usual dose 50-100 mg/day) and these are commonly given with hydrochlorothiazide. Serum Potassium should be monitored because amiloride and spironolactone are both potassium sparing and may lead to hyperkalemia. It should be appreciated that for TZD to work, the individual must have endogenous insulin secretion. In the Type 1 Diabetic or in the Type 2 with longstanding disease and little or no endogenous insulin secretion, TZD does not work

Dr. J. Robin Conway