From the Guidelines
Pioglitazone does not cause hypoglycemia when used alone, but it may increase the risk of hypoglycemia when used in combination with insulin or insulin secretagogues. This is because pioglitazone works by improving insulin sensitivity in peripheral tissues rather than directly increasing insulin secretion from the pancreas, as stated in the 2019 standards of medical care for type 2 diabetes in China 1. The medication enhances the body's response to existing insulin by activating peroxisome proliferator-activated receptor gamma (PPAR-γ), which leads to increased glucose uptake in muscle and fat cells and decreased glucose production in the liver.
When considering the use of pioglitazone, it's essential to be aware of its potential side effects, including:
- Weight gain
- Fluid retention
- Potential bone fracture risk
- Rarely, bladder cancer As noted in the 2019 guidelines 1, these side effects can be more pronounced when pioglitazone is used in combination with insulin.
In comparison to other antidiabetic medications, thiazolidinediones like pioglitazone have a lower risk of hypoglycemia, especially when compared to sulfonylureas, as shown in a 2012 clinical practice guideline from the American College of Physicians 1. However, the primary concern with pioglitazone is its potential to increase the risk of heart failure, which is a critical consideration in patients with pre-existing heart conditions, as contraindicated in the 2019 guidelines 1.
Given the potential benefits and risks, the use of pioglitazone should be carefully considered, particularly in patients at risk for hypoglycemia or those with a history of heart failure, and patients should be closely monitored for any adverse effects while on this medication.
From the FDA Drug Label
Unlike sulfonylureas, pioglitazone is not an insulin secretagogue Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Pioglitazone does not cause hypoglycemia as it is not an insulin secretagogue and it enhances the effects of circulating insulin by decreasing insulin resistance. It does not lower blood glucose in the absence of endogenous insulin. 2 2 2
From the Research
Pioglitazone and Hypoglycemia
- Pioglitazone is an antihyperglycaemic agent that increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake 3.
- The incidence of hypoglycemia with pioglitazone is low, with a study showing that 77 patients out of 12,772 experienced at least one hypoglycaemic episode (9.64 per 1000 patient-years) 4.
- Factors that may increase the risk of hypoglycaemia with pioglitazone include concomitant therapy with sulfonylurea or insulin, and female gender 4.
- Pioglitazone has been shown to improve postload glycemia and composite insulin sensitivity index (CISI) more than metformin or gliclazide when used as monotherapy or in combination therapy in patients with type 2 diabetes 5.
- A prospective, randomized trial found that adding pioglitazone to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control resulted in less hypoglycemia compared to adding bedtime insulin 6.
- A review of the literature found that pioglitazone is associated with a low incidence of hypoglycemia, especially compared to sulfonylureas 7.
Comparison with Other Antihyperglycaemic Agents
- Pioglitazone has been compared to other oral antihyperglycaemic agents, including metformin, sulfonylureas, and dipeptidyl peptidase-4 inhibitors, and has been found to have similar efficacy in improving glycosylated haemoglobin, fasting glucose, insulin parameters, and β-cell function 7.
- Pioglitazone has also been found to reduce vascular risk and inflammatory markers, and improve carotid intima media thickness independent of its glycaemic effect 7.
- However, pioglitazone is associated with an increased risk of heart failure and fractures, which is related to the increased incidence of oedema due to fluid retention 7.