Can pioglitazone be given as a 2nd line option to a patient with Type 2 Diabetes Mellitus (T2DM) on metformin?

From the Guidelines

Pioglitazone can be considered as a second-line option for a patient with Type 2 Diabetes Mellitus (T2DM) on metformin, especially when cost is a limiting factor or in specific patient populations. According to the 2016 American Diabetes Association standards of medical care in diabetes 1, when monotherapy with a noninsulin agent at the maximum tolerated dose does not achieve or maintain the HbA1c target over 3 months, a second agent should be added. Pioglitazone, a thiazolidinedione, improves insulin sensitivity by activating PPAR-gamma receptors, which helps reduce insulin resistance in peripheral tissues and the liver.

The typical starting dose of pioglitazone is 15-30 mg once daily, which can be titrated up to a maximum of 45 mg daily based on glycemic response. When adding pioglitazone to metformin, no special dose adjustments of either medication are typically needed, though monitoring for side effects is important. Patients should be aware of potential side effects including fluid retention (which may worsen heart failure), weight gain, increased risk of bone fractures, and rarely, bladder cancer with long-term use.

As noted in the Israel National Diabetes Council recommendations 1, for patients where cost is not a key limiting factor, second-line therapy agents that do not cause hypoglycemia, weight gain, or significant side effects are preferred. However, when cost is a major limiting factor, pioglitazone is considered a less preferable but still viable option. It is particularly beneficial for patients with insulin resistance and may have cardiovascular benefits in certain populations. Regular monitoring of liver function tests is recommended, especially during the first year of treatment. This combination is most appropriate for patients without heart failure, significant edema, or history of bladder cancer.

Key considerations for the use of pioglitazone as a second-line agent include:

• Patient's individual characteristics, such as BMI and presence of insulin resistance
• Cost considerations and availability of other treatment options
• Potential side effects and the need for regular monitoring
• The importance of achieving glycemic control to reduce the risk of diabetes complications.

From the FDA Drug Label

Add-on to Metformin Trials Two clinical trials were conducted with pioglitazone hydrochloride in combination with metformin Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone hydrochloride or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with pioglitazone hydrochloride as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin

Yes, pioglitazone can be given as a 2nd line option to a patient with Type 2 Diabetes Mellitus (T2DM) on metformin, as it has been shown to produce statistically significant improvements in HbA1c and FPG when used in combination with metformin 2.

• The therapeutic effect of pioglitazone hydrochloride in combination with metformin was observed in patients regardless of the metformin dose.
• The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the 45 mg dose.
• The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.

From the Research

Pioglitazone as a 2nd Line Option for T2DM

• Pioglitazone can be given as a 2nd line option to a patient with Type 2 Diabetes Mellitus (T2DM) on metformin, as it can be administered in combination with metformin 3.
• The addition of pioglitazone to metformin has been shown to improve glycemic control with an extremely low incidence of hypoglycemia 3.
• Pioglitazone also exhibits favorable pleiotropic effects, including anti-inflammatory, antioxidant, vasoprotective, antihypertensive, and hypolipidemic actions 3.

Comparison with Other 2nd Line Options

• A study comparing pioglitazone with glimepiride as add-on to metformin plus alogliptin found that pioglitazone provided comparable glycemic control and various benefits, including improvements in lipid profiles, insulin resistance, and hypoglycemia risk 4.
• Another study found that sodium-glucose co-transporter 2 (SGLT2) inhibitors were more effective than sulfonylureas as add-on to metformin in the longer term, with less hypoglycemic events and greater reductions in weight and blood pressure 5.
• Dipeptidyl peptidase-4 (DPP-4) inhibitors were found to be inferior to glucagon-like peptide-1 (GLP-1) agonists and similar to pioglitazone in reducing HbA1c, but had a favorable weight profile compared to sulfonylureas and pioglitazone 6.

Considerations for 2nd Line Therapy

• Patient characteristics and the beneficial and adverse effects of the drug should be considered when selecting second-line therapy 7.
• Thiazolidinediones, such as pioglitazone, should be reserved for patients with contraindications to all other oral drugs, and those who will not tolerate injectable drugs due to their adverse-effect profiles 7.