Can Actos and Trulicity Be Taken Together?
Yes, Actos (pioglitazone) and Trulicity (dulaglutide) can be safely taken together in patients with type 2 diabetes, and this combination has been specifically studied and approved for clinical use. 1, 2, 3
Evidence Supporting This Combination
Clinical Trial Data
Dulaglutide has been directly studied in combination with pioglitazone plus metformin in the AWARD-1 trial, demonstrating superior glycemic control compared to exenatide twice daily, with dulaglutide showing greater HbA1c reductions when added to this regimen. 1, 3
The AWARD program specifically evaluated dulaglutide's efficacy and safety when combined with metformin and pioglitazone, confirming this is an established and evidence-based combination therapy. 2, 3
Complementary Mechanisms of Action
Pioglitazone works by increasing insulin sensitivity through activation of peroxisome proliferator-activated receptors, reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. 4, 5
Dulaglutide works through GLP-1 receptor agonism, stimulating glucose-dependent insulin secretion, suppressing glucagon, increasing satiety, and slowing gastric emptying—mechanisms that are entirely complementary to pioglitazone's insulin-sensitizing effects. 1, 3
Because these medications work through different pathways, they provide additive glucose-lowering effects without mechanistic redundancy. 4, 1
Important Safety Considerations
Fluid Retention and Heart Failure Risk
The most critical concern when using pioglitazone is fluid retention and potential heart failure exacerbation, particularly when combined with other medications. 6
Pioglitazone is contraindicated in patients with NYHA class III or IV heart failure and should be used with extreme caution in patients with any degree of heart failure or significant cardiac disease. 6
Monitor patients closely for signs of fluid retention (weight gain, edema, dyspnea) when using this combination, as both medications can affect fluid balance through different mechanisms. 6
Hypoglycemia Risk
This combination has a low inherent risk of hypoglycemia since both medications work in glucose-dependent manners, unlike sulfonylureas or insulin. 1, 3
If the patient is also taking sulfonylureas or insulin, dose reductions of those agents should be considered to minimize hypoglycemia risk. 6
Gastrointestinal Effects
Expect transient nausea, vomiting, and diarrhea when initiating dulaglutide, which can be minimized by starting at the lowest dose (0.75 mg weekly) and titrating gradually. 6, 1
These gastrointestinal symptoms are self-limited with longer-acting GLP-1 receptor agonists like dulaglutide and typically resolve within several weeks. 6
Clinical Context and Positioning
When This Combination Makes Sense
For patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists like dulaglutide provide proven MACE reduction benefits, making this combination appropriate when pioglitazone is already providing glycemic benefit. 6
For patients with NASH (nonalcoholic steatohepatitis) and type 2 diabetes, pioglitazone has specific evidence for reversing steatohepatitis, while dulaglutide reduces liver fat content, making this combination particularly valuable. 6
Dulaglutide demonstrated cardiovascular benefit in the REWIND trial with an HR of 0.88 for MACE, including in patients without established CVD, supporting its use in high-risk patients. 6
Important Caveats
Pioglitazone causes weight gain (typically 2-4 kg), while dulaglutide at 1.5 mg weekly promotes weight loss, so the net effect on weight may be neutral or modest weight loss depending on doses used. 4, 1
Pioglitazone requires 3-6 months to achieve maximal glucose-lowering effects, so patience is needed when assessing the full benefit of this combination. 5
Both medications are well-tolerated long-term, with pioglitazone showing sustained glycemic control for up to 2 years and dulaglutide maintaining efficacy for similar durations. 5, 1
Monitoring Recommendations
Assess for fluid retention at every visit: Monitor weight, check for peripheral edema, and ask about dyspnea or orthopnea. 6
Evaluate cardiovascular status before initiating pioglitazone: Obtain baseline assessment of cardiac function, particularly if any history of heart failure or significant cardiac disease exists. 6
Check HbA1c every 3 months initially to assess glycemic response and determine if further intensification is needed. 6
Monitor liver function tests periodically, though pioglitazone does not carry the hepatotoxicity risk of the withdrawn troglitazone. 4