General Information

ACTOS is a thiazolidinedione. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization. ACTOplus Met combines thiazolidinedione with metformin, a biguanide. Biguanides act primarily by decreasing endogenous hepatic glucose production.

ACTOS is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.

ACTOplus Met is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate.

ACTOS and ACTOplus Met are both supplied as tablets for oral administration. The recommended dosing is as follows:

• ACTOS: Initiate ACTOS at 15 mg or 30 mg once daily. Limit initial dose to 15 mg once daily in patients with NYHA Class I or II heart failure. If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily
• ACTOplus Met: Starting dose for patients inadequately controlled on metformin monotherapy
  Based on the usual starting dose of pioglitazone (15-30 mg daily), ACTOplus met may be initiated at either the 15 mg/500 mg or 15 mg/850 mg tablet strength once or twice daily, and gradually titrated after assessing adequacy of therapeutic response.
  Starting dose for patients who initially responded to pioglitazone monotherapy and require additional glycemic control
  Based on the usual starting doses of metformin (500 mg twice daily or 850 mg daily), ACTOplus met may be initiated at either the 15 mg/500 mg twice daily or 15 mg/850 mg tablet strength once daily, and gradually titrated after assessing adequacy of therapeutic response.
  Starting dose for patients switching from combination therapy of pioglitazone plus metformin as separate tablets
  ACTOplus met may be initiated with either the 15 mg/500 mg or 15 mg/850 mg tablet strengths based on the dose of pioglitazone and metformin already being taken.

Mechanism of Action

Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects [except in specific circumstances, and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Side Effects

Adverse effects associated with the use of ACTOS may include, but are not limited to, the following:

• upper respiratory tract infection
• headache
• sinusitis
• myalgia
• pharyngitis

Adverse events associated with the use of ACTOplus met may include, but are not limited to, the following:

• Upper Respiratory Tract Infection
• Diarrhea
• Nausea
• Headache
• Urinary Tract Infection
• Sinusitis
• Dizziness
• Edema Lower Limb
• Weight Increased

The ACTOS and ACTOplus Met drug labels both come with the following Black Box Warning: 

Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients. After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered. ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. If lactic acidosis is suspected, discontinue ACTOplus Met and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Clinical Trial Results

ACTOS: The FDA approval of ACTOS was based on a review of data from 6 U.S. studies involving more than 4,500 patients with type II diabetes. In each trial, there was a statistically significant reduction in blood glucose levels. Across the approved doses Actos reduced HbA1c compared to placebo by an average of 1.5%. 

ACTOplus Met: At the time of FDA approval, no efficacy studies had been conducted with ACTOplus Metsingle tablets. However, efficacy and safety of the separate components had been previously established. In addition, the co-administration of the separate components was evaluated for efficacy and safety in two clinical studies, demonstrating the bioequivalence with ACTOplus Met.
Study One
This randomized, controlled study enrolled 328 subjects receiving metformin, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. The subjects received either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their established metformin regimen. The addition of pioglitazone 30 mg once daily to metformin treatment significantly reduced the mean A1C by 0.83% and the mean fasting plasma glucose (FPG) by 37.7 mg/dL at Week 16 from that observed with metformin alone.
Study Two
This randomized, controlled study enrolled 827 subjects receiving metformin, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. The subjects received either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their established metformin regimen. The mean reductions from Baseline at Week 24 in A1C were 0.80% and 1.01% for the 30 mg and 45 mg doses, respectively. Mean reductions from Baseline in FPG were 38.2 mg/dL and 50.7 mg/dL, respectively. Based on these reductions in A1C and FPG, the addition of pioglitazone to metformin resulted in significant improvements in glycemic control irrespective of the metformin dose.