Understanding the differences in TZDs

Each PPAR agent, including TZDs, has a distinct molecular fingerprint

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  • PPARs modify gene expression.[1-3]
  • PPAR(peroxisome proliferator-activated receptor gamma) is a regulator in:[1-3]
    • Glucose metabolism.
    • Lipid metabolism.
    • Inflammation.
  • PPAR agents modify gene expression differently.[4,5]

ACTOS and Avandia regulate different genes[6]

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  • The effects of specific gene regulation on clinical outcomes have not been determined.
  • Not all genes regulated by PPAR agents result in clinically significant effects.

*Results from an in vitro study analyzing gene expression of TZDs with microarrays and VAMPIRE (Variance-Modeled Posterior Inference with Regional Exponentials) in 3T3-L1 murine adipocytes.

View an in-depth animation that illustrates how the different molecular fingerprints of PPAR agents result in clinical differences.

These unique fingerprints may result in clinical differences[2,7,8]

Greater improvements in both triglycerides and HDL-C vs metformin alone†[8,9]

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†Results from a 104-week, double-blind, randomized, double-dummy, multicenter, parallel-group study using ACTOS 15, 30, or 45 mg QD plus metformin. Mean change at endpoint statistically significant vs baseline at P<0.0001. Baseline LDL-C: 129.0 mg/dL, total cholesterol: 217.8 mg/dL, n=310.

  • Improved Total-C/HDL-C ratio.[8]
  • In this study, increases of 2% in LDL-C and 1% in Total-C were seen with ACTOS vs baseline.[8]

“The TZDs either have a beneficial or neutral effect on atherogenic lipid profiles, with pioglitazone having a more beneficial effect than rosiglitazone.”[10]

— The American Diabetes Association and the European Association for the Study of Diabetes

Convert to ACTOplus met for additional lipid improvements

In patients who were on a stable statin therapy, switching from rosiglitazone plus metformin to ACTOS plus metformin improved key lipid parameters.[8]

  • Prior to conversion, patients with type 2 diabetes and dyslipidemia were taking:[8]
    • Rosiglitazone ≥90 days.
    • Metformin.
    • A stable dose of a statin.‡
  • After conversion, patients were taking:[8]
    • ACTOS.
    • Metformin.
    • A stable dose of a statin.‡

All lipid changes were independent of glycemic control, which remained stable after treatment conversion from rosiglitazone to ACTOS.[8]

Key lipid parameters improved after conversion to ACTOS plus metformin[8]

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  • No change in LDL-C from baseline.

‡Concomitant use of a statin included: atorvastatin (51%), simvastatin (30%), pravastatin (8%), fluvastatin (5%), lovastatin (4%), or rosuvastatin (3%). 305 subjects were enrolled to receive ACTOS in combination with a stable statin therapy (276 completed; 90.5%). Patients taking antidiabetic therapy during the pre-study period were on metformin (49.7%), sulfonylureas (34.7%), and/or insulin (31.5%). 13% of all patients were on a stable dose of an additional lipid-lowering agent. Rosiglitazone dosing at the beginning of the screening period: 38.8% of patients were on 4 mg and 54.4% were on 8 mg (total daily dose). 47% of patients were titrated to 45 mg during the treatment period.

§Results from a subanalysis of a 17-week, open-label, single-arm, multicenter study of patients with type 2 diabetes and dyslipidemia. Baseline triglycerides: 314.7 mg/dL, HDL-C: 42.6 mg/dL, total cholesterol: 198.8 mg/dL, n=183.

Statin therapy remained stable after conversion.[8]

While ACTOS may confer some lipid benefits, ACTOS is not indicated to treat lipid disorders and should not be used as a substitute for lipid-lowering therapy.

The effects of these lipid changes on morbidity and mortality have not been determined.

Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.

Please see Important Safety Information, including boxed warnings for ACTOplus met, below.

References:
1. ACTOS package insert, Takeda Pharmaceuticals America, Inc.
2. Avandia® (rosiglitazone maleate) package insert, GlaxoSmithKline.
3. Staels B, Fruchart J-C. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes. 2005;54:2460-2470.
4. Camp HS, Li O, Wise SC, et al. Differential activation of peroxisome proliferator-activated receptor- by troglitazone and rosiglitazone. Diabetes. 2000;49:539-547.
5. Tian Q, Stepaniants SB, Mao M, et al. Integrated genomic and proteomic analyses of gene expression in mammalian cells. Mol Cell Proteomics. 2004;3:960-969.
6. Hsiao A, Worrall DS, Olefsky JM, Subramaniam S. Variance-modeled posterior inference of microarray data: detecting gene-expression changes in 3T3-L1 adipocytes. Bioinformatics. 2004;20:3108-3127.
7. ACTOplus met package insert, Takeda Pharmaceuticals America, Inc.
8. Data on file, Takeda Pharmaceuticals North America, Inc.
9. Charbonnel B, Schernthaner G, Brunetti P, et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia. 2005;48:1093-1104.
10. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29:1963-1972.

Avandia® is a registered trademark of GlaxoSmithKline.

Boxed Warning: Congestive Heart Failure

• Thiazolidinediones (TZDs), including pioglitazone, a component of ACTOplus met, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOplus met and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of ACTOplus met must be considered.[1]
• ACTOplus met is not recommended in patients with symptomatic heart failure. Initiation of ACTOplus met in patients with established NYHA Class III or IV heart failure is contraindicated.[1]

Boxed Warning: Lactic Acidosis

Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during therapy with ACTOplus met.[1] • The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1000 patient-years), but may be fatal in approximately half these instances. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking ACTOplus met and by use of the minimum effective dose of ACTOplus met. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. ACTOplus met should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, ACTOplus met should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.[1] • Patients should be cautioned against excessive alcohol intake when taking ACTOplus met. In addition, ACTOplus met should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.[1] • The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Patients should be made aware of the possible importance of such symptoms and instructed to notify their health professional immediately if they occur.[1]

Contraindications
1. Renal disease or renal dysfunction (serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females]). 2. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. 3. Initiation of ACTOplus met in patients with established NYHA Class III or IV heart failure is contraindicated.[1]

ACTOplus met should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.[1]

Cardiac considerations
Like other TZDs, ACTOplus met can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. ACTOplus met should be used with caution in patients at risk for heart failure. Patients should be monitored for symptoms of heart failure or other adverse events related to fluid retention. In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop CHF when treated with pioglitazone in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease.[1]

Hepatic safety
Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in postmarketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established. Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOplus met, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with ACTOplus met.[1]

Other considerations
ACTOplus met may also be associated with hypoglycemia, edema, anemia, weight gain, and/or ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women. Macular edema has been reported in some diabetic patients receiving TZD therapy, although a causal relationship is unknown. Persons with diabetes should have routine eye exams and be instructed to immediately report any visual changes to their healthcare provider. An increased incidence of bone fracture was noted in female patients taking pioglitazone. The risk of fracture should be considered in the care of patients treated with ACTOplus met, particularly females, and attention should be given to assessing and maintaining bone health according to current standards of care.[1]

Well-tolerated therapy
In clinical trials using pioglitazone in combination with metformin, the most common adverse events (≥5%) were upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight.[1]

Indications and usage
ACTOplus met is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and metformin, or whose diabetes is not adequately controlled with metformin alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.[1]

ACTOplus met should not be used in patients with type 1 diabetes. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed and exercise.[1]

The major metabolic defects in type 2 diabetes are peripheral insulin resistance in muscle and fat, decreased pancreatic insulin secretion, and increased hepatic glucose output.[2] Dyslipidemia in insulin resistance is represented by hypertriglyceridemia, decreased HDL levels, and increased small dense LDL particles.[3] Renal and gastrointestinal function are also clinical considerations when prescribing an oral agent for type 2 diabetes.[4]

References:
1. ACTOplus met package insert, Takeda Pharmaceuticals America, Inc. 2. Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674-682. 3. American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care. 2004;27(suppl 1):S68-S71. 4. American Diabetes Association. Standards of medical care in diabetes–2007. Diabetes Care. 2007;30(suppl 1):S4-S41.
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