For Healthcare Professionals

Therapies should target both insulin resistance and beta-cell dysfunction

Type 2 diabetes is a result of chronic insulin resistance and beta-cell failure[2,10-14]

Insulin resistance and beta-cell dysfunction are core defects of type 2 diabetes that should be addressed.[1,2]

Click to enlarge

  • Insulin resistance in the periphery results in compensatory actions by the pancreas such as increased pancreatic insulin production and also leads to relative insulin deficiency and increased hepatic glucose output.[15]
  • If left untreated, over time, insulin resistance continues and complications may develop.[16]
  • The presence of insulin resistance is often associated with many abnormalities and can have an impact on lipid and protein metabolism, cardiovascular functions, and gene expression.[12]

“The iceberg effect”: some markers may be a sign of a deeper problem[17-19]

Click to enlarge

  • Over time, increased insulin resistance can lead to insufficient beta-cell function and affect the body's ability to maintain healthy glucose levels.[17]
  • Insulin resistance and loss of beta-cell function may begin as early as 10–12 years prior to diagnosis.[2,20,21]
  • Insulin resistance is present in 92% of patients with type 2 diabetes.[22]

ACTOS targets three defects of type 2 diabetes

  • TZDs sustain glycemic control by decreasing hepatic glucose output, decreasing insulin resistance, and improving beta-cell function, according to HOMA (Homeostasis Model Assessment).[4,23-25]

Click to enlarge

Targeting insulin resistance can have many benefits

  • Therapies that directly reduce insulin resistance can significantly modify several major cardiovascular risk markers, such as hyperglycemia, hyperinsulinemia, and dyslipidemia.[28]
  • Agents that directly reduce insulin resistance can decrease circulating insulin levels and have been associated with improvements in beta-cell function, according to HOMA calculations.[29,30]

The UKPDS found traditional therapies failed to maintain A1C levels over time[31]

Click to enlarge

Patients on metformin who failed to achieve the ADA A1C goal of <7.0%[31]

  • 56% after 3 years.
  • 66% after 6 years.
  • 87% after 9 years.

Adding ACTOS to metformin resulted in reductions in insulin resistance†[32]

Click to enlarge

†Statistically significant at P≤0.05. Results from a 16-week, double-blind, randomized, multicenter, placebo-controlled study (n=328, insulin resistance based on HOMA calculations). HOMA is based on the following calculation: HOMA–IR = (fasting insulin x fasting glucose)/22.5.

‡Statistically significant vs placebo + metformin at P≤0.05.

ACTOS targets insulin resistance and beta-cell function, to help improve glycemic control[3-9]

ACTOS reduces insulin resistance and improves beta-cell function (HOMA)[3-6,9]

Click to enlarge

§Results from a 26-week, double-blind, randomized, multicenter, placebo-controlled study. HOMA is based on the following calculations: HOMA–IR = (fasting insulin x fasting glucose)/22.5; HOMA–BCF = (20 x fasting insulin)/(fasting glucose – 3.5). Values indicate the difference between the changes from baseline of ACTOS and placebo.

ACTOS targets the defects to sustain A1C reductions[8]

ACTOS 45 mg QD vs placebo in drug-naïve patients (P≤0.05)

  • In this study, across all patients, ACTOS 45 mg QD reduced A1C by 1.6 percentage points vs placebo.||[8]
  • In this same study, ACTOS 30 mg QD reduced mean A1C by 1.0 percentage point vs placebo.||[8]

||Results from a 26-week, double-blind, randomized, multicenter, placebo-controlled study. HOMA is based on the following calculations: HOMA–IR = (fasting insulin x fasting glucose)/22.5; HOMA–BCF = (20 x fasting insulin)/(fasting glucose – 3.5). A1C data: patients not previously treated with diabetes medications and not adequately controlled by diet and exercise alone and receiving ACTOS 45 mg QD, n=21, baseline A1C: 10.0%. Across all patients receiving ACTOS 45 mg QD, n=76, baseline A1C: 10.3%. Across all patients receiving ACTOS 30 mg QD, n=85, baseline A1C: 10.2%. (P≤0.05.)

Evidence ACTOS provides sustained A1C reductions¶[3,7]

Click to enlarge

¶Results from a 104-week, double-blind, randomized, double-dummy, multicenter, parallel-group study using ACTOS 30 or 45 mg QD monotherapy. Completer analysis, n=147. Mean change at endpoint statistically significant vs baseline at P<0.0001. Baseline A1C: 8.4%.

ACTOS durability:
A1C reductions were sustained out to 2 years.[3,7]

Click to enlarge

Physicians were encouraged to treat patients with standard of care according to IDF guidelines with metformin, sulfonylurea, or insulin.[3,33]

  • In addition to lowering A1C levels, ACTOS reduced the need for insulin.[33]
    • 21% began permanent insulin use in the placebo arm during this study.
    • 11% began permanent insulin use in the ACTOS arm during this study.
  • During the study, the use of metformin decreased by 3.1% for patients taking ACTOS + standard of care and increased by 1.8% for patients taking standard of care.[3,33]
  • 47% of study participants had a previous MI, and 19% had a previous stroke.[33]

#Results from a randomized, double-blind, placebo-controlled trial in 5,238 patients with type 2 diabetes and evidence of macrovascular disease. Mean duration of follow-up: 34.5 months. Baseline A1C: 8.1%.
**Standard of care is defined as the optimum level of all therapies (particularly lipid-altering, antiplatelet, and antihypertensive therapies), according to the International Diabetes Federation (IDF) European Region 1999 guidelines.

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

Please see Important Safety Information, including boxed warning for congestive heart failure, below.

References:
1. Glaser B, Cerasi E. Early intensive insulin treatment for induction of long-term glycaemic control in type 2 diabetes. Diabetes Obes Metab. 1999;1:67-74.
2. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996;45:1661-1669.
3. Data on file, Takeda Pharmaceuticals North America, Inc.
4. ACTOS package insert, Takeda Pharmaceuticals America, Inc.
5. Miyazaki Y, Matsuda M, DeFronzo RA. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care. 2002;25:517-523.
6. Miyazaki Y, Mahankali A, Matsuda M, et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care. 2001;24:710-719.
7. Tan MH, Baksi A, Krahulec B, et al, for the GLAL Study Group. Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes. Diabetes Care. 2005;28:544-550.
8. Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL, and the Pioglitazone 001 Study Group. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. Diabetes Care. 2000;23:1605-1611.
9. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
10. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic ß-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796-2803.
11. Hsueh WA, Law RE. Cardiovascular risk continuum: implications of insulin resistance and diabetes. Am J Med. 1998;105:4S-14S.
12. American Diabetes Association. Consensus development conference on insulin resistance. Diabetes Care. 1998;21:310-314.
13. National Diabetes Information Clearinghouse (NDIC) website. Diabetes, heart disease, and stroke. Available at: http://diabetes.niddk.nih.gov/dm/pubs/stroke. Accessed February 7, 2007.
14. American Diabetes Association website. Diabetes: heart disease and stroke. Available at: http://www.diabetes.org/diabetes-heart-disease-stroke.jsp. Accessed February 7, 2007.
15. DeFronzo RA. The triumvirate: ß-cell, muscle, liver: a collusion responsible for NIDDM [Lilly Lecture 1987]. Diabetes. 1988;37:667-687.
16. Nesto RW. The relation of insulin resistance syndromes to risk of cardiovascular disease. Rev Cardiovasc Med. 2003;4(suppl 6):S11-S18.
17. Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol. 1999;58:1511-1520.
18. Bailey CJ. Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab. 2005;7:675-691.
19. American Heart Association website. Insulin resistance. Available at: http://www.americanheart.org/presenter.jhtml?identifier=3044761. Accessed March 27, 2007.
20. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care. 1992;15:815-819.
21. Holman RR. Assessing the potential for a-glucosidase inhibitors in prediabetic states. Diabetes Res Clin Pract. 1998;(suppl 40):S21-S25.
22. Haffner SM, D’Agostino R Jr, Mykkänen L, et al. Insulin sensitivity in subjects with type 2 diabetes: relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. Diabetes Care. 1999;22:562-568.
23. Kendall DM. Thiazolidinediones: the case for early use. Diabetes Care. 2006;29:154-157.
24. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med. 2001;134:61-71.
25. Del Prato S, Marchetti P. Targeting insulin resistance and ß-cell dysfunction: the role of thiazolidinediones. Diabetes Technol Ther. 2004;6:719-731.
26. American Diabetes Association website. Other diabetes medications. Available at: http://www.diabetes.org/type-2-diabetes/oral-medications.jsp. Accessed August 29, 2007.
27. Januvia website. How Januvia works. Available at: http://www.januvia.com/sitagliptin_phosphate/januvia/consumer/about/
about_how.jsp. Accessed August 29, 2007.
28. Martens FMAC, Visseren FLJ, Lemay J, de Koning EJP, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs. 2002;62:1463-1480.
29. Wyne KL, Bell DSH, Braunstein S, Drexler AJ, Miller JL, Nuckolls JG. Trends in management of type 2 diabetes: role of thiazolidinediones. Endocrinologist. 2003;13(suppl 1):S1-S21.
30. Reasner CA. Where thiazolidinediones will fit. Diabetes Metab Res Rev. 2002;18(suppl 2):S30-S35. 
31. Turner RC, Cull CA, Frighi V, Holman RR, for the UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281:2005-2012.
32. Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL, for the Pioglitazone 027 Study Group. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. Clin Ther. 2000;22:1395-1409.
33. Dormandy JA, Charbonnel B, Eckland DJA, et al, on behalf of the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.

In brief
Insulin resistance and beta-cell dysfunction are two main defects of type 2 diabetes.[1,2]

ACTOS targets the defects to help improve glycemic control.[3-9]

Boxed Warning: Congestive Heart Failure

• Thiazolidinediones (TZDs), including ACTOS, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOS 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 ACTOS must be considered.[1]
• ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated.[1]

Cardiac considerations
Like other TZDs, ACTOS can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. ACTOS 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 ACTOS 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 ACTOS, 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 ACTOS.[1]

Other considerations
ACTOS 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 ACTOS. The risk of fracture should be considered in the care of patients treated with ACTOS, particularly females, and attention should be given to assessing and maintaining bone health according to current standards of care.[1]

Well-tolerated therapy
In US placebo-controlled ACTOS monotherapy clinical trials, the most common adverse events (≥5%) were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.[1]

Indications and usage
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. ACTOS is approved for use as monotherapy and in combination with sulfonylureas, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control.[1] • ACTOS 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]

Please see Complete Prescribing Information, including boxed warning for congestive heart failure, and Medication Guide.

References:
1. ACTOS 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–2008. Diabetes Care. 2008;31(suppl 1):S12-S54.
Privacy Policy Terms and Conditions of Use Site Map
Copyright ©1999, 2009 Takeda Pharmaceuticals North America, Inc.
This site is intended for use by U.S. residents only.
ACTOS®, ACTOplus met®, and duetact® are registered trademarks of Takeda Pharmaceutical Company Limited
and are used under license by Takeda Pharmaceuticals America, Inc.