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For Healthcare Professionals
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Targeting 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 main defects of type 2 diabetes that should be addressed.[1,2]
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- 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 risk factors may be a sign of a deeper problem[17-19]
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- 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—a component of duetact—targets three defects of type 2 diabetes[4]
- 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]
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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.[29]
- 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.[30,31]
The UKPDS found traditional therapies failed to maintain A1C levels over time[32]
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Patients on metformin who failed to achieve the ADA A1C goal of <7.0%[32]
- 56% after 3 years.
- 66% after 6 years.
- 87% after 9 years.
Adding ACTOS to metformin resulted in reductions in insulin resistance†[33]
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†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.
Duetact targets the defects to sustain A1C reductions
Duetact achieves significantly greater A1C reductions than a sulfonylurea alone.[3,4]
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- ACTOS 30 mg added to sulfonylurea (24 weeks).
§Results from a 24-week, double-blind, randomized, multicenter study. Baseline A1C for 30 mg QD: 9.8%, n=351.
Duetact durability: A1C reductions were sustained out to 2 years.[8]
Duetact targets insulin resistance and beta-cell function
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||Results from a 16-week, double-blind, randomized, multicenter, placebo-controlled study, n=521. Insulin resistance (IR) and beta-cell function (BCF) based on Homeostasis Model Assessment (HOMA) calculations. 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).
ACTOS—a component of duetact—provides significant and durable A1C reductions¶[3,4,7]
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¶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%.
Duetact durability: A1C reductions were sustained out to
2 years.[8]
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Physicians were encouraged to treat patients with standard of care according to IDF guidelines with metformin, sulfonylurea, or insulin.[3,35]
- In addition to lowering A1C levels, ACTOS reduced the need for insulin.[35]
- 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.[3,35]
- 47% of study participants had a previous MI, and 19% had a previous stroke.[35]
#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. Duetact 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. 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.
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 α-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. ACTOS package insert, Takeda Pharmaceuticals America, Inc.
27. American Diabetes Association website. Other diabetes medications. Available at:
http://www.diabetes.org/type-2-diabetes/oral-medications.jsp. Accessed August 29, 2007.
28. Januvia website. How Januvia works. Available at: http://www.januvia.com/sitagliptin_phosphate/
januvia/consumer/about/about_how.jsp. Accessed August 29, 2007.
29. Martens FMAC, Visseren FLJ, Lemay J, de Koning EJP, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs. 2002;62:1463-1480.
30. 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.
31. Reasner CA. Where thiazolidinediones will fit. Diabetes Metab Res Rev. 2002;18(suppl 2):S30-S35.
32. 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.
33. 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.
34. Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med. 2001;111:10-17.
35. 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.
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Boxed Warning: Congestive Heart Failure
• Thiazolidinediones (TZDs), including pioglitazone, which is a component of duetact, cause or exacerbate congestive heart failure in some patients. After initiation of duetact, 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 of duetact must be considered.[1]
• Duetact is not recommended in patients with symptomatic heart failure. Initiation of duetact in patients with established NYHA Class III or IV heart failure is contraindicated.[1] Contraindication
Diabetic ketoacidosis (DKA), with or without coma. DKA should be treated with insulin.[1] Cardiac considerations
Like other TZDs, duetact can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. Duetact 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] • The UGDP trial found that tolbutamide, a sulfonylurea, was associated with an increased risk of cardiovascular mortality. Glimepiride was not studied in this trial; however, it is prudent to consider that this warning may apply to all sulfonylureas.[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 duetact, 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 duetact.[1] Other considerations
Duetact may also be associated with 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. As with all sulfonylureas, severe hypoglycemia may occur. Elderly, debilitated, or malnourished patients, or patients with adrenal, pituitary, renal, or hepatic insufficiency, may be more sensitive to the glucose-lowering effect of sulfonylureas and should be started on the lowest dose of duetact. 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 duetact, 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 a sulfonylurea, the most common adverse events (≥5%) were hypoglycemia, upper respiratory tract infection, weight increase, headache, diarrhea, edema, urinary tract infection, pain in limb, and nausea.[1] Indications and usage
Duetact is indicated with diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.[1] • Duetact 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. Duetact 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. |
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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 North America, Inc.
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