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Targeting Insulin Resistance: The Ongoing Paradigm Shift in Diabetes Prevention
Tara Dall, MD; Dawn Thiselton, PhD; and Stephen Varvel, PhD
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Kim Farina, PhD
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Targeting Insulin Resistance: The Ongoing Paradigm Shift in Diabetes Prevention

Tara Dall, MD; Dawn Thiselton, PhD; and Stephen Varvel, PhD
To date, there are no medications with US Food and Drug Administration indication for use in prediabetes. There are, however, clinical trials showing safety and benefit of several classes of antidiabetic therapies in the setting of prediabetes and insulin resistance. Metformin has long been the frontline medical  treatment for diabetes, and has been shown repeatedly to slow or prevent progression to diabetes in prediabetics by enhancing insulin sensitivity. 36,37  Quick-release bromocriptine, a newly approved antidiabetic therapy with unique mechanism of action (a dopamine agonist), may also be effec tive in the  setting of insulin resistance and prediabetes, as it helps correct the dyslipidemia, postprandial hyperglycemia, elevated free fatty acids, and effects due to increase in sympathetic tone.38,39 Thiazolidinediones (TZDs) have proved to be very effective insulin sensitizers, and several large trials have shown reductions in progression from prediabetes to diabetes of 62% to 72%.40,41 Further, GLP-1 agonists, DPP-4 inhibitors, or quick-release bromocriptine may be indicated when signs of beta cell stain are present.42,43 Importantly, these medications can be safely used in prediabetes, as they do not cause hypoglycemia. While more randomized clinical trial data are needed before guidelines can be established, physicians are already using biomarker profiles  to guide treatment approaches and are experiencing impressive success not only in preventing progression to diabetes but in actually reversing the  underlying pathology. For example, a recent report described an approach that assigned patients in clinical practice to treatment with either metformin + pioglitazone or metformin + pioglitazone + exenatide based on indices of underlying insulin resistance and beta cell function. This approach sucdiabetes cessfully reverted more than 50% of prediabetics back to normal glycemic status.44

Return on Investment

Not only does a focus on detection and therapeutic correction of insulin resistance hold the promise of reducing diabetes incidence and the devastating

impact this has on people’s lives, but it could also have a huge impact on efforts to reduce overall health expenditures. A recent analysis of the potential for  cost savings estimates that reducing diabetes and hypertension prevalence by just 5% would result in annual savings of approximately $9 billion in the short  term and up to $25 billion in the medium term.45 The ADA recommends that such diabetes prevention programs be covered by third-party payers due to the  potential cost savings. 46

The largest diabetes prevention trial in the United States, the DPP, has shown that intensive lifestyle interventions or metformin treatment were cost-effective or cost saving during the 3-year intervention47 and after 10 years of follow-up.48 Further, economic modeling has suggested that when glycemic control is not achieved solely with lifestyle or metformin monotherapy, combination with a TZD is also costeffective. 49,50 Cost analysis of  individual A1C cutoffs suggests that the high-cost interventions used in the DPP should be cost-effective down to the current lower limit of prediabetes (A1C =  5.7%), and that intervening at even lower A1C values could also be cost-effective if the cost of the intervention were lowered.51 By diagnosing the early signs of insulin resistance, those who are not yet technically prediabetic but would still benefit from intervention (ie, are most likely to progress to diabetes)  can be identified and treated appropriately. As our interventions become more efficient and effective, the large population of high-risk patients currently being missed can be identified and treated cost-effectively.


In order to achieve a better return on prevention efforts, 3 things must happen. First, patient screening must improve in order to better identify those at risk.  Key to this is recognizing that the target is insulin resistance. Second, interventions must be more effective at not only slowing disease progression but in  reversing disease itself—restoring normal insulin sensitivity and protecting against beta cell death. This will be achieved in part by recognizing that diabetes  is a multifaceted disease and interventions should be tailored to the individual based on their particular underlying pathophysiology. Finally, only when a  full cardiometabolic risk profile is evaluated on an individual basis can the most effective and efficient steps be taken to prevent diabetes and cardiovascular disease and promote future health in the population at large. EBDM

Author Affiliation: From Advanced Lipidology (TD), Delafield, WI; Health Diagnostic Laboratory (HDL), Inc (DT, SV), Richmond, VA.

Funding Source: None.

Author Disclosures: Dr Dall reports employment with HDL, Inc, and has received invitations from a commercial sponsor, Santaris, to lecture. Drs Thiselton and Varvel report employment with Health Diagnostic Laboratory, Inc, which performs diagnostic testing of diabetes risk factors.

Authorship Information: Concept and design (DT, SV); acquisition of data (TD); analysis and interpretation of data (TD); drafting of the manuscript (TD, DT, SV); critical revision of the manuscript for important intellectual content (TD, DT, SV); provision of study materials or patients (TD); and administrative, technical, or  logistic support (DT).

Address correspondence to: Stephen Varvel, PhD, Director of Clinical Trials, Health Diagnostic Laboratory, Inc, 737 N 5th St, Ste 103, Richmond, VA 23219. Email:

1. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics – 2013 update. Circulation. 2013;127(1):143-152.

2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association [published  correction appears in Circulation. 2012;125(22):e1022]. Circulation. 2012;125:e2-e220.

3. Gregg EW, Cheng YJ, Saydah S, et al. Trends in death rates among US adults with and without diabetes between 1997 and 2006. Diabetes Care. 2012;35(6):1252-1257.

4. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med. 1993; 329(14):977-986.

5. UK Prospective Diabetes Study (UKPDS)Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and  risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998;352(9131):837-853.

6. Groop PH, Forsblom C, Thomas MC. Mechanisms of disease: pathway-selective insulin resistance and microvascular complications of diabetes.Nat Clin Prac Endo Metab. 2005;1(2):100-110.

7. Mottillo S, Filion KB, Genest J, et al. The metabolicsyndrome and cardiovascular risk. J Am Coll Cardiol. 2010;56(14):1113-1132.

8. DeFronzo RA, Abdul-Ghani MA. Preservation of β-cell function: the key to diabetes prevention. J Clin Endocrinol Metab. 2011;96(8):2354-2366.

9. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363(14):1341-1350.

10. Davis GL, Roberts WL. The healthcare burden imposed by liver disease in aging Baby Boomers. Curr Gastroenterol Rep. 2010;12(1):1-6.

11. American Diabetes Association. The economic costs of diabetes in the US in 2007. Diabetes Care. 2008;31(3):596-615.

12. UnitedHealth Group’s Center for Health Reform & Modernization. The United States of diabetes: challenges and opportunities in the decade ahead.

13. Boudreau DM, Malone DC, Raebel MA, et al. Health care utilization and costs by metabolic syndrome risk factors. Metab Syndr Relat Disord.2009;7(4):305-314.

14. Baumeister SE, Völzke H, Marschall P, et al. Impact of fatty liver disease on health care utilization and costs in a general population: a 5 year observation. Gastroenterology. 2008;134(1):85-94.

15. DeFronzo R, Muhammad A. Type 2 diabetes can be prevented with early pharmacological intervention. Diabetes Care. 2011;34(2):S202-S209.

16. Nathan D, Davidson M, DeFronzo R, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007;30(3):753-759.

17. Buijsse B, Simmons RK, Griffin SJ, Schulze MB. Risk assessment tools for identifying individuals at risk of developing type 2 diabetes. Epidemiol Rev. 2011;33(1):46-62.

18. Frazier-Wood AC, Garvey WT, Dall T, Honigberg R, Pourfarzib R. Opportunities for using lipoprotein subclass profile by nuclear magnetic resonance spectroscopy in assessing insulin resistance and diabetes prediction. Metab Syndr Relat Disord. 2012;10(4):244-251.

19. Garvey WT, Kwon S, Zheng D, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic imaging. Diabetes. 2003;52(7):453-462.

20. Festa A, Williams K, Hanley AJ, et al. Nuclear magnetic resonance lipoprotein abnormalities in prediabetic subjects in the Insulin Resistance  Atherosclerosis study. Circulation.2005;111(25):3465-3472.

21. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev. 1998;14(4):263-283.

22. Boden G. Obesity and free fatty acids (FFA). Endocrin Metab Clin North Am. 2008;37(3):635- 643.

23. Turer AT, Scherer PE. Adiponectin: mechanistic insights and clinical interpretations. Diabetologia. 2012;55(9):2319-2326.

24. Konner AC, Bruning JD. Selective insulin and leptin resistance in metabolic disorders. Cell Metab. 2012;16(2):144-152.

25. Gall WE, Beebe K, Lawton KA, et al. Alphahydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS One. 2010;5(5):e10883.

26. Ferrannini E, Natali A, Camastra S, et al. Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance [published online November 16, 2012]. Diabetes.

27. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetologia. 2012;55(6):1577-1596.

28. Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes
with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.

29. Tuomilehto J, Lindström J, Eriksson JG, et al;Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.N Engl J Med. 2001;344(18):1343-1350.

30. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20(4):537-544.

31. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006;49(2):289-297.

32. Kosaka K, Noda M, Kuzuya T. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract. 2005;67(2):152-162.

33. Yamaoka K, Tango T. Effects of lifestyle modification on metabolic syndrome: a systematic review and meta-analysis. BMC Med. 2012;10:138.

34. Caporaso N, Morisco F, Camera S, Graziani G, Donnarumma L, Ritieni A. Dietary approach in the prevention and treatment of NAFLD. Front Biosci. 2012;17:2259-2268.

35. Davis GL, Roberts WL. The healthcare burden imposed by liver disease in aging Baby Boomers. Curr Gastroenterol Rep. 2010;12(1):1-6.

36. Bergman M. Pathophysiology of prediabetes and treatment implications for the prevention of type 2 diabetes mellitus [published online November 2012]. Endocrine.

37. Bosi E. Metformin – the gold standard in type 2 diabetes: what does the evidence tell us? Diabetes Obesity Metab. 2009;11(s2):3-8. 38. Mikhail N. Quick- release bromocriptine for treatment of type 2 diabetes. Curr Drug Deliv. 2011;8(5):511-516.

39. Vinik AI, Cincotta AH, Scranton RE, Bohannon N, Ezroki M, Gaziano JM. Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled  hyperglycemia on one or two oral anti-diabetes agents. Endocr Pract. 2012;18(6):931-943.

40. Gerstein HC, Yusuf S, Bosch J, et al; DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of  rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet. 2006;368(9549):1096-1105.

41. DeFronzo RA, Tripathy D, Schwenke DC, et al. ioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364(12):1104-1115.

42. Aroda VR, Henry RR, Han J, et al. Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther. 2012;34(6):1247-1258.

43. Meloni AR, DeYoung MB, Lowe C, Parkes DG. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obesity Metab. 2013;15(1):15-27.

44. Armato J, DeFronzo RA, Abdul-Ghani M, Ruby R. Successful treatment of prediabetes in clinical practice: targeting insulin resistance and β-cell dysfunction. Endocr Pract. 2012;18(3):342-350.

45. Ormond BA, Spillman BC, Waidmann TA, Caswell KJ, Tereschchenko B. Potential national and state medical care savings from primary disease prevention. Am J Public Health. 2011;101(1):157-164.

46. American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care. 2011;34(suppl 1):s11-s61.

47. Herman WH, Hoerger TJ, Brandle M, et al. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med. 2005;142(5):323-332.

48. Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention. Diabetes Care. 2012;35(4):723-730.

49. Shearer AT, Bagust A, Liebl A, Schoeffski O, Goertz A. Cost-effectiveness of rosiglitazone oral combination for the treatment of type 2 diabetes in Germany. Pharmacoeconomics. 2006;24(s1):35-48.

50. Beale S, Bagust A, Shearer AT, Martin A, Hulme L. Cost-effectiveness of rosiglitazone combination therapy for the treatment of type 2 diabetes mellitus  in the UK. Pharmacoeconomics.24(s1):21-34.

51. Zhuo X, Zhang P, Selvin E, et al. Alternative HbA1c cutoffs to identify high-risk adults for diabetes prevention. Am J Prev Med 2012;42(4):374-81.
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