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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:

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