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Metformin Prescription for Insured Adults With Prediabetes From 2010 to 2012: A Retrospective Cohort StudyMetformin Prescription for Insured Adults With Prediabetes

Tannaz Moin, MD, MBA, MSHS; Jinnan Li, MPH; O. Kenrik Duru, MD, MSHS; Susan Ettner, PhD; Norman Turk, MS; Abigail Keckhafer, MBA, MPH; Sam Ho, MD; and Carol M. Mangione, MD, MSPH
[+] Article, Author, and Disclosure Information

From Veterans Affairs Greater Los Angeles Health System; Veterans Affairs Health Services Research and Development Service; and University of California, Los Angeles, Los Angeles, California, and UnitedHealthcare, Minneapolis, Minnesota.

Disclaimer: The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC) or the National Institutes of Health (NIH). Drs. Moin and Mangione had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: The authors thank Mr. Robert Luchs and Mr. Charlie Chan for their help with obtaining the data used in this analysis, Ms. Lindsay Kimbro for her administrative and project management support, and all NEXT-D (Natural Experiments for the Translation of Diabetes) collaborators for their support.

Grant Support: This study was jointly funded by the CDC (Division of Diabetes Translation) and the National Institute of Diabetes and Digestive and Kidney Diseases as part of the NEXT-D study (grant U58DP002722-05). Dr. Moin received support from the Veterans Affairs (VA) Office of Academic Affiliations through the VA Health Services Research and Development Advanced Fellowship Program (TPM65-010) of the VA Greater Los Angeles Health System from 2011 to 2014. Dr. Mangione received support from the University of California, Los Angeles (UCLA)/Drew Center for Health Improvement of Minority Elderly (under NIH/National Institute on Aging grant P30-AG021684) and the NIH/National Center for Advancing Translational Sciences and UCLA Clinical and Translational Science Institute (grant UL1TR000124). Dr. Mangione holds the Barbara A. Levey and Gerald S. Levey Endowed Chair in Medicine, which partially supported her work. Dr. Duru is supported in part by the UCLA/Drew Center for Health Improvement of Minority Elderly (under NIH/National Institute on Aging grant P30-AG021684) and an NIH career development award (K08-AG033360).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1773.

Reproducible Research Statement:Study protocol: A version with redacted confidential information is available to approved persons through written agreement with the authors (e-mail, tmoin@mednet.ucla.edu). Statistical code: Available through written agreement with the authors (e-mail, tmoin@mednet.ucla.edu). Data set: Not available due to confidentiality agreements between the academic and health plan partners.

Requests for Single Reprints: Tannaz Moin, MD, MBA, MSHS, David Geffen School of Medicine at University of California, Los Angeles, Division of General Internal Medicine and Health Services Research, 911 Broxton Avenue, Los Angeles, CA 90024; e-mail, tmoin@mednet.ucla.edu.

Current Author Addresses: Dr. Moin: David Geffen School of Medicine at University of California, Los Angeles, Division of General Internal Medicine and Health Services Research, 911 Broxton Avenue, Los Angeles, CA 90024.

Drs. Duru and Mangione, Ms. Li, and Mr. Turk: David Geffen School of Medicine at University of California, Los Angeles, 10940 Wilshire Boulevard, Suite 700, Los Angeles, CA 90095.

Dr. Ettner: David Geffen School of Medicine at University of California, Los Angeles, Division of General Internal Medicine and Health Services Research, 911 Broxton Plaza, Room 106, Box 951736, Los Angeles, CA 90095.

Ms. Keckhafer: UnitedHealthcare, PO Box 1459, Minneapolis, MN 55440.

Dr. Ho: UnitedHealthcare, 5995 Plaza Drive, Cypress, CA 90630.

Author Contributions: Conception and design: T. Moin, S. Ettner, S. Ho, C.M. Mangione.

Analysis and interpretation of the data: T. Moin, J. Li, O.K. Duru, S. Ettner, N. Turk, A. Keckhafer, S. Ho, C.M. Mangione.

Drafting of the article: T. Moin.

Critical revision of the article for important intellectual content: T. Moin, J. Li, O.K. Duru, S. Ettner, A. Keckhafer, S. Ho, C.M. Mangione.

Final approval of the article: T. Moin, O.K. Duru, S. Ettner, A. Keckhafer, C.M. Mangione.

Provision of study materials or patients: T. Moin, A. Keckhafer, S. Ho.

Statistical expertise: S. Ettner, N. Turk.

Obtaining of funding: O.K. Duru, S. Ettner, C.M. Mangione.

Administrative, technical, or logistic support: S. Ho, C.M. Mangione.

Collection and assembly of data: J. Li, N. Turk, A. Keckhafer, S. Ho.


Ann Intern Med. 2015;162(8):542-548. doi:10.7326/M14-1773
Text Size: A A A

Background: Prediabetes affects 1 in 3 Americans. Both intensive lifestyle intervention and metformin can prevent or delay progression to diabetes. Over the past decade, lifestyle interventions have been translated across various settings, but little is known about the translation of evidence surrounding metformin use.

Objective: To examine metformin prescription for diabetes prevention and patient characteristics that may affect metformin prescription.

Design: Retrospective cohort analysis over a 3-year period.

Setting: Employer groups that purchased health plans from the nation's largest private insurer.

Participants: A national sample of 17 352 working-age adults with prediabetes insured for 3 continuous years between 2010 and 2012.

Measurements: Percentage of health plan enrollees with prediabetes who were prescribed metformin.

Results: Only 3.7% of patients with prediabetes were prescribed metformin over the 3-year study window. After adjustment for age, income, and education, the predicted probability of metformin prescription was almost 2 times higher among women and obese patients and more than 1.5 times higher among patients with 2 or more comorbid conditions.

Limitation: Missing data on lifestyle interventions, possible misclassification of prediabetes and metformin use, and inability to define eligible patients exactly as defined in the American Diabetes Association guidelines.

Conclusion: Evidence shows that metformin is rarely prescribed for diabetes prevention in working-age adults. Future studies are needed to understand potential barriers to wider adoption of this safe, tolerable, evidence-based, and cost-effective prediabetes therapy.

Primary Funding Source: Centers for Disease Control and Prevention (Division of Diabetes Translation) and the National Institute of Diabetes and Digestive and Kidney Diseases.

Figures

Grahic Jump Location
Figure.

Study flow diagram.

The study window was 3 y (2010 to 2012). Prediabetes was defined as any of the following: ≥2 ICD-9 diagnostic codes of 790.2x from an inpatient or outpatient claim, last hemoglobin A1c level of 5.7% to 6.4%, last fasting plasma glucose level of 5.55 to 6.94 mmol/L (100 to 125 mg/dL), or last 2-h plasma glucose level of 7.77 to 11.04 mmol/L (140 to 199 mg/dL) on an oral glucose tolerance test. Pregnancy was defined as ≥1 pregnancies during the study. Elevated creatinine level was defined as ≥132.6 µmol/L (≥1.5 mg/dL) for men and ≥123.8 µmol/L (≥1.4 mg/dL) for women. ICD-9 = International Classification of Diseases, Ninth Revision; PCOS = the polycystic ovary syndrome.

Grahic Jump Location

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Is Metformin the real solution for Diabetes Prevention?
Posted on April 27, 2015
Rene Rodriguez-Gutierrez M.D.1 Victor M. Montori M.D.1*
1 Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Conflict of Interest: None Declared
Moin et al. show that the use of metformin in patients with prediabetes is infrequent (3.7%), they suggest this rate should be higher, and call for more research on how to get there . Although rigorous, we think this paper promotes a notion that is highly problematic: that patients with prediabetes benefit from metformin.

The case for metformin use for diabetes prevention is based on the results of the Diabetes Prevention Program (DPP) that found metformin effective in delaying the diagnosis of diabetes (1) and on metformin’s track record of safety. Moin et al. assume, along with some endocrine guidelines, that delaying the diagnosis of diabetes with an antihyperglycemic agent offers net benefit to at-risk patients. Yet, several studies have failed to demonstrate that metformin prevents diabetes, i.e., its use interrupts the pathophysiologic path to type 2 diabetes (2,3). The main mechanism responsible for delaying the diagnosis of diabetes, therefore, results from metformin’s glycemia lowering effect. This amounts to treating prediabetes as diabetes. Thus, the diagnosis of diabetes is delayed, but not its treatment. And there is no evidence, to our knowledge, that premature treatment leads to better outcomes that patients experience. Indeed, one could imagine patients in whom the diagnosis of diabetes was delayed being worse off: consider the de-emphasis on lifestyle changes now that a pill takes care of the problem, or how the implementation of protocols linked to the diabetes diagnosis – e.g., consideration of statin use, foot and eye examination – may be delayed along with the diagnosis of diabetes.


We believe in the importance of turning the tide of the diabetes worldwide tsunami. Ecological and social interventions that make it easier to be active at home, at work, and in the community, that facilitate access to healthy food, and that reduce the allostatic load – the stress of living in poverty, in violence, and in isolation (4), may reflect a level of response commensurate with the huge magnitude of the problem (5). These interventions reflect a different assumption: that a problem of this scale cannot result from an epidemic of bad individual lifestyle choices. Emphasis on clinical interventions in doctor’s offices – labeling healthy people as having prediabetes and treating them as if they have diabetes with individual counseling and diabetes drugs – does not match the nature or magnitude of the problem, and removes pressure from societies to adequately address the root causes, social and ecological, of this epidemic.

References


1. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, 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 Feb 7;346(6):393-403.

2. Yudkin JS, Montori VM. The epidemic of pre-diabetes: the medicine and the politics. BMJ. 2014 Jul 15;349:g4485.

3. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677-86.

4. Steptoe A, Hackett RA, Lazzarino AI, Bostock S, La Marca R, Carvalho LA et al. Disruption of multisystem responses to stress in type 2 diabetes: investigating the dynamics of allostatic load. Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15693-8.

5. Ludwig J, Sanbonmatsu L, Gennetian L, Adam E, Duncan GJ, Katz LF, Kessler RC, Kling JR, Lindau ST, Whitaker RC, McDade TW. Neighborhoods, obesity, and diabetes--a randomized social experiment. N Engl J Med. 2011 Oct 20;365(16):1509-19.
Author's Response
Posted on June 23, 2015
Tannaz Moin, MD, MBA, MSHS, O. Kenrik Duru, MD, MSHS, Carol M. Mangione, MD MSPH
VA Greater Los Angeles Health System, David Geffen School of Medicine, UCLA
Conflict of Interest: None Declared
We appreciate the comments by Drs. Rodrigues-Gutierrez and Montori. However, we respectfully disagree with key points in their response, specifically 1) that patients with prediabetes do not benefit from metformin and 2) that a focus on “in-office” clinical approaches distracts from needed societal interventions to address the problem at a larger scale.

The process by which diabetes develops is more complicated than a simple “on/off” switch at a particular glycemic threshold. There is a clear continuum of risk from normal glycemia to prediabetes to diabetes(1). Across this continuum, it is critical that providers and patients are aware of all available evidence-based approaches shown to lower the risk of progression. In the Diabetes Prevention Program (DPP), most of the metformin effect persisted after a 2-week “washout” period, resulting in a 25% reduction in diabetes risk even among patients no longer taking the medication.(2) Metformin was also associated with a small, but durable amount of weight loss. We have yet to fully understand all the molecular actions of metformin (3) but studies have also shown us this medication is safe, tolerable and marginally cost-saving for diabetes prevention.(4, 5) In fact, if the DPP and DPPOS outcome of incident diabetes had also included HbA1c>6.5%, metformin and lifestyle would have been similarly effective.(6) We believe the published evidence strongly supports that metformin is effective in preventing or delaying diabetes.

While we agree that worldwide action to create healthier societies is an ideal goal, we also believe that withholding information from patients about an evidence-based option to prevent diabetes is not only counterproductive but also unethical and could lead to loss of trust. When presented with clear information about both their level of risk and options for diabetes prevention, patients are more than capable of working with their providers to make the best treatment decision. This could include both lifestyle and metformin since these therapies are not necessarily competing. While there remain diagnostic challenges for prediabetes, the sheer number of individuals affected makes this an important public health issue necessitating multifaceted interventions. This is our call to action and our time to act if we are going to make any progress in curbing the ever-expanding prediabetes and diabetes epidemics worldwide. While we wait for societies to address the root causes of these epidemics, we should not be paralyzed. We believe the key to progress is doing what we can now, one patient-at-a-time.


References:
1. Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012;379(9833):2279-90.
2. Diabetes Prevention Program Research G. Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care. 2003;26(4):977-80.
3. Hostalek U, Gwilt M, Hildemann S. Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention. Drugs. 2015.
4. Diabetes Prevention Program Research G. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35(4):731-7.
5. Diabetes Prevention Program Research G. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care. 2012;35(4):723-30.
6. Diabetes Prevention Program Research G. HbA1c as a predictor of diabetes and as an outcome in the diabetes prevention program: a randomized clinical trial. Diabetes Care. 2015;38(1):51-8.


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