Prediabetes and diabetes prevention: Are we doing enough? What could we be doing differently?

Time and time again, as I work with prediabetes patients in clinic, I see many individuals come in feeling defeated.  At our last visit, my patient was really ready to “get serious” about watching portions, making healthy food choices, and getting in the recommended physical activity of moderate aerobic exercise for 150 minutes per week.  My patient did well for a week or two, and then life happened.  They had a sick child, work asked for some overtime, and there were multiple family gatherings that revolved around food (think holidays).  And my patient “fell off the bandwagon” so to speak.  After a couple of days of dietary indiscretion, and not making it to the gym, they thought, “to heck with it” and binged on comfort foods while watching T.V. as a method of stress reduction.  They gained a few more pounds.  Guilt crept in, and that turned into missing a follow-up appointment with me, because they were embarrassed that I would think poorly about the lack of effort.

What I described is too often a reality, and becomes a dangerous cycle for patients.  A cycle that leads to depression, which can lead to giving up the treatment plan, then worsening glycemic control, a feeling of overwhelm or lack of control, and then finally, despair—once prediabetes becomes Type 2 diabetes.

We know from the Diabetes Prevention Program (DPP) that intensive lifestyle modifications are effective, and the efforts needed don’t seem too difficult to those of us who are already doing them on a habitual basis.1 But for many with prediabetes, the modifications needed are a complete overhaul from what they are already doing.  For example, you can’t easily go from two double cheeseburgers with fries and regular soda for lunch on the run, to an expectation of eating a large plate of green leafy vegetables with a 3 oz. portion of protein and 30-45 grams of carbohydrate on the side.  It sets a person up for failure. Change takes discipline, but also, time and planning.  You start with subtracting one cheeseburger, lots of encouragement, and maybe a 10 minute walk around the block.  Add in a behavioral health session or two to rid the mind of focusing on failure, and what is not possible, and instead think about what is possible.

Diabetes Prevention Program outcomes, which included a 58% reduction in 3-year diabetes incidence and 34% reduction in 10-year diabetes incidence were achieved in the intensive lifestyle group, but not without significant efforts on the part of both participants and the clinicians and educators working with them.1,2  Lifestyle measures included a healthy, low calorie, low-fat diet (flexible, individualized, and culturally sensitive) and the 150 minutes of physical activity per week described.  Participants in this group had an incredible amount of support to achieve this:  1) A 16-lesson curriculum covering diet, exercise, and behavior modification designed to help achieve goals, 2) one-to-one meetings for 16 sessions occurring over 24 weeks, 3)subsequent individual sessions (at least every other month), AND 4) group sessions with case managers to reinforce behavioral changes.  This all occurred in the first year.  There was support that followed that as well.  Participants got frequent reminders of what they needed to do, frequent encouragement, and mild “nagging” if they didn’t show up to exercise (“we missed seeing you today, Mr. Smith”).  Don’t forget that study participants get financial compensation as well.  Could our patients do better with a free gym membership, cooking lessons, constant encouragement from prediabetes “cheerleaders” and financial rewards?  Probably!  Also, we cannot discount the concept that study participants tend to be more motivated in general than those who don’t have the time or interest in participating in a study.

Why do people still progress on to developing type 2 diabetes, despite some attempt at lifestyle measures?  There could be a strong family history of rapid progression of disease.  The ability to replicate the DPP in a real-world setting is very challenging.  Positive outcomes in the intensive lifestyle group outcomes were more commonly seen in patients with impaired glucose tolerance (IGT), so the measures may not have fully addressed impaired fasting glucose (IFG).1  Women with a history of gestational diabetes mellitus (GDM) faired equally well with metformin as with lifestyle interventions, as did patients in the largest BMI group (≥35 kg/m2).1,3, 4 There may be other pathophysiologic reasons that are not fully addressed with lifestyle measures alone.  A progressive disease, by nature, often requires add-on therapies.  We also know that when prediabetes is identified by use of A1C criteria, we are only getting part of the picture.  A1C is still not an ideal diagnostic measure, and there can be lower sensitivity when using the A1C for diagnostic purposes—especially at the lower end of the A1C range.5   A1C can be affected by a number of factors that influence hemoglobin glycation. 5 In addition, The American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE), often partnered with the American College of Endocrinology (ACE), are not consistent in defining diagnostic cut points for A1C as it relates to prediabetes.5,6.  Lastly, there are the individual reasons already stated previously—life gets busy!  There may be a multitude of other reasons; but we know that translation of DPP to real world settings can be less than ideal and outcomes are not always identical.  For example, a systematic review and meta-analysis which included 22 translational diabetes prevention programs showed that the mean level of weight loss was approximately one-half to one-third of the levels reported in the DPP.7

We also need to remember that Diabetes Prevention Program outcomes did include positive results for metformin—just to a lesser degree than for the intensive lifestyle group.  Metformin at a dose of 850 mg twice daily resulted in a 31% reduction in progression from prediabetes to Type 2 diabetes within the almost 3 year follow-up period, and resulted in an 18% reduction in the 10-year follow up period.1,2  The metformin group in the DPP did not receive any lifestyle intervention, but were provided with “standard” care or counseling that could be more similar to what is received in many typical primary care settings.  I often wonder, how powerful would it have been to have had a group studied with the combination of intensive lifestyle AND metformin?  Nonetheless, the data with metformin alone doesn’t look too shabby!  In the words of the simple-minded Peter Griffin, “why are we NOT funding this??”8

Lifestyle interventions were considered more cost effective than metformin in the DPP; however, metformin was not available as a generic formulation at the time.With the availability of $4 per month immediate-release metformin at many pharmacies across the nation, it almost seems like a no brainer for a prediabetes patient without contraindication.  Metformin therapy for diabetes prevention is now a grade A level recommendation in the American Diabetes Association Standards of Medicare Care for 2018; especially for those with BMI ≥35 kg/m2, those aged <60 years, and women with prior GDM—all the groups that benefitted the most in the DPP.10

For patients that cannot tolerate an inexpensive immediate-release metformin at a dose of 850 mg twice daily; generic extended release formulations are a slightly more expensive, but a reasonable alternative that often results in less GI intolerance.11-15  The least costly formulations are available as 500 mg tablets.  I start with 500 mg of the extended release daily, and titrate to at least 1500 mg daily (typically, 500 mg in the morning and 1000 mg in the evening), and increase up to 2000 mg daily, in divided doses.  For previous cases of GI intolerance, I have better luck avoiding future intolerance when I recommend that the extended release formulation be administered twice daily, instead of opting for once daily.  If adherence issues surface, once daily administration can be tried.

For patients who still cannot take metformin, there are multiple other good pharmacotherapeutic options for prediabetes, although often at a higher cost.  Most patients would not prefer to use basal insulin for diabetes prevention; however the work and theories set forth by Dr. Ralph DeFronzo and subsequent research certainly support its use, consistent with the concept of beta cell defect occurring early in disease. 16,17,18  We know from this research that there appears to be a period of glucose intolerance and pathophysiologic changes that long precede the development of diabetes.16,17  The other treatment modalities described in the table below are supported by good outcomes and share a physiologic basis for use (see the hyperlink for the actions targeted).17  Consider these alternatives to metformin in select patients, as appropriate.

Diabetes Prevention Pharmacotherapy Table 1.18.18

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5317235/figure/F3/

In summary, I would never advocate for eliminating completely lifestyle measures in prediabetes or diabetes; these should always be encouraged.  But I’m more of a realist than an idealist.  And I think that we could be more aggressive in employing all types of diabetes prevention strategies, especially pharmacotherapy, than what appears to be the current standard of practice in many clinical settings in the United States.  Pharmacists can be pivotal in educating others and employing strategies toward type 2 diabetes prevention.

References:

  1. Diabetes Prevention Program Research Group, Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
  2. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study [Erratum in Lancet. 2009;374:2054]. Lancet. 2009;374:1677-86.
  3. Ratner RE, Christophi CA, Metzger BE, et al.; Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 2008;93:4774–4779.
  4. Aroda VR, Christophi CA, Edelstein SL, et al.; Diabetes Prevention Program Research Group.  The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program Outcomes.  Study 10-year follow-up. J Clin Endocrinol Metab 2015;100:1646–1653.
  5. American Diabetes Association. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes 2018.  Diabetes Care 2018;41(Suppl. 1):S13–S27.
  6. American Association of Clinical Endocrinologists and American College of Endocrinology. Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan—2015.  Endocr Pract. 2015;21(Suppl 1).
  7. Dunkley AJ, Bodicoat DH, Greaves CJ, et al. Diabetes prevention in the real world: effectiveness of pragmatic lifestyle interventions of the prevention of type 2 diabetes and of the impact of adherence to guideline recommendations.  A systematic review and meta-analysis.  Diabetes Care 2014;37:922-933.
  8. Fox TV: Family Guy. McStroke: Season 6, Episode 9.  Full episode first aired on January 13, 2008.  Short clip: https://www.youtube.com/watch?v=TRtlkcQ6brE.  Accessed 1/17/18.
  9. Within-Trial Cost-Effectiveness of Lifestyle Intervention or Metformin for the Primary Prevention of Type 2 Diabetes. Diabetes Prevention Program Research Group.  Diabetes Care 2003;26:2518-2523.
  10. American Diabetes Association.  Prevention or delay of type 2 diabetes: Standards of Medical Care in Diabetes 2018. Diabetes Care 2018;41(Suppl.1):S51–S54.
  11. Fujioka K, Pans M, Joyal S. Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation.  Clin Ther. 2003;25(2)515-29.
  12. Blonde L, Dailey GE, Jabbour S, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study.  Curr Med Res Opin. 2004;20(4)565-72.
  13. Feher MD, Al-Mrayat M, Brake J, Leong KS. Tolerability of prolonged-release metformin (Glucophage) in individuals resistant to standard metformin—results from four UK Centeres.  Brit J Diabetes Vasc Dis. 2007; 225-228.
  14. Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study.  Diabetes Obes Metab. 2009;11:338-342.
  15. Levy J, Cobas RA, Gomes MB. Assessment of efficacy and tolerability of once-daily extended-release metformin in patients with type 2 diabetes mellitus.  Diabetol Metab Syndr. 2010;2:16.
  16. DeFronzo R. From the triumvarariate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
  17. Schwartz SS, Epstein S, Corkey B, Grant SFA, Gavin III JR, Aguilar RB. The time is right for a new classification system for diabetes: rationale and implications of the β-cell-centric classification schema.  Diabetes Care 2016;39:179-186.
  18. Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-28.
  19. STOP-NIDDM Trial Research Group, Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-7.
  20. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364:1104-15.
  21. DREAM (Diabetes REduction Assessment with rampipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial [Erratum in: Lancet. 2006:368:1770]. Lancet. 2006;368:1096-105.
  22. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308
  23. Le Roux C, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomized, double-blind trial.  Lancet. 2017;368:1096-105.
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