Diabetes Prevention in the New Year

We commonly think of diabetes in terms of ‘cutoff’ diagnostic values…126 mg/dL (FPG) and 6.5% (A1C). We swing into action and follow guidelines to initiate lifestyle counseling, diabetes education, nutritional counseling and metformin therapy…all justified by this new diagnosis. But we all know that diabetes doesn’t flip a switch and become a problem at 126 mg/dL and have no consequence at say 125 mg/dL, or 115 mg/dL, etc.

Between the values of 100 and 126 mg/dL lies the netherworld of ‘pre-diabetes.’ The recent ADA Standards of Medical Care in Diabetes defined patients with A1C values of 5.7 to 6.4% as having high risk for future diabetes. When a provider sees a patient during this time, he or she can use the ICD-10 code R73.0X (Abnormal Glucose; where X=1 if IFG, X=2 if found during an OGTT, or X=9 where the word ‘prediabetes’ appears in the coding books.) The most important part, however, is not what the 5th digit of the ICD-10 code is. The most important part is what you do NOW with the patient. Indeed, what you do now, can influence when (or if) the patient goes on to develop frank diabetes according to the diagnostic parameters already mentioned.

The results of the now famous Diabetes Prevention Program made it clear that significant lifestyle modification could prevent (delay?) the development of diabetes in people with impaired glucose tolerance 58% of the time. In a separate arm of the study, metformin administration had a lower, but nonetheless significant reduction of 31% compared with placebo. While the effectiveness of both interventions waned over time (diabetes incidence at 15 years reduced by 27% for lifestyle and by 18% for metformin…DPPRG Lancet Diabetes and Endocrinology 2015;3:866), we know that the participants in DPP/DPPOS who returned to normal glucose were the ones who had the greatest long term effectiveness of their intervention (Perreault, et al Lancet 2012;379:2243). Weight loss (with lifestyle or metformin) seems to be the key, with metformin adherence being pivotal to the sustained weight loss seen with the medication.

An article published several years ago (Zhuo, X. et al. Am J Prev Med 2012;42:374) looked at the potential impact of lowering the A1C cutoff for pre-diabetes. Assuming a conventional $50,000/QALY cost-effectiveness benchmark, A1C cutoffs of 5.7% and higher were found to be cost effective vis-à-vis implementing measures known to be effective at reasonable cost. Lowering the cutoff from 5.7% to 5.6% or even lower also may be cost effective, if costs of preventive interventions were lowered.

The 10-year follow-up of the cost effectiveness of lifestyle or metformin (DPPRG Diabetes Care 2012;35:723) concluded that “…from a payer perspective, lifestyle was cost-effective and metformin was marginally cost-saving compared with placebo. Investment in lifestyle and metformin interventions for diabetes prevention in high-risk adults provides good value for the money spent.” In that same issue, the long term effects of metformin adherence on weight loss were also highlighted by the DPPRG. We all know that current lifestyle interventions to prevent diabetes are rarely as effective as they were in the DPP. In addition, at the time of the DPP, metformin was available only as a brand name product, and it is now generically available. These realities suggest that the potential cost per case prevented with intensive lifestyle management may be significantly higher than the cost per case prevented with metformin.

Despite all these data and analyses, very few people with pre-diabetes are currently receiving metformin. In the coming year, a collaboration of several governmental agencies and medical associations will unveil a major push to prevent diabetes. We have at hand an effective, safe, well-tolerated and cost-saving medication that we simply aren’t using effectively. So dust off your ‘Prediabetes’ slide talk as you may be tapped for a presentation or two, and start asking if some of your patients should be taking metformin… what are you waiting for?

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2 thoughts on “Diabetes Prevention in the New Year

  1. Thank you Kim for starting this blog. I’m wondering who’s also running into problems with dosing metformin in this population? I’m all for recommending lifestyle modifications along with metformin, in those willing patients, and do so regularly. The bigger hurdle comes when I discuss target dosing with prescribers. Although many are willing to initiation metformin 500mg once daily, it is a challenge to encourage dosing increases to 850mg twice daily (DPP) or 1000mg twice daily to optimize potential benefits–especially when A1c reduction is not the “goal”. What are your thoughts? Just be happy with 500mg once daily or pick the battle to push to target dosing for the full potential benefit of your patients? And is it really these target doses where we see the benefit or could we be pleased with metformin 500mg once daily when A1c drops below 5.7%?

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  2. Krystal,

    Great question!! I too always recommend changes in lifestyle (being as specific as possible and getting the patient to recite back to me what he/she is going to do) but in my experience and that of others the response to ‘lifestyle’ is abysmal. That doesn’t mean not to recommend it, but it leads to the purpose of my blog which is on the use of metformin for prediabetes. I recommend that metformin a) be initiated in the majority of prediabetes patients, and b) be maximized…which goes to the second part of your question. We know from the DPP(OS) that metformin was initiated and then pushed to 850 mg twice daily. While the push was a bit rapid, it seemed to work well, and in the event it is too rapid for your patient the recommended T2DM algorithm of the ADA consensus group in 2009 has a great table of upward dose titration. (Diabetes Care 2009;32:193). We do know that the effectiveness of metformin is related to weight loss, which in turn related to adherence with the regimen (Lachin, et al. Diabetes 2007;56:1153). We know also of the benefits of the regression from prediabetes to normal glucose tolerance in reducing CV Risk (Perreault, et al. Diabetes Care September 2014;37: 2622) a clear benefit of intervention if it can be accomplished, and is associated with weight loss as this and other publications by Perreault have shown). I also favor early maximization of the dose not only because the benefits are dose related [in T2DM and prediabetes as well] but also because of a factor called ‘clinical inertia’ whereby a health care provider gives 500 mg then says ‘yep, I’m treateing prediabetes with metformin, but never revisits the dose! I see that often…

    I am personally not a fan of using A1C for the diagnosis of diabetes or as cutoffs for ‘pre-diabetes’ either. There is still a lot of controversy on the former, and a study on the latter suggests a significant discrepancy between the A1C of 5.7% and the FPG values use to determine ‘prediabetes’. (Mann, et al. Diabetes Care 2010;33:2190)

    There is a great article that addresses a number of these ideas by Hostalek, et al (Drug 2015;75:1071) that is free to download!

    Kim
    PS: It is exciting to think that the effect of metformin may be on the gut microbiome at least in part, and whether the increase in certain bacteria play a role in what we classically teach as the “liver mechanism” is fascinating to say the least (Buse, et al. Diabetes Care 2015;Online August 18) (Lee & Ko, Applied Environmental Microbiology 2014;Online July 18)

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