Diabetes Mellitus Type 2, Metformin, Disease Risk and You

What follows is an amalgamation of information I have amassed over the years on this topic. Metabolic anomalies are common during recovery from an eating disorder and therefore the diagnosis of diabetes mellitus type 2 and treating it using metformin comes up enough in discussion threads on the Eating Disorder Institute forums that makes sense to synthesize the material here.

Flickr.com: Wellness GM

Flickr.com: Wellness GM

Metformin is a drug designed to “improve blood glucose control” in patients diagnosed with diabetes mellitus type 2.

As for metformin’s impact on weight loss (an off-label application for the drug), systematic review would suggest nothing more substantial than what can be achieved (and sustained) through any method of purposeful weight loss— i.e. in the range of 2.5 kg (5.5 lbs.).1 However, most people are prescribed metformin in response to an elevated fasting blood glucose reading. But it is very important to note blood glucose levels can be elevated in recovery from an eating disorder and will often resolve of their own accord.2

If metformin has been recommended for you while you are in recovery from an eating disorder, then discuss with your physician the possibility of a wait-and-see approach being the better option (it will depend on what tests were performed and the exact levels that were recorded of course).

Metformin is a drug that is FDA approved for the treatment of diabetes mellitus type 2. However, many patients are prescribed this drug on the basis of a single fasting blood glucose level (which cannot dependably confirm type 2), or they are diagnosed with the nebulous (and contentious) “pre-diabetes”.

A recent meta-analysis of randomized controlled trials suggest that metformin has no significant effect on the risk of developing cardiovascular conditions (heart attack & stroke).3

Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR) = 0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR = 1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR = 0.90 (95% CI: 0.74 to 1.09); all strokes, RR = 0.76 (95% CI: 0.51 to 1.14); heart failure, RR = 1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR = 0.90 (95% CI: 0.46 to 1.78); leg amputations, RR = 1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR = 0.83 (95% CI: 0.59 to 1.17).” 4

Wait, why have I suddenly flipped into discussing cardiovascular disease when we were talking about type 2? Well, diabetes mellitus type 2 is not a disease— it’s a risk factor for developing disease. That means that not everyone with diabetes type 2 (treated or untreated) will ever develop any disease state that is more strongly correlated with the presence of type 2 than for those who don’t have the condition.

The effort to control blood glucose levels for diabetes mellitus type 2 tends to be disproportionately focused on evading the onset of cardiovascular disease because the mortality is more of a concern with that disease state than it is with retinopathy (eye disease) or nephropathy (kidney disease) and there is a reasonably strong correlation between hyperglycemia and cardiovascular disease. 5

The risk factor for actual vision-threatening diabetic retinopathy is 10%. 90% of those with type 2 will never experience vision-threatening retinopathy. 6

Kidney disease in type 2 takes more than a decade to show up. At year 10 beyond diagnosis, 24.9% have microalbuminuria (the presence of a small amount of albumin in the urine suggesting impaired kidney function), 5.3% have macroalbuminuria and 0.8% have renal replacement therapy (dialysis or transplant). Interestingly those with macroalbuminuria around year 10 are far more likely to die of cardiovascular disease than progress to end-stage kidney failure (renal replacement therapy). 7

And 66% of those with microalbuminuria never progress to macroalbuminuria. 8 So all in for a lifetime risk, 22.2% of those with type 2 may develop nephropathy at a level that increases mortality risk.

And the risk factors for retinopathy and nephropathy arising from type 2 are not strongly or exclusively linked to prolonged high blood glucose levels (or hyperglycemia). Therefore, treating the blood glucose levels doesn’t necessarily remove the risk for the minority with type 2 who will go on to develop these diseases. 9

Type 2 diabetes is a condition that is known to affect the elderly. The vast majority of those with the condition (treated or not) will die of something other than any disease onset that is linked to type 2. That type 2 is being diagnosed in younger patients is a confluence of over diagnosis, over treatment and also likely a reflection of true early onset of the condition likely attributable to factors such as electric light at night, sleep disruption and deficits, endocrine disruptors in our environments, and the kinds of unrelenting stress often experienced by those of low socioeconomic status. But because there are drugs available to lower blood glucose levels and not drugs that shut down light at night, or provide more hours’ sleep, or remove BPA, BPB and BPC from retail receipts, or that develop ways to redistribute wealth more evenly across the population, then when all you have is a hammer, everything looks like a nail.

There are also conditions linked to type 2 that greatly impede quality of life, but rarely impact mortality, such as neuropathies and circulatory problems that can also result in extremity infections (usually the feet). Peripheral neuropathies appear at a prevalence of around 6% at baseline and about 20% 10 years out. The mean score for pain intensity appears to be 3.4 (using the usual 1-10 pain scale). 10 Foot ulceration is correlated with peripheral neuropathy and about 5% with peripheral neuropathy developed foot ulceration. 11

Foot fungus associated with diabetes is predominantly found in older male patients, but with a high frequency (80+%). 72% with this condition are male and the mean age is 61 years. In these cases, poorly managed blood glucose is correlated to the presence of these fungal infections. 12 Peripheral neuropathies, circulatory problems and their secondary infections associated with the long-term progression of type 2 are not going to impact the majority with type 2 at all.

And all of this would suggest that using metformin to treat type 2, let alone a very contentious ‘diagnosis’ of pre-diabetes, is not as black and white as many might think.

Pre-diabetes actually requires an HbA1C of 5.7%-6.4% (so elevated fasting blood glucose should not generate a pre-diabetes ‘diagnosis’ or a prescription of metformin either). Several peer-reviewed published papers suggest that using the HbA1C cutoffs for pre-diabetes do not dependably reflect those who will progress to develop diabetes, let alone actual heart disease down the line. 13, 14

There is a dangerous skew towards over diagnosis in this area. Metformin is yet another lifestyle drug that is a blockbuster for the pharmaceutical maker: the patient lives out a long life and stays on the prescription the entire time. A blockbuster drug = annual sales of $1 billion or more. Metformin pulled in $1.57 billion in 2011.

These are things to discuss with your physician and family and consider before you begin taking such a drug, or continue taking it for that matter.

And finally, we need to reaffirm that the vagaries of blood glucose and insulin levels for those actively in recovery from an eating disorder can mimic the onset of diabetes mellitus type 2 but may not actually represent the onset of type 2 at all. Given that spontaneous adjustment of aberrant blood glucose and/or insulin levels back to the norm will occur for most as recovery from an eating disorder progresses, then we would be stretching diagnostic frameworks to refer to something transient and self-correcting as equivalent to diabetes mellitus type 2 in its usual presentation in old age.

I will now make self-evident the usual disclaimers regarding the information collated in this particular post: the purpose of the above information and references is solely to provide you with as fulsome a set of data as is available on the topic of diabetes mellitus type 2, metformin, disease state risks and outcomes. To actually determine what is in your best interests when it comes to diagnosis and treatment, you need a medical doctor who a) is aware of the above, or willing to become aware, and b) will engage with you on the topic of risks, benefits and options based on his or her exemplary professional advice in relation to your stated health outcome goals. There is nothing prescriptive embedded in the above material because it fundamentally lacks the subjectivity that you and your medical doctor must apply to it.

1. Vilsbøll, Tina, Mikkel Christensen, Anders E. Junker, Filip K. Knop, and Lise Lotte Gluud. "Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials." Bmj 344 (2012): d7771.

2. Mehler, Philip S., and Carrie Brown. "Anorexia nervosa–medical complications." Journal of eating disorders 3, no. 1 (2015): 11.

3. Boussageon, R., Supper, I., Bejan-Angoulvant, T., Kellou, N., Cucherat, M., Boissel, J. P., ... & Cornu, C. (2012). Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS medicine, 9(4), 465.

4. ibid.

5. Laakso, M. (1999). Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes, 48(5), 937-942.

6. Yau, J. W., Rogers, S. L., Kawasaki, R., Lamoureux, E. L., Kowalski, J. W., Bek, T., ... & Meta-Analysis for Eye Disease (META-EYE) Study Group. (2012). Global prevalence and major risk factors of diabetic retinopathy. Diabetes care, DC_111909.

7. Adler, A. I., Stevens, R. J., Manley, S. E., Bilous, R. W., Cull, C. A., & Holman, R. R. (2003). Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney international, 63(1), 225-232.

8. Hovind, P., Tarnow, L., Rossing, P., Jensen, B. R., Graae, M., Torp, I., ... & Parving, H. H. Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study.

9. Ravid, M., Brosh, D., Ravid-Safran, D., Levy, Z., & Rachmani, R. (1998). Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Archives of internal medicine, 158(9), 998-1004; Knowler, W. C., Bennett, P. H., & Ballintine, E. J. (1980). Increased incidence of retinopathy in diabetics with elevated blood pressure: a six-year follow-up study in Pima Indians. New England Journal of Medicine, 302(12), 645-650.

10. Davies, M., Brophy, S., Williams, R., & Taylor, A. (2006). The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes care, 29(7), 1518-1522.

11. Kumar, S., Ashe, H. A., Parnell, L. N., Fernando, D. J. S., Tsigos, C., Young, R. J., ... & Boulton, A. J. M. (1994). The Prevalence of Foot Ulceration and its Correlates in Type 2 Diabetic Patients: a Populationbased Study. Diabetic medicine, 11(5), 480-484.]

12. Eckhard, M., Lengler, A., Liersch, J., Bretzel, R. G., & Mayser, P. (2007). Fungal foot infections in patients with diabetes mellitus–results of two independent investigations. Mycoses, 50(s2), 14-19.; Saunte, D. M. L., Holgersen, J. B., Hædersdal, M., Strauss, G., Bitsch, M., Svendsen, O. L., ... & Svejgaard, E. L. (2006). Prevalence of toe nail onychomycosis in diabetic patients. Acta dermato-venereologica, 86(5), 425-428.

13. Yudkin, J. S., & Montori, V. M. (2014). The epidemic of pre-diabetes: the medicine and the politics. Bmj, 349, g4485

14. Morris, D. H., Khunti, K., Achana, F., Srinivasan, B., Gray, L. J., Davies, M. J., & Webb, D. (2013). Progression rates from HbA1c 6.0–6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis. Diabetologia, 56(7), 1489-1493.