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Metformin is the first-line drug in people with type 2 diabetes; pros and cons.

Nov 06, 2018

Metformin, the only available biguanide, was introduced as a human medication in 1957 after a publication in Moroccan Medical Journal [1] where Jean Sterne named metformin as a “glucophase” or “glucose eater”. Since then, it was extensively used in Europe. After approval by the FDA in 1994, its popularity increased.

UKPDS in 1998 and follow ups showed that intensive glycemic control with metformin reduces diabetes related co-morbidities in T2DM patients. Since metformin is associated with weight neutrality, lower hypoglycemia, CV benefits, low cost and overall favorable risk benefit ratio, it became the first-line glucose lowering agent in most guidelines [2][3].

The ADA and EASD in their joint position statement in 2012 and in 2015, stated that metformin was recommended as initial monotherapy unless there is intolerance or contraindication. Similar recommendations were given from NICE in the UK, IDF and ACP.

Metformin, “Pros”:

  • Metformin reduces hyperglycemia through two basic mechanisms: reduction of hepatic gluconeogenesis and increase of insulin sensitivity. It increases secretion of native GLP-1.
  • Metformin, as mono-therapy, is a low-cost drug associated with low risk of hypoglycemia.
  • Metformin alters the gut microbiome; expands gut population of Akkermansia spp., and is linked to reduced chronic inflammation and suppressed hyperglycemia [6].
  • Metformin offers a myriad of non-glycemic effects by: reducing pro-inflammatory cytokines, hs-CRP, PAI-1, fibrinogen, and by reducing monocyte differentiation, it offers anti-atherogenic and anti-thrombotic activities.
  • In addition to cardiovascular prevention, metformin prevents cognitive decline [7], cancer risks [8], gives anti-aging effects [9] and boosts immune response.

Metformin “Cons”

  • In spite of pleiotropic beneficial effects, metformin is not a panacea. The large sized tablet, gastro-intestinal side effects, metallic taste reduces adherence to metformin. Although such problems can be minimized in different ways, 5% population remains intolerant to metformin due to genetic variation [10].
  • Ethnic disparities exist. For example, African Americans have better glycemic response to metformin compared to European Americans [11].
  • Metformin responder and non-responder is also a problem. Due to genetic polymorphism, non-responders are even associated with abnormal liver functions [12].
  • About 21% of patients who started on metformin fail to meet glycemic control in the first 5-years [13]. This rate exceeds 50% in youth with newly diagnosed T2DM, which is increasing [14].
  • Although rare (3-10/100000/year), lactic acidosis is a problem. Vulnerable populations are patients with sepsis, cardiogenic shock, alcoholism, and previous history of lactic acidosis. Nine percent of Europeans have a mutation in the CYP2D6 gene and are at risk of lactic acidosis.
  • Metformin may lead to impaired absorption of vitamin B12 and folic acid causing anemia and neuropathy.
  • Metformin should not be used in patients with advanced liver diseases and CKD. Metformin users can continue it untill the eGFR≥30ml/min/1.73M2 but should not start if the eGFR ≤45ml/min/1.73M2.

Future perspectives:

Several recent trials have found significant cardiovascular and renal benefits from non-biguanide therapies (e.g. SGLT-2 inhibitors and GLP-1RA) in T2DM patients. Therefore, large outcome trials to compare one or more of these agents with metformin as initial therapy are indicated. Until new evidence is available, metformin will remain the first-line drug in type 2 diabetes.

Please consider the following questions:

From your clinical experience

  1. What do you do when a first time metformin user complaints about abdominal problem?
  2. One of the main causes of CKD is diabetes, specifically T2DM. Do you recommend renal assessment in patients with T2DM at diagnosis?
  3. Do you screen for vitamin B12 and folate for those who are prescribed with long-term use of metformin?
  4. What is your overall opinion of metformin as the initial first-line drug in people with type 2 diabetes?

Thinking of your own personal experience

  1. Your first medication, metformin, has been prescribed by your physician upon your diagnosis of type 2 diabetes. If after a few days you are experiencing (negative) side effects, what would you do?
  2. Some people you know who are living with diabetes are taking small tablets like glimepiride or gliclazide and their diabetes is well controlled. Your tablets of metformin are big and sometimes difficult to swallow. What would you do?

Recommended links for more information:

Reference reading:

  1. Sterne J (1957) Du nouveau dans les antidiabétiques. La NN dimethylamine guanyl guanidine (N.N.D.G.) Maroc Med 36:1295–1296 [article in French]
  2. Wiernsperger NF (2007) 50 years later: is metformin a vascular drug with antidiabetic properties? Br J Diabetes Vasc Dis 7:204–21
  3. Bailey CJ (2008) Metformin: effects on micro and macrovascular complications in type 2 diabetes. Cardiovasc Drug Ther 22:215–22
  4. Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabetic Medicine 2005;22:497–502.
  5. Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006;49:930–6.
  6. McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract. Diabetologia 59:426–435.
  7. Markowicz-Piasecka M et al. Metformin - a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla. Pharm Res 2017 Dec;34(12):2614-2627.
  8. Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258.
  9. Valencia WM, Palacio A, Tamariz L, Florez H (2017). Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia doi: 10.1007/s00125-017-4349-5
  10. Kirpichnikov D, McFarlane SI, Sowers JR (2002) Metformin: an update. Ann Intern Med 137:25–33.
  11. Williams LK, Padhukasahasram B, Ahmedani BK et al (2014) Differing effects of metformin on glycemic control by race-ethnicity. J Clin Endocrinol Metab 99:3160–3168.
  12. Mahrooz A et al. The role of clinical response to metformin in patients newly diagnosed with type 2 diabetes: a monotherapy study. Clin Exp Med. 2015 May;15(2):159-65
  13. Kahn SE, Haffner SM, Heise MA et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:24272443Zeitler P, Hirst K, Pyle L et al (2012) A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 366:2247–2256

Information about the discussion leader

Dr. Gauranga Chandra Dhar MD is a family physician from Bangladesh, graduated from Rostov State Medical Institute, Russia in 1983. He is an assistant professor of the Bangladesh Institute of Family Medicine and Research, University of Science and Technology of Chittagong (USTC), Bangladesh. He is involved in teaching diabetes and other cardiometabolic diseases in postgraduate medical courses since 2011. He has 30-yrs of extensive experience in the management of cardiometabolic diseases including diabetes. He has a number of research papers presented in both national and international conferences on diabetes and related topics.