Metformin in the Treatment of Diabetes Mellitus

In the control of type 2 diabetes, metformin, a relatively safe compound from the drug class of the biguanides, is usually the first drug utilized [1]. Its mechanism of action is widely accepted to work by inhibiting the mitochondrial complex 1 in hepatic cells, thereby reducing gluconeogenesis[1]. This mechanism helps in preventing hyperglycemia and maintenance of blood glucose levels by reducing the intrinsic release of glucose into the bloodstream.

Metformin is frequently prescribed orally for adults starting at 500 mg, incrementally increasing dosage by 500 mg every week, with a maximum dose of 2,000 mg per day[2]. If an individual requires higher doses, more than 2,000 mg, metformin will need to be administered 3 times per day, not exceeding 2,550 mg[2]. Children under 10 years old may also start at 500 mg, and increase by 500 mg weekly, however, their dosages must be administered twice per day, not exceeding 2,000 mg per day[2].

After oral administration metformin is absorbed at a rate of 50-60% via intestinal plasma membrane monoamine transporters (PMAT), hepatic OCT1 and OCT3 transporters, and renal OCT2 transporters [1]. Metformin has a relatively long half-life of 5 hours because of its exclusive elimination through the kidneys, and the absence of biotransformation [3]

While being one of the safest options in the biguanide class, metformin consumers may still experience serious side effects. Therapists should be mindful of the following adverse events and the signs and symptoms that are associated with them. Lactic acidosis, a rare but dangerous side-effect experienced, may present with confusion, lethargy, stupor, shallow breathing, hypotension, nausea and vomiting[2]. Hypoglycemia may display as anxiety, restlessness, paresthesia, cold sweat, confusion, headache, instability, and irritability[4]. While vitamin B deficiency may be seen with neural signs (confusion, paresthesias, and agitation), cardiovascular arrhythmias, pins and needles sensation and skin lesions[5]. Along with these signs, therapists should always monitor blood pressure, which could be an indication of diabetes mismanagement[6]. If symptoms are present and can’t be managed or brought under control, patients must be immediately referred to their physician.

Those taking metformin should be wary of the consumption of certain items which may increase metformin’s side effect profile. The main substances that should be cautioned are alcohol, which increases the risk of lactic acidosis, the use of amiloride, digoxin, and morphine, because of their competition for elimination pathways and cimetidine and furosemide which increase metformin’s effect.[2]

Education is also is extremely important when working with a patient taking metformin. Therapists must educate the patient on their role in monitoring their glucose levels. They should be reminded to eat before therapy or physical activity, to avoid hypoglycemia[7]. They must monitor for changes and signs and symptoms of hyperglycemia, hypoglycemia, lactic acidosis, vitamin B deficiencies, and gastrointestinal discomfort. Patients must also be counseled on proper administration, and storage of metformin at room temperature, avoiding extreme temperatures and light[8]. Abnormalities, or apprehensions must be reported and discussed with primary healthcare provider so dosage can be modified or patient switched to a different medication.

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References

  1. 1.0 1.1 1.2 Rena, G., Pearson, E. R., & Sakamoto, K. (2013). Molecular mechanism of action of metformin: old or new insights?. Diabetologia, 56(9), 1898-1906.
  2. 2.0 2.1 2.2 2.3 2.4 Company, B.-M. S. (n.d.). GLUCOPHAGE. Priceton: Bristol-Myers Squibb Company.
  3. Madiraju, A. K., Qiu, Y., Perry, R. J., Rahimi, Y., Zhang, X. M., Zhang, D., ... & Casals, G. (2018). Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nature medicine, 1.
  4. Low Blood Glucose (Hypoglycemia). (2016, August). Retrieved from National Institute of Diabetes and Digestive and Kidney Diseases: https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/low-blood-glucose-hypoglycemia    
  5. Healton, E. B., Savage, D. G., Brust, J. C., Garrett, T. J., & Lindenbaum, J. (1991). Neurologic aspects of cobalamin deficiency. Medicine70(4), 229-245.
  6. Adler, A. I., Stratton, I. M., Neil, H. A. W., Yudkin, J. S., Matthews, D. R., Cull, C. A., ... & Holman, R. R. (2000). Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. Bmj321(7258), 412-419.    
  7. Type 2 diabetes. (2018, September 15). Retrieved from Mayo Clinic: https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/diagnosis-treatment/drc-20351199      
  8. Metformin. (2018, March 15). Retrieved from Medline Plus:https://medlineplus.gov/druginfo/meds/a696005.html (DiaBeta (glyburide) Tablets USP 1.25, 2.5 and 5 mg, 2009)