Metformin therapy

Metformin. Metformin [657-24-9] (1,1-dimethylbiguanide), mol wt 129.17, forms crystals from propanol, mp 218—220°C, and is soluble in water and 95% ethanol, but practically insoluble in ether and chloroform. Metformin, an investigational dmg in the United States, does not increase basal or meal-stimulated insulin secretion. It lowers blood glucose levels in hyperglycemic patients with Type II diabetes but has no effect on blood glucose levels in normal subjects. It does not cause hypoglycemia. Successful metformin therapy usually is associated with no or some weight loss. 

There is a risk of acute renal failure when iodi-nated contrast material that is used for radiological studies is administered with metformin. Metformin therapy is stopped for 48 hours before and after radiological studies using iodinated material. Alcohol, amiloride, digoxin, morphine, procainamide, quini-dine, quinine ranitidine, triamterene, trimethoprim, vancomycin, cimetidine, and furosemide all increase the risk of hypoglycemia. There is an increased risk of lactic acidosis when metformin is administered with the glucocorticoids. 

MANAGING LACTIC ACIDOSIS. When taking metformin, the patient is at risk for lactic acidosis. The nurse monitors die patient for symptoms of lactic acidosis, which include unexplained hyperventilation, myalgia, malaise, gastrointestinal symptoms, or unusual somnolence If the patient experiences these symptoms, the nurse should contact the primary care provider at once. Elevated blood lactate levels of greater than 5 mmol/L are associated with lactic acidosis and should be reported immediately. Once a patient s diabetes is stabilized on metformin therapy, the adverse GI reactions that often occur at the beginning of such therapy are unlikely to be related to the drug therapy. A later occurrence of GI symptoms is more likely to be related to lactic acidosis or other serious disease. 

Metformin also has been shown to produce beneficial effects on serum lipid levels and thus has become a first-line agent for type 2 DM patients with metabolic syndrome. Triglyceride and low-density lipoprotein (LDL) cholesterol levels often are reduced by 8% to 15%, whereas high-density lipoprotein (HDL) cholesterol improves by approximately 2%. A modest weight loss of 2 to 3 kg (4.4—6.6 lb) also has been reported with metformin therapy. Metformin often is used in combination with a sulfonylurea or a thiazolidinedione for synergistic effects. 

Primary side effects associated with metformin therapy are gastrointestinal in nature, including decreased appetite, nausea, and diarrhea. These side effects can be minimized through slow titration of the dose and often subside within 2 weeks. Discontinuation because of side effects occurs in only 3% to 5% of patients. 

Charbonel B, Karasik A, Ji Liu, Mei Wu, Meininger G, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006 29 2638-43. 

Post-study monitoring showed that 5 years after the closure of the UKPDS, the benefits of intensive management on diabetic endpoints was maintained and the risk reduction for a myocardial infarction became significant. The benefits of metformin therapy were maintained. 

The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), which occur in up to 20% of patients. They are dose-related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3-5% of patients because of persistent diarrhea. Absorption of vitamin B12 appears to be reduced during long-term metformin therapy, and annual screening of serum vitamin B12 levels and red blood cell parameters has been encouraged by the manufacturer to determine the need for vitamin B12 injections. In the absence of hypoxia or renal or hepatic insufficiency, lactic acidosis is less common with metformin therapy than with phenformin therapy. 

Six experts in intensive care or metabolic disease reviewed all case reports of lactic acidosis from 1957 to 1999—37 articles reporting 80 cases (85). To be assessed the reports had to meet strict criteria, including a diagnosis of type 2 diabetes, metformin therapy before lactic acidosis, a pH of 7.35 or less, or a plasma bicarbonate concentration below 22 mmol/1 and a lactic acid concentration of at least 5 mmol/1. Because of lack of information, 33 cases were excluded. There were other susceptibility factors for lactic acidosis besides metformin in 46 of 47 cases. Only 13 of the 47 cases were classified as probably due to metformin by at least three experts. The authors suggested a rethink about the relation between lactic acidosis and metformin. However, they still recommended withdrawing therapy in acute renal insufficiency and when contrast dyes are used for radiological investigation. 

Sulkin TV, Bosnian D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997 20(6) 925-8. 

Holstein A, Nahrwold D, Hinze S, Egberts EH. Contraindications to metformin therapy are largely disregarded. Diabet Med 1999 16(8) 692-6. 

Lalau JD, Race JM, Brinquin L. Lactic acidosis in metformin therapy. Relationship between plasma metformin concentration and renal function. Diabetes Care 1998 21(8) 1366-7. 

Tymms DJ, Leatherdale BA. Lactic acidosis due to metformin therapy in a low risk patient. Postgrad Med J 1988 64(749) 230-1. 

Lalau JD, Race JM. Lactic acidosis in metformin therapy searching for a link with metformin in reports of metformin-associated lactic acidosis . Diabetes Obes Metab 2001 3(3) 195-201. 

Fujita H, Narita T, Yoshioka N, Hosoba M, Ito S. A case of megaloblastic anemia due to vitamin B12 deficiency precipitated in a totally gastrectomized type II diabetic patient following the introduction of metformin therapy. Endocr J 2003 50 483 1. 

Azzam H, Bergman R, Friedman-Birnbaum R. Lichen planus associated with metformin therapy. Dermatology 1997 194(4) 376. 

Dore P, Perault MC, Recart D, Dejean C, Meurice JC, Fougere MC, Vandel B, Patte F. Pneumopathie medica-menteuse a la metformine . [Pulmonary diseases induced by metformin .] Therapie 1994 49(5) 472-3. 

Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, Kohanovski M, Rotzak R, Schneider H, Behar S, Motro M. Oral antidiabetic treatment in patients with coronary disease time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up Clin Cardiol 2001 24(2) 151-8. 

Simmons D, Walters BNJ, Rowan JA, Mclntryre HD. Metformin therapy and diabetes in pregnancy. Med J Aust 2004 180 462-4. 

Brock B, Smidt K, Ovesen P, Schmitz O, Rungby J. Is metformin therapy for polycystic ovary syndrome safe during pregnancy Basic Chn Pharmacol Toxicol 2005 96 410-2. 

Worth L, Elliott J, Anderson J, Sasadeusz J, Street A, Lewin S. A cautionary tale fatal lactic acidosis complicating nucleoside analog and metformin therapy. Clin Infect Dis 2003 37 315-6. 

Egan, J., Rubin, C., Mathisen, A., and Pioglitazone 027 Study Group. (1999). Adding Pioglitazone to Metformin Therapy Improves Lipid Profile in Patients with Type 2 Diabetes (Abstract 459). Diabetes 48, (Suppl. 1), 106. 

Houwerzijl EJ, Snoek WJ, van Haastert M, Holman ND. Ernstige lactaatacidose bij metforminegebruik bij een patient met contra-indicates voor metformine. [Severe lactic acidosis due to metformin therapy in a patient with contraindications for metformin.] Ned Tijdschr Geneeskd 2000 144(40) 1923-6. 

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