Draft Drug Monograph - Metformin - Case Study Example

 Introduction Metformin is an oral biguanide anti-diabetic drug indicated for diabetes mellitus type 2 (non-insulin dependent diabetes mellitus or NIDDM) for patients without kidney dysfunction but also indicated for other disorders not related to diabetes like polycystic ovary syndrome. It is the least toxic and the safest compound of the biguanide anti-diabetics family, though lactic acidosis is the most serious but rare side effect of this drug. Metformin is a white crystalline product of N,N-dimethylguanidine synthesis derived from the French lilac or “goat’s rue”, galega officinalis1. It is a water-soluble compound with an acid dissociation constant of 12.4, has a pH of 6.68 when 1% of the substance is dissolved in water and has a molecular weight of 165.63 2. Figure 1 shows its structural formula. Mechanism of Action Many studies attempted to explain the mechanism of action of Metformin, but the exact mechanism is still unknown, as early claims are being disputed by some studies. Diabetes Mellitus Type 2 / Non-Insulin Dependent Diabetes Mellitus (NIDDM) In diabetes mellitus type 2, a limited beta cells response to high glucose in blood will decrease its efficiency in regulating glucose (desensitization) and resistance of liver and muscle and fat tissues on insulin activity (insulin resistance). This will allow the liver to further produce glucose beyond the normal levels while glucose uptake of muscles and fat does not increase3. Metformin is theorized to respond to these reactions without affecting insulin production. Figure 2 shows the detailed concept map of how metformin works on diabetes mellitus type 2. Though the exact mechanism of action of metformin is not clear on diabetes mellitus type 2, metformin works on both glucose regulation of the liver and the muscle and fat tissues (corrects desensitization and insulin resistance), regulating liver gluconeogenesis and increasing glucose uptake respectively. Table 1 shows the evidence of metformin’s effects on glucose production and gluconeogenesis. Table 1: Effects of Metformin on Glucose Production and Gluconeogenesis after 3-Month Treatment 4 Glucose Production mmol x m(-2) min(-1) Gluconeogenesis mmol x m(-2) min(-1) Before 0.70 +/- 0.05 0.59 +/- 0.03 After 0.53 +/- 0.03 0.38 +/- 0.03 Many studies previously proposed the role of AMP-activated protein kinase (AMPK) in the mechanism of action of metformin wherein the activation of such inhibits glucose production by reducing the activity of acetyl-CoA carboxylase (ACC), promoting fatty acid oxidation and suppressing the lipogenic enzyme 5 6 7. The controversy arises when a study found out that the glucose lowering effect was the same even without AMPK, and also discovered that gluconeogenesis is better regulated in AMPK-deficient environment8. Another proposed mechanism of action of metformin is the inhibition of AMP deaminase instead of AMP activation, leaving the mechanism of AMPK activation still unknown9. Beyond the liver physiology, metformin is also believed to stimulate the insulin-induced component in the cell membrane of skeletal muscle and fat cells, resulting to enhanced glucose uptake reducing the circulating glucose, which is dependent on insulin10. Polycystic Ovary Syndrome Insulin resistance is one of the metabolic categories of polycystic ovary syndrome, but the mechanism is unclear11. The syndrome is associated with hyperinsulinemia and insulin resistance which increases risk for diabetes mellitus type 2 producing the same hyperglycemic manifestations12. Metformin is used as a symptomatic management for hyperglycemic episodes secondary to polycystic ovary syndrome. Studies show positive effects of metformin also in ovulation, menstruation and pregnancy 13 but have no effect in follicle-stimulating hormone and lutenizing hormone14. Interestingly so, there are other significant hormonal changes as a result of metformin administration, which are not clearly understood. The net action of metformin, whether directly or indirectly, improved ovulation15 and resumption of normal menstruation16. Table 2: Effects of metformin on resumption of menstruation, body mass index, fasting serum insulin, testosterone and estradiol16. Before Treatment After treatment Percentage of women who had regular menstruation Amenorrhea 91% Mean body mass index 36.4 kg/m2 35.1 kg/m2 Mean fasting blood insulin 26 uU/mL 22 uU/mL Blood testosterone levels 61 ng/dL 47 ng/dL Blood estradiol levels 41pg/mL 71 pg/mL The mechanisms of action of metformin in diabetes mellitus and polycystic ovary syndrome are poorly understood, as it is still uncertain on how metformin works on the cellular level. Therapeutic Use and Efficacy Diabetes Mellitus Type 2 (NIDDM) Metformin is primarily used in diabetes mellitus type 2 as the first line anti-diabetic drug of choice for patients without renal disease or dysfunction 17 18 19. It is initiated slowly at 500 mg twice to thrice a day and may increase in steps of 500mg in one week intervals; maximum of 2250mg a day 20. A laboratory test to measure the ability of the body to regulate glucose is the postload or postprandial glucose to determine the glucose uptake of the muscle and adipose tissues. Table 3 shows evidences on how metformin decreases both fasting and post-prandial plasma glucose. Table 3: Effects of Metformin in Fasting and Post-Prandial Plasma Glucose after 3-Month Therapy 21 Fasting Plasma Glucose Post-Prandial Plasma Glucose Before 0% (70 mg/dL) 0% (104%) After -20% (58 mg/dL) -25% (87 mg/dL) A decreased liver gluconeogenesis and increased glucose uptake of peripheral tissues will allow a significant reduction of glucose in blood and decreases liver’s glucose production, which can be assessed through the fasting blood glucose laboratory examination. On the other hand, glycosulated hemoglobin (HbA1c) analyzes the blood glucose control for 3 months backwards, evaluating a long-term glucose control. Table 4 shows an evidence of improvement of fasting plasma glucose, fasting hepatic glucose production and glycosulated hemoglobin after metformin therapy. Table 4: Effects of Metformin on Fasting Hepatic Glucose Production and Glycosulated Hemoglobin After 15 Weeks of Treatment22 Fasting Plasma Glucose mg/dL Fasting Hepatic Glucose Production umol//kg.min Glycosulated Hemoglobin Before 196 +/- 18 12.9 +/- 1.0 12.5 +/- 0.6 % After 152 +/- 12 11.0 +/- 0.5 9.2 +/- 0.3 % Metformin, when used in monotherapy, stands out among other diabetes treatment regimen. Compared with respective monotherapies of sulphonylureas, thiazolidinediones, insulin, meglitinides and glucosidase inhibitors, metformin has greater benefits for diabetes-related outcomes, blood glucose control and weight23. Metformin also increases insulin resistance in increasing doses (Table 5). Table 5: Metformin use in increasing doses using step-wise dosing protocol 24 Fasting Blood Glucose Insulin Sensitivity Basal metabolic clearance of glucose Base Value (4 months without metformin) 0% (9.7 ±1.0 mmol/L) 0% (10.3 ± 2.1 μmoL/kg/min) 0% (1.69 ±0.16 mL/kg/min) Metformin 500mg -13% (8.4 mmol/L) No data 30% (2.2 mL/kg/min) Metformin 500mg TID -34% (6.4 mmol/L) 23% (12.7 μmoL/kg/min) 53% (2.9 mL/kg/min) Metformin 1000mg TID -41% (5.7 mmol/L) 29% (13.3 μmoL/kg/min) 44% (2.4 mL/kg/min) Polycystic ovary syndrome Metformin may be used in addition to hormonal therapy in symptomatic management. It is initially started at 500mg once a day for one week, then twice a day, then 1500mg to 1700mg in two or three divided doses6. Metformin decreases insulin resistance and fasting blood insulin concentration while increasing insulin sensitivity among patients with polycystic ovary syndrome11. There is an evidence of effects of metformin on regulation of sex hormones16. Distribution in the Body Absorption Half of metformin is absorbed into systemic circulation when taken orally (40% to 60%), but decreases with escalating doses (Metformin 850mg has a 14% less bioavailability than a Metformin 500mg tablet), and further decreased by 24% when taken with food 25 26. The peak plasma concentration of metformin can be reached after 4 to 5 hours, but the extended release form can take 7 to 8 hours, and further prolonged with meals by 3 hours 27. Distribution Metformin is negligibly bound to plasma protein, allowing a shorter duration of action and able to move freely in intracellular space, having a volume of distribution of 654 +/- 358 L 2. Metabolism Metformin does not undergo hepatic metabolism and evidenced by absence of metabolites22. It is excreted in the urine unchanged. Elimination Metformin has an elimination half-life from the plasma of 1.7 hours28. It is mainly excreted through the urine by tubular secretion but also through feces. For the first 24 hours, 90% of the drug is excreted in the urine2. 30% of the drug is passed through the feces29. Excretion of metformin varies with renal function (see Table 6). Table 6: Relationship between Estimated Glomerular Filtration Rate and Serum Metformin Concentration 30 Median serum metformin concentrations umol/l Estimated glomerular filtration rate > 60 4.5 Estimated glomerular filtration rate: 30-60 7.71 Estimated glomerular filtration rate < 30 8.88 Adverse Drug Reactions The more prevalent side effects of metformin are of gastrointestinal in origin. Diarrhea is the most common side effect of the drug, followed by nausea and vomiting, flatulence, asthenia and indigestion2. Taking metformin with meals will reduce gastrointestinal symptoms. Lactic acidosis, though rare, is the single most important adverse drug reaction to watch for. Half (50.3%) of the patients who developed lactic acidosis died31. However, only 3 to 4 out of 100,000 will develop lactic acidosis from taking metformin32, and the occurrence is linked with renal failure. Inhibition of gluconeogenesis is a causative factor for accumulation of lactic acid33. Though lactate is excreted through the urine, impairment in the renal function will lead to accumulation of lactic acid and trigger metabolic acidosis. Lactic acidosis is also possible for patients without renal impairment34. Increase in blood lactate and pyruvate (fermented to produce lactate) is shown at Table 7. Table 7: Lactate and Pyruvate Increase with Metformin Treatment35 Percent Increase Serum Pyruvate 35% Serum Lactate 35% Following the recommendations in metformin administration, especially the precautions and warnings in renal disorders, will reduce the incidence of lactic acidosis36. Another rare side effect, though not as lethal as lactic acidosis, is leukocytoclastic vasculitis, though only a single case was reported37 and requires further research. Drug Interactions Cationic drugs The renal tubular secretion of metformin is can lead to drug interactions with cationic drugs as it may compete with the common renal tubular system. This competition will increase the plasma and blood concentrations of metformin and prolong the half-life. Any drug that alters the renal excretion of metformin increases the risk for developing lactic acidosis. Examples of cationic drugs are listed in Table 8. Table 8 : Examples of Cationic Drugs that may Interact with Metformin Amiloride Digoxin Morphine Procainamide Quinidine Quinine Ranitidine Triamterene Trimethoprim Vancomycin Furosemide These drugs compete with renal tubular excretion, which increases the plasma and blood concentrations of each drug. Furosemide and metformin increases each other’s plasma and blood concentrations and decreases their terminal half-lives2. Nifedipine Nifedipine enhances the absorption of metformin, but metformin has a little additive effect on nifedipine2. Chromium, cocoa and fenugreek Some food supplements tend to cause hypoglycemia when taken with metformin, which includes chromium38 39, cocoa40 and fenugreek41. Contraindications Renal dysfunction Metformin is generally not given for patients with impaired renal function2. The primary consideration in metformin is the prevention of lactic acidosis, and is generally linked to impaired renal function. Metformin is excreted by the kidneys, and impairment in its function will allow the drug to accumulate in the circulation. Moreover, the lactate as a product of metformin-altered gluconeogenesis will also accumulate, which will trigger lactic acidosis. Congestive Heart Failure (CHF) and Dehydration Both CHF and dehydration has an altered systemic circulation, which affects renal circulation, impairing renal excretion of metformin and lactate. Radiological and Surgical Procedures Metformin is suggested to be discontinued in both radiological procedures (involving injection of a contrast medium) and surgical procedures due to lactic acidosis risk2. Metformin therapy is routinely withdrawn 48 hours before surgery42. However, one study revealed positive effects of metformin prior to surgery43. In radiological studies using intravenous contrast medium, the risk of lactic acidosis exists only for patients with renal impairment44, thus it was suggested that the contraindication for metformin therapy following a radiological study be applied only to those with renal impairment45. One study revealed one incidence of lactic acidosis without renal impairment, but concluded the safety of intravenous contrast medium to patients taking metformin with normal renal function46. For vigilance purposes, metformin should be discontinued for patients undergoing surgery or radiological imaging with use of intravenous contrast medium. Geriatric (without normal kidney function) Metformin is not given to patients 80 years of age and above unless proven to have normal renal function2 due to the progressive decline of kidney function with age, increasing the risk for lactic acidosis 47 48 Summary Metformin is a biguanide anti-diabetic drug indicated for diabetes and polycystic ovary disease. How the drug exactly works is still unknown, but it is theorized that metformin activates AMPK on liver and peripheral tissues wherein the process leads to regulated glucose production and increased glucose uptake respectively. Adverse reactions are more commonly of gastrointestinal in origin, but should watch out for the serious and fatal lactic acidosis. It is not given to patients with renal dysfunction and other factors that may affect the renal excretion. It is generally a safe drug provided that precautions and recommendations on its use are adhered upon. Read More