P&T News: July 1995, Vol. 16, No. 1

The Rational Use of 5-HT3 Antagonists for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Adult Cancer Patients

Amy J. Becker, Pharm.D. and Douglas E. Morgan, M.S.
Peer Review Status: Internally Peer Reviewed by C. Patrick Burns, M.D., Professor and Director, Division of Hematology-Oncology, Department of Internal Medicine

The discovery and clinical development of the 5-HT3 (5hydroxytryptamine subtype 3) receptor antagonists have had a profound impact on the care of the chemotherapy patient. Ondansetron plus dexamethasone demonstrates efficacy equivalent to the high dose metoclopramide regimen. However, ondansetron requires fewer doses and has a much more favorable side effect profile.2 It rarely causes sedation or extrapyramidal effects; its major side effect is headache, which occurs in up to 25% of patients. Ondansetron's primary disadvantage is its cost ($138 for a standard 32 mg dose), which is approximately six times the cost of the high-dose metoclopramide regimen.

A second 5-HT3 receptor antagonist, granisetron, has recently been marketed. The cost of a standard 1 mg intravenous dose of granisetron ($93) is approximately two-thirds the cost of 32 mg of ondansetron. Switching from ondansetron to granisetron for the prevention of nausea and vomiting due to highly or very highly emetogenic chemotherapy could result in a cost savings to UIHC of approximately $125,000 per year.

At the time of the FDA's approval of granisetron, there were no published clinical trials comparing the FDA-approved doses of ondansetron and granisetron. With this in mind, the Drug Use Evaluation Subcommittee and the Division of Hematology-Oncology undertook a study to evaluate the clinical outcomes of the two agents in patients with similar demographics and chemotherapy regimens. The purpose of this study was to demonstrate that patient outcomes are not compromised when the less costly of the two agents is used in this setting.

This prospective, cohort study evaluated control of nausea and vomiting for 24 hours after chemotherapy in 40 cycles of highly or very highly emetogenic chemotherapy in 33 patients. In 80 % of the cycles, dexamethasone was given with the 5-HT3 antagonist to enhance the antiemetic effect. There was no nausea and no vomiting in 55 % of the 20 cycles in which ondansetron was used; and no nausea and no vomiting in 70% of the 20 cycles in which granisetron was used. This difference in the success rate was not statistically significant, nor were there any significant differences in side effects or patient satisfaction. Decision analysis was used to determine the less costly of the two regimens, taking into consideration the cost of the 5-HT3 antagonist and the cost of rescue antiemetics that were administered when the 5-HT3 antagonist failed to provide complete control. In this analysis, granisetron was found to be the more cost-effective of the two agents for the prevention of nausea and vomiting due to highly or very highly emetogenic chemotherapy.

Recently, Navari et al published the results of a double-blind, randomized trial comparing FDA-approved doses of ondansetron and granisetron in 987 patients receiving highly emetogenic chemotherapy.3 Concomitant use of dexamethasone was not allowed. Complete protection from nausea and vomiting, defined as no nausea or vomiting or use of rescue antiemetics, was achieved in 38% of the patients receiving granisetron and in 39% of the patients receiving ondansetron. This difference was not statistically significant. In addition, there were no statistically significant differences in incidence or type of adverse reactions. The most common adverse effect was headache (17 %).

Prescribing Criteria
Based on the determination of therapeutic equivalence, and the decision analysis of the financial implications of the two agents, the Pharmacy and Therapeutics Subcommittee, in conjunction with the Drug Use Evaluation Subcommittee and Hematology/Oncology faculty members, established prescribing criteria for these agents for adult patients in oncology settings, as well as guidelines for the prevention and treatment of nausea and vomiting associated with chemotherapy. The suggested choice of antiemetic prophylaxis is based on emetogenic risks anticipated for the chemotherapy (Table 1), literature-supported efficacy of the antiemetic regimen, duration of effect, cost-associated factors, and the adverse effect profile of the regimen. The suggested antiemetic regimens are outlined in Tables 2-4.

For highly or very highly emetogenic chemotherapy (Table 2), a single 1 mg IV dose of granisetron combined with dexamethasone is the preferred antiemetic regimen. The concurrent use of dexamethasone (unless contraindicated or otherwise prohibited by protocol) improves efficacy, thereby reducing the need for subsequent use of PRN doses of rescue antiemetics.2s4 Oral granisetron, approved for chemotherapy regimens, including those that contain cisplatin, is a viable option in patients who will likely tolerate both doses of the every 12-hour regimen. Metoclopramide-based regimens may be a reasonable alternative for the rare patient who does not tolerate granisetron, with a complete or major antiemetic response in 60% and 83% of high-dose cisplatin recipients. Lorazepam sharply reduces the frequency of extrapyramidal reactions or restlessness associated with metoclopramide.

For moderately emetogenic chemotherapy (Table 3), more conventional regimens, particularly phenothiazine and dexamethasone-containing combination regimens, may be effective and well tolerated in many instances.5 A single dose of 8 or 10 mg IV ondansetron, combined with dexamethasone, is the preferred 5HT3 receptor antagonist regimen for moderately emetogenic chemotherapy. In some cases, oral ondansetron may be an effective substitute for IV ondansetron.

For chemotherapy regimens that pose minimal emetic risk, scheduled antiemetic prophylaxis may be unnecessary. In this setting, scheduled prochlorperazine and dexamethasone5 _ standing PRN orders of conventional antiemetics (e.g., prochlorperazine 10 mg IM/IV/PO Q6hrs PRN nausea and/or vomiting) may be a reasonable strategy.

Table 1. Emetogenic Potential of Cancer Chemotherapy Agents*

Very Highly Emetogenic Cisplatin Cytarabine (500 or more mg/m2) Dacarbazine Ifosfamide Mechlorethamine Melphalan IV Streptozocin

Highly Emetogenic Carmustine Cyclophosphamide Dactinomycin Etoposide (500 or more mg/m2) Lomustine Methotrexate (200 or more mg/m2) Thiotepa (15 or more mg/m2)

Moderately Emetogenic Carboplatin Cytarabine (200-500 mg/m2) Daunorubicin Idarubicin Mitomycin Plicamycin

Low Emetogenic Risk Azathioprine BCG Vaccine Bleomycin Busulfan Chlorambucil Cladribine (2-CDA) Cytarabine (200 or less mg/m2) Etoposide Floxuridine Fludarabine Fluorouracil Flutamide Hydroxyurea Interferon, Alfa-2 L-Asparaginase Leuprolide acetate Levamisole Megestrol Melphalan (oral) Mercaptopurine Methotrexate (200 or less mg/m2) Mitotane Mitoxantrone Paclitaxel Tamoxifen Teniposide Thioguanine Thiotepa (15 or less mg/m2) Vincristine Vinorelbine

* The specific dose, duration of infusion, the concurrent use of other memtogenic agents, among other factors, will influence this predicted risk.

Table 2. Highly to Very Highly Emetogenic Chemotherapy
REGIMEN
A) Granisetron   with   B) Dexamethasone	1 mg IV x 1 dose, begin 30 minutes before chemotherapy Patients greater than 100 kg, 10 mcg/kg rounded to nearest 0.1 mg Give only one dose for each 24 hr period of emesis risk PRN dosing is not permitted   10 to 20 mg IV x 1 dose, or 4 mg PO Q6hrs x 24 hrs Give daily for each day of granisetron Improves efficacy; avoid only if contraindicated or otherwise prohibited by protocol
OR
A) Granisetron   with   B) Dexamethasone	1 mg PO Q12hrs x 2 doses; begin 60 minutes before chemotherapy Give only two doses for each 24 hr period of emesis risk PRN dosing is not permitted   10 to 20 mg IV x 1 dose, or 4 mg PO Q6hrs x 24 hrs Give daily for each day of granisetron Improves efficacy; avoid only if contraindicated or otherwise prohibited by protocol
OR
A) Metoclopramide with B) Dexamethasone with C) Lorazepam	3 mg/kg IV Q2hrs x 2 doses; begin 30 minutes before chemotherapy 10 to 20 mg IV x 1 dose before metoclopramide   1 to 2 mg IV x 1 dose before metoclopramide

Table 3. Moderately Emetogenic Chemotherapy
REGIMEN
A) Ondansetron with B) Dexamethasone	8 or 10 mg IV x 1 dose; begin 30 minutes before chemotherapy Adult standardized IV doses: 8 or 10 mg Give only one dose for each 24 hr period of emesis risk PRN dosing is not permitted   10 to 20 mg IV x 1 dose, or 4 mg PO Q6hrs x 24 hrs Give daily for each day of ondansetron Improves efficacy; avoid only if contraindicated or otherwise prohibited by protocol
OR
A) Ondansetron with B) Dexamethasone	8 mg PO; begin 30 minutes before chemotherapy, then 4 and 8 hrs later. Thereafter 8 mg PO BID or TID, not to exceed 3 days following completion of chemotherapy.   10 to 20 mg IV x 1 dose, or 4 mg PO Q6hrs x 24 hrs Give daily for each day of ondansetron Improves efficacy; avoid only if contraindicated or otherwise prohibited by protocol
OR
A) Prochlorperazine with B) Dexamethasone	10 mg IV x 1 dose; begin 30 minutes before chemotherapy, then 10 mg IV/PO Q6hrs for risk period; infuse IV dose over 15 to 30 minutes   10 to 20 mg IV x 1 dose, or 4 mg PO; begin 30 minutes before chemotherapy, then 4 mg PO Q6hrs x 4 doses for each day of emesis risk

For delayed nausea and vomiting, oral metoclopramide and dexamethasone is the antiemetic regimen of choice. The use of scheduled ondasetron and dexamethasone is an alternative, especially for those patients who are unable to tolerate metoclopramide (Table 4).

Table 4. Delayed Nausea and Vomiting
REGIMEN
Metoclopramide with Dexamethasone	20 to 30 mg PO TID to QID x 2 to 3 days, starting 16 to 24 hrs after cisplatin therapy   4 to 8 mg PO BID x 2 to 3 days
or if above has failed
Ondansetron with Dexamethasone	8 mg PO BID to TID x 2 to 3 days, starting 16 to 24 hrs after cisplatin therapy   4 to 8 mg PO BID x 2 to 3 days (avoid only if contraindicated or otherwise prohibited by protocol)

Summary
Effective antiemetic therapy provides patient comfort, may avoid complications, and may reduce length of stay and unnecessary readmissions. When selecting among antiemetic regimens with equal efficacy, the least expensive regimen should be chosen. Single-dose antiemetic strategies may be less resource-intensive and are attractive in outpatient settings for facilitating shorter visits.

When granisetron or ondansetron is deemed appropriate, the following cost saving strategies should be considered:

• Use concurrent dexamethasone to improve the efficacy of granisetron or ondansetron.2,4
• Avoid PRN use of granisetron or ondansetron. Alternative PRN antiemetics (e.g., prochlorperazine, lorazepam, metoclopramide) are a more rational choice as an adjunct to properly scheduled granisetron or ondansetron.
• When appropriate, use oral ondansetron or granisetron as an effective substitute for IV therapy.

Copies of the UIHC pocket-sized "Guide to Antiemetic Use in Oncology Settings" may be obtained by calling the Drug Use Evaluation Program (6-3870).

References

1. Cancer 1987; 60:2816-22.

2. J Cam Oncol 1994- 12:596-600.

3. J Clin Oncol 1995,13:1242-8.

4. Br J Cancer 1994- 70:1161-4.

5. J Cain Oncol 1988; 6:1397-400.

Metformin: Its Place in Therapy

Renu F Singh, Pharm.D.
Peer Review Status: Internally Peer Reviewed by William I. Sivitz, M.D., Associate Professor, Division of Endocrinology, Department of Internal Medicine

Metformin (Glucophage (R)) an oral biguanide hypoglycemic agent, was recently approved by the FDA for the treatment of Type II noninsulin dependent diabetes mellitus (NIDDM). Metformin has been available for use in Europe, Canada, and Australia for more than a decade. It is chemically and pharmacologically unrelated to sulfonylureas. Metformin is indicated as monotherapy as an adjunct to diet, or it may be used in combination with a sulfonylurea when diet or monotherapy with a sulfonylurea or metformin does not result in adequate glycemic control. This article provides guidelines for patient selection with an emphasis on safety issues.

Pharmacology
Unlike sulfonylureas, metformin does not stimulate pancreatic insulin secretion as circulating levels of insulin or C-peptide are not increased in patients with NIDDM receiving metformin therapy. l Metformin requires the presence of insulin to be effective. Although the precise cellular mechanism of action is unknown, metformin appears to improve insulin sensitivity by increasing the peripheral utilization of glucose. Metformin acts at the postreceptor level of skeletal muscle cells to increase glucose transport across the cell membrane.2,3 In addition to increasing hepatic insulin sensitivity,4 metformin has also been reported to reduce intestinal glucose absorption5 and inhibit hepatic glucose production. However, this evidence is conflicting in many studies,4 6 and these effects do not appear to account for the full ability of the drug to reduce hyperglycemia. Metformin has a lower propensity than sulfonylureas to induce hypoglycemia, which is most likely due to its lack of effect on insulin secretion; hence, as glucose levels decrease so do insulin levels, and hypoglycemia does not occur. A secondary factor may be metformin increasing the supply of lactate to the liver from the intestine, thereby providing the substrate to override any inherent antigluconeogenesis action of the drug.

Pharmacokinetic Properties
The absolute bioavailability of oral metformin is 50 to 60 % with absorption occurring over six hours. Food decreases the extent and slightly delays the absorption of metformin. The clinical relevance of this is unknown, and it is recommended to administer metformin with food to minimize gastrointestinal intolerance. Metformin is excreted unchanged in the urine (via filtration and renal tubular secretion) with 90% cleared in 12 hours. Elimination is prolonged in patients with renal dysfunction. Metformin is efficiently removed by hemodialysis.7

Efficacy
Metformin has been evaluated in several studies as monotherapy or in combination with a sulfonylurea or insulin in patients with NIDDM.

Hermann et al compared metformin and micronized glyburide (1.75 mg or 3.5 mg: equivalent to regular glyburide 2.5 mg and 5 mg, respectively) alone and in various combinations in 144 NIDDM patients with a fasting blood glucose concentration (FBG) 2 120 mg/ dl and/or an abnormal glucose tolerance test.8 After six weeks of dietary treatment alone, patients were randomized to three treatment groups: metformin plus glyburide, metformin alone, or glyburide alone. Dose escalation was performed every two weeks until the target of a FBG < 120 mg/dl was achieved, after which the resulting dosage was maintained for six months. If the target FBG was not reached with maximal monotherapy (3000 mg/day metformin or 10.5 mg/day glyburide), combination therapy was initiated. Patients in the initial combination group started with low doses of 500 mg/day metformin and 1.75 mg/day glyburide; doses were increased, if necessary, to maximal doses of each. Patients in all groups had a significant reduction in FBG and glycosylated hemoglobin (HbAIC). Patients in the monotherapy or low-dose combination groups had a lower baseline FBG than the high-dose combination groups, with a mean FBG of 167 + 7 mg/dl which was reduced to a mean FBG of 126 + 3.6 mg/dl, with no significant difference in reduction of FBG and HbAlC between these groups. Fasting C-peptide levels rose in the glyburide monotherapy and low-dose combination groups. Body weight rose by approximately 3 kg in the glyburide monotherapy group, but this was not significantly changed in the low dose combination group or metformin monotherapy group. There were no significant differences in lipid levels. Patients in the high-dose combination groups had higher baseline FBGs than those on monotherapy or the low-dose combination therapy, but there was still a large reduction in the mean FBG from a baseline of 239 + 14.4 mg/dl to ultimately 140 + 10.8 mg/dl. Fasting levels of insulin and C-peptide were unchanged in these groups; there was no change in body weight. A significant 12.5 % decrease in triglyceride levels and a 5% increase in HDL cholesterol were observed in the high-dose combination group only. Sixteen (11%) patients withdrew from the study due to side effects, with patients in the metformin treatment group having more gastrointestinal symptoms than the other groups. Hypoglycemia was observed in all groups, from 21 to 33%, although the severity was not specified.

In a large, prospective three-year study, metformin was compared to diet, sulfonylurea therapy and insulin therapy for newly diagnosed NIDDM patients.9 Exclusion criteria included severe cardiovascular disease (myocardial infarction in the past year, current angina, or heart failure), accelerated hypertension, retinopathy, and renal failure (serum creatinine > 2.0 mg/dl). After a three-month dietary run-in period, 2520 patients who had a fasting plasma glucose concentration (FPG) of 109 to 260 mg/dl without hyperglycemic symptoms were stratified for obesity and randomized to diet alone or the addition of a sulfonylurea (chlorpropamide or glyburide), insulin or metformin. Only obese patients (defined as 2 20% of ideal body weight) were placed in the metformin treatment group. Doses were increased weekly until the FPG was < 108 mg/dl or to a maximum of 500 mg/day chlorpropamide, 20 mg/day glyburide, or 2550 mg/day metformin. If maximum oral hypoglycemic therapy was insufficient, the patient was transferred to insulin. After three years all treatment therapies were more effective than diet alone, with comparable reductions in hyperglycemia in all groups. However, patients treated with a sulfonylurea or insulin had a 3 to 5 kg increase in body weight and increased fasting plasma insulin concentrations during the period, whereas obese patients who received metformin did not gain weight and were observed to have reduced fasting plasma insulin concentrations from baseline. Hypoglycemic episodes occurred less often with metformin (6.3%) than with sulfonylureas or insulin, but more often than diet alone. Most episodes, although minor, occurred with insulin and glyburide therapies (33.4% and 27.8%, respectively). Major hypoglycemic episodes were uncommon with all treatments.

The efficacy of metformin has also been evaluated in 50 obese NIDDM patients poorly controlled by insulin after secondary failure to respond to sulfonylureas.10 All patients had NIDDM for three or more years with an unsuccessful trial of maximal sulfonylurea therapy for at least one year and had mean plasma glucose levels of > 282 mg/dl. Patients were required to have been on insulin for at least three months, and this was continued throughout the study. Patients were randomized to receive placebo or metformin for six months. Metformin was given at a dose of 850 mg twice daily. The insulin dose was not increased if metformin inadequately controlled hyperglycemia, but it could be reduced if necessary. The mean daily dose of insulin was 90 units. Exclusion criteria included age greater than 70 years, serum creatinine > 1.2 mg/dl, ischemic or wasting disease, or any acute severe diseases. The addition of metformin to previous insulin therapy led to a significant reduction in the glucose profile and HbAIC, which was significant after two months of therapy and persisted for six months. Approximately 50% (14) of patients on metformin achieved a plasma glucose levels of c 180 mg/dl. The daily dose of insulin and the fasting insulin concentration were significantly lower in the metformin treated group from the second month onward. Serum C-peptide levels did not change significantly. There were significant reductions in total cholesterol (4%) and triglyceride (11%) levels and an increase in HDL (11%) levels. The body weight of all patients remained stable throughout the study.

Overall, metformin has proven to be as effective as sulfonylureas in both obese and non-obese NIDDM patients in reducing hyperglycemia, and it provides additional reduction of hyperglycemia when combined with a sulfonylurea or insulin. Metformin reduces blood glucose levels by 20 to 40% without causing weight gain or an increase in plasma insulin levels, and the drug causes less hypoglycemia than sulfonylureas or insulin.

Adverse Effects
Metformin is structurally related to phenformin, a biguanide which was withdrawn from the market in many countries, including the U.S. in 1976, due to a high incidence of lactic acidosis. Biguanides affect lactate metabolism, causing an increase in blood lactate levels. The source of this lactate is unclear, but may be from increased peripheral production, increased intestinal or hepatic production, or reduced hepatic clearance.1l The risk of developing lactic acidosis from metformin (5 cases/100,000 patients/year) is estimated to be six to fifty times lower than with phenformin.l2 This lower incidence of lactic acidosis may be partly explained by the fact that metformin is not metabolized and is completely excreted by the kidney, whereas phenformin undergoes hydroxylation in the liver to an inactive metabolite.l3 A significant proportion of individuals (approximately 9 % of Caucasians) inherits a defect of hepatic metabolism that impairs their ability to hydroxylate phenformin, which results in higher concentrations of the active drug.l4 It has been demonstrated that lactic acidosis from metformin is largely preventable by strict adherence to the contraindications to its use15 (see "Contraindications/Precautions" section). Symptoms of lactic acidosis include chills, muscle pain, bradycardia, dizziness, somnolence, difficulty breathing and weakness.

The most common side effects of metformin therapy are gastrointestinal in nature and occur in 5 to 20% of patients. Symptoms include abdominal discomfort, metallic taste, nausea, and diarrhea; these effects are generally transient and can be minimized by taking the drug with meals and titrating the dose slowly.

Drug Interactions
Concomitant therapy with cimetidine has increased serum concentrations of metformin, presumably by decreasing the renal clearance of metformin,7 requiring careful monitoring and possible dose adjustment of metformin. Metformin may decrease absorption of vitamin B12 and folic acid, and may rarely cause anemia during long-term therapy; hematologic parameters should be measured annually.

Dose
Metformin is marketed in 500 mg and 850 mg tablets. The initial dose is 500 mg twice daily or 850 mg twice daily given with the morning and evening meals to minimize gastrointestinal intolerance (Table 1). The dose may be increased weekly by 500 mg or 850 mg every other week, respectively, up to a maximum of 2550 mg/day. The usual dosage is 850 mg twice daily. Generally, clinical responses are not seen at doses below 1500 mg/day. Table 2 provides a cost comparison of metformin with other hypoglycemics on the UIHC formulary.

Table 1. Dosing Guidelines for Metformin

DOSING Regimen 1: Initial dose - 500 mg twice daily may increase dose by 500 mg weekly, if necessary, to a maximum of 2500 mg/day (in 2 to 3 divided doses) Regimen 1 may be preferred to Regimen 2 in patients with a history of gastrointestinal intolerance Regimen 2: Initial dose - 850 mg twice daily may increase dose by 850 mg every other week, if necessary, to a maximum of 2550 mg/day (in 2 to 3 divided doses)

Contraindications/Precautions
When lactic acidosis occurs, it carries a poor prognosis; the mortality rate is 30 to 50%. As a result, strict adherence to contraindications and a knowledge of conditions that may predispose the patient to lactic acidosis are essential (Table 3). Metformin should be avoided in any condition that may result in metformin accumulation or increased peripheral lactate production. Renal impairment is an absolute contraindication, as is acute or chronic metabolic acidosis. Patients with hepatic disease may have reduced hepatic lactate clearance, and hence metformin should generally be avoided. Hypoxic states, such as cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, acute and chronic pulmonary disease, or septicemia, have been associated with lactic acidosis (secondary to increased peripheral lactate production) and may also cause prerenal azotemia. In the event of such a condition, metformin should be discontinued. Because of the risk of inducing renal dysfunction, metformin should be withheld for at least 48 hours in patients undergoing radiologic studies involving radiocontrast materials (e.g., IV urogram, IV cholangiography, angiography, scans with contrast materials) and for 48 hours subsequent to the procedure. Metformin should only be restarted after normal renal function has been confirmed. Similarly, metformin should be suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and restarted only after normal renal function has been reestablished. Metformin should also be avoided in patients with a history of chronic alcohol abuse as alcohol may potentiate the effect of metformin on lactate metabolism.

Table 2. Cost Comparisons of Hypoglycemic Agents
Drug	Average Daily Dosage	Cost ($)*
Chlorpropamide	250 mg q.d.	4.02
Glipizide	10 mg b.i.d.	33.79
Glyburide	10 mg q.d.	31.00
Insulin	100 units/ml (1 to 2 10 ml bottle)	17.42-34.84#
Metaformin (Glucophage)	850 mg b.i.d.	47.20
Tolazamide	250 mg q.d.	7.95
Tolbutamide	500 mg b.i.d.	4.00
_______ * Average cost to the pharmacist for 30 days of therapy based on average whosesale price (AWP) listings in Drug Topics Red Book 1995 for a generic product, when available. # This cost does not reflect the cost of insulin syringes necessary to administer the drug.

Table 3. Contraindications/Precautions for the Use of Metformin

Absolute Contraindications Renal dysfunction (serum creatinine 1.5 or more mg/dl in men; 1.4 or more mg/dl in women) Acute or chronic metabolic acidosis, including diabetic ketoacidosis Relative Contraindications History of alcholism Hepatic impairment Suicidal intent Previous history of lactic acidosis Peripheral vascular disease Angina Conditions Requiring Discontinuation Radiologic Studies involving parenteral administration of iodinated contrast material withhold for 48 hours prior to and subsequent to the procedure restart only after normal renal function re-established Surgical procedures (unless minor and not associated with restricted food and fluid intake) restart only after normal renal function re-established Hypoxic states acute myocardial infarction, uncontrolled congestive heart failure, septicemia, cardiovascular collapse (shock), acute pulmonary disease Dehydration severe diarrhea and/or vomiting

Conclusion
Metaformin is a unique oral hypoglycemic agent which acts by increasing tissue sensitivity to insulin without affecting its secretion. Its antihyperflycemic efficacy is similar to sulfonylureas in obese and non-obese patients with NIDDM. When added to a sulfonylurea or insulin, metformin confers enhanced antihyperglycemic effect. Unlike sulfonylureas and insulin, metformin is not associated with an increase in body weight although its ability to cause weight reduction is minimal (1 to 1.5 kg). It is also less likely to induce hypoglycemia. Metformin may have a beneficial effect on lipid levels, notably triglyceride and HDL levels, although the long term clinical implications of these effects are unclear.

However, metformin is more expensive than sulfonylureas or insulin; it causes more gastrointestinal intolerance than oral sulfonyulureas; and many NIDDM patients have co-existing morbid conditions, such as renal impairment, which prohibit the use of metformin. Prescribing guidelines must be strictly followed to prevent potentially fatal lactic acidosis. Based on these factors, metformin should be considered after failure of maximal doses of a sulfonylurea, and be given as either monotherapy or in combination with a sulfonylurea. Metformin can be considered as first-line monotherapy in obese patietns with Type II diabetes who have failed on diet and exercise. In addition, metformin may have a role in reducing the total daily dose of insulin when used in addition to insulin therapy in NIDDM. The main advantages of metformin in NIDDM are enhancement of insulin action and lack of stimulation of insulin secretion; therefore, metformin (unlike insulin or sulfonylureas) does not cause weight gain and does not worsen the hyperinsulinemia associated with Type II diabetes.

References

1. Diabetes Care 1990;13(6):696-704.

2. Clin Sci 1973;44:55-62.

3. Biochem Pharmacol 1972;21:3153-62.

4. Diabetes 1987;36:632-40.

5. Diabetologia 1971;7:195-203.

6. Acta Endocrinol 1989;120:257-65.

7. Bristol-Myers Squibb. Glucophage Package Insert. Princeton, NJ. 1995 Feb.

8. Diabetes Care 1994;17(10):1100-9.

9. BMJ 1995;310:83-8.

10. Eur J Clin Pharmacol 1993;44:107-12.

11. Balliere's Clin Endocrin & Metab 1988;2(2):455-76.

12. Arch Intern Med 1992;152:2333-6.

13. Horm Metab Res 1985;15(Supp):111-5.

14. Drug Safety 1994;11(4):223-41.

15. Can Med Assoc 1983;128:24-6.

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