Tag Archives: Glucophage
Walking Away From Diabetes
The National Institutes of Health announced study results showing that diet and exercise can lower the risk of diabetes by 58 percent for 10 million Americans on the cusp of developing this common but deadly illness. The results were so impressive that federal officials halted the study a year early. We know you have questions about what this means for you and your family. Some answers follow.
Oh, boy, more people telling me to lose weight and get up off the couch. What’s the big deal this time?
This study is one of the best demonstrations that a few simple changes in lifestyle can have a powerful impact on preventing disease in high-risk people. In this research, people on the brink of developing diabetes followed a lower-fat diet, walked or did some other form of moderate exercise about 30 minutes a day five days a week and lost around 10 to 15 pounds. These changes reduced their chances of getting type 2 diabetes by almost 60 percent. Even better, this program worked in men and women, in young adults and seniors, and in all races. And the lifestyle changes were nearly twice as effective as the expensive medication to which it was compared.
Hey, wait, I know statistics can exaggerate the importance of a study. What were the chances of these people getting diabetes without any treatment? What were their chances if they made the changes?
Wow, you’re good. Each year, 10 percent of the people in this study who got no treatment developed diabetes. Do the math over a period of years and you can see this group is at very high risk indeed. About 5 percent of those who followed the moderate diet and exercise program developed the disease each year. That’s an impressive drop in risk — but it’s not a perfect record. The lifestyle program does not appear to prevent the disease in everybody who is at risk, but it improves their odds significantly.
Why are we so worried about diabetes all of a sudden? I thought heart disease and high blood pressure were the real killers.
Type 2 diabetes has reached epidemic proportions, and the number of people at risk for developing it increases every year. Some 16 million people have the disease and an estimated 800,000 Americans will be diagnosed this year. Type 2 diabetes is a chronic degenerative disease characterized by elevated blood sugar levels; it’s the leading cause of kidney disease, limb amputations and acquired blindness in adults. It also increases the risk of heart disease and stroke. (Many deaths blamed on heart attack and stroke are associated with diabetes.) Rates of type 2 diabetes have tripled in the last 30 years because of the rise in obesity and sedentary living. Worse, type 2 diabetes is being diagnosed in people at increasingly younger ages — even in kids. So diabetes is one of the most pervasive and deadly results of the American lifestyle.
How do I know if I’m enough like the people in this study to benefit from the lifestyle changes?
Most people in this study were overweight and sedentary adults. To be eligible, they also had to have “impaired glucose tolerance” — a pre-diabetic condition in which the body fails to process glucose efficiently, elevating blood sugar levels. (Over time, high blood sugar damages organs and blood vessels throughout the body, leading to kidney failure, blindness, amputations and heart disease.) An estimated 10 million Americans have this pre-diabetic condition, and most have lifestyles that put them at risk for developing it. Strictly speaking, the benefits demonstrated in the study apply only to those who already have impaired glucose intolerance — but researchers believe that similar interventions can reduce risk for others.
How do I know if I’m “overweight”?
If your friends won’t tell you, we will. You can start with body mass index — a figure that considers height and weight. If you have a BMI of 30 or above — technically the cutoff for “obesity” — you’re in the diabetes danger zone. At 5 feet 10 inches tall, that’s 209 pounds; at 5-4, it’s 174 pounds. (To compute your BMI on the Web, go to www.nhlbisupport.com/bmi/ You’ll also find a link there to a BMI chart.)
A BMI above 25 (128 for a five-footer, 164 for someone 5-8, 184 for a six-footer) is considered “overweight” and is also associated with an increased risk for impaired glucose tolerance.
Every time you guys write about the body mass index, people write in and say it’s inaccurate, deeming even those who have muscular physiques “fat.”
If you have a muscular physique and low body fat like the professional athletes cited by those letter writers, chances are you’re not at risk for diabetes. We’ll be politic and say that if your BMI is 30 or over, chances are pretty good that you are at increased risk. If you prefer, measure your body fat instead — but it’s hard to do accurately without professional help. Healthy ranges vary by age and sex, but if you’re a woman with a body fat number above 35 percent or a man whose number is over 24 percent, you should be worried. (Log on to www.shapeup.org/bodylab/ frmst.htm for more information on body fat.)
Are there other things aside from body mass or body fat that put me in a high-risk group?
Having a family member with diabetes adds to your risk. African Americans, Hispanics and Native Americans also face much higher risk of diabetes. So do women who developed gestational diabetes while pregnant, about half of whom develop full-blown diabetes later in life. People in these groups may want to consider preventive lifestyle changes even if their BMIs are not near 30.
How can I find out if my glucose tolerance is impaired?
Ask your doctor for a fasting glucose tolerance blood test. You’ll have to go without food for 10 hours before the test. At the doctor’s office, you drink a sugary liquid and then have your blood drawn at regular intervals over the next two hours to see how your body metabolizes the sugar.
Sounds like fun. How much is this going to cost me?
It’s a bargain: about $15 to $35. It’s often covered by health insurance. It’s also the only way to definitively tell whether you are moving toward diabetes — or perhaps already have it.
What happens if I have an abnormal result?
Depends on how abnormal. If your fasting blood sugar — that’s the first sample they take — is between 95 and 125 milligrams, you have impaired glucose tolerance and are a candidate for treatment. The same goes for a two-hour blood sugar level — that’s the last one drawn in the test — of 140 to 199 milligrams. Treatment could be lifestyle changes or a prescription for metformin (Glucophage), a drug that is approved to treat diabetes.
If your fasting blood sugar is 126 milligrams or above, or if your two-hour blood sugar level is 200 milligrams or above — sorry, but you already have diabetes. You’ll need to consult your doctor for immediate treatment.
So what were these lifestyle changes, anyway?
Participants ate between 1,200 and 1,800 calories per day, with about 25 percent of total calories coming from fat — not a huge reduction below the 30 percent-from-fat maximum recommended by many health authorities, and not as strict as many low-fat weight loss diets. They also learned how to exercise daily. Most walked for 30 minutes a day at least five times a week. Those unable to walk because of arthritis — or disinclined to do so — did other activities including swimming, tennis and jogging that equaled the number of calories burned by walking.
I’ve tried these diets and programs a thousand times, but I always fail. How did the study manage to keep people with the program?
Participants got a lot of hand-holding and group support. While this aspect of the study has gotten little attention, it’s very important. Many people need help to sustain lifestyle changes.
The people in this study received intensive, one-on-one weekly diet counseling for nearly six months. They got personal coaching for workouts and attended small groups that taught low-fat cooking and emphasized healthful grocery shopping. They kept daily records of their diet and exercise.
You could duplicate the program a number of ways, some of them free, some costly. You can take a low-fat cooking class, join a walking group or gym, form a network of support, check out local hospitals or your insurance group for support services or hire a personal trainer or dietitian.
When lifestyle changes fail, it’s often because the pressures that trigger the condition in the first place — the constant rushing that leads to fast-food meals, the stress and exhaustion that leads to evenings in front of the TV, the lack of exercise in most daily activity patterns — undermine the best intentions to change. So creating a structured environment, ideally involving other people attempting the same changes, may be very useful. Enlisting the family may help, too.
If I can’t make the lifestyle changes, can’t I take a pill?
Maybe. If you don’t think you can make diet and exercise changes, taking metformin may be the choice for you — provided you don’t have liver or kidney disease or suffer from congestive heart failure. Therapy with Glucophage, the brand name for metformin, costs between $2 and $4 per day, but generic metformin is expected to hit the market in the fall, bringing prices way down.
Yes, participants in the study who took Glucophage lost a few pounds and reduced reduced their risk of diabetes significantly, although not nearly as much as the lifestyle group. But if you continue to live a sedentary life, take in more calories than you burn off, eat a high-fat diet with few fruits, vegetables and whole grains, experts believe that you won’t be as effective at lowering your risk of diabetes, heart disease, high blood pressure, arthritis, stroke and other equally entertaining conditions. It’s your choice. Really.
Metformin Hydrochloride
Drug Approvals
(British Approved Name Modified, US Adopted Name, rINN)
International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):
Hidrocloruro de metformina; LA-6023 (metformin or metformin hydrochloride); Metformiinihydrokloridi; Metformin Hidroklorur; Metformin hydrochlorid; Metformine, chlorhydrate de; Metformin-hidroklorid; Metforminhydroklorid; Metformini hydrochloridum; Metformino hidrochloridas.
C4H11N5,HCI = 165,6.
CAS — 657-24-9 (metformin); 1115-70-4 (metformin hydrochloride).
ATC — A10BA02.
Pharmacopoeias. In China, Europe, Japan, and US.
European Pharmacopoeia, 6th ed. (Metformin Hydrochlonde). White or almost white crystals. Freely soluble in water slightly soluble in alcohol practically insoluble in acetone and in dichloromethane.
The United States Pharmacopeia 31, 2008 (Metformin Hydrochloride). A white crystalline powder. Freely soluble in water slightly soluble in alcohol practically insoluble in acetone and in dichloromethane.
Adverse Effects, Treatment, and Precautions
As for biguanides in general.
Breast feeding. Based on animal studies the UK and US licensed product information warns that metformin may be distributed into breast milk, and that the possible effects on the infant should be considered if women wish to breast feed while receiving the drug. However, a study in 7 breast-feeding women receiving metformin at a median dose of 1.5 g daily found the concentrations in milk to be about a third of those in maternal plasma, resulting in a mean calculated dose to the infants of 40 micrograms/kg daily. Blood samples were taken from 4 of the infants: metformin concentrations were undetectable in 2, and were very low (10 to 15% of maternal values) in the others. Given these results the authors considered that women receiving metformin need not be discouraged from breast feeding. Similar results from 3 other studies’ that included 13 women have provided further evidence that metformin is distributed into breast milk, that concentrations in milk are less than those in maternal plasma, and that breast-fed infants would be exposed to a very small percentage of the maternal dose. Six infants were breastfed with no adverse effects that could be attributed to metformin. A prospective study of weight, height, and motor-social development over 6 months, in infants of women taking metformin (1.5 to 2.55 g daily) for poly cystic ovary syndrome, found no difference between 61 infants who were breast-fed and 50 who were formula-fed.
Fasting. For the view that metformin could be used with little risk of hypoglycaemia in fasting Muslim patients during Ramadan, and suggestions for modifying the timing of doses, see under Precautions of Insulin.
Pregnancy. Insulin is generally preferred for treatment of diabetes during pregnancy. However, there are limited data to suggest that metformin does not increase the risk of congenital abnormalities and does not adversely affect pregnancy outcome in diabetic women. A controlled study comparing insulin with metformin in gestational diabetes is underway.The use of metformin to improve ovulation in polycystic ovary syndrome (PCOS) is increasing. There is growing evidence to suggest that metformin used before and during pregnancy in these women does not increase the risk of congenital abnormalities, and may reduce first trimester spontaneous abortion,’which is common in women with PCOS.
Interactions
As for biguanides in general.
Pharmacokinetics
Metformin hydrochloride is slowly and incompletely absorbed from the gastrointestinal tract the absolute bioavailability of a single 500-mg dose is reported to be about 50 to 60%, although this is reduced somewhat if taken with food. Once absorbed, protein binding in plasma is negligible the drug is excreted unchanged in the urine. The plasma elimination half-life is reported to range from about 2 to 6 hours after oral doses. Metformin crosses the placenta and is distributed into breast milk in small amounts.
Uses and Administration
Metformin hydrochloride is a biguanide antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus, and is the drug of first choice in overweight patients. Initial dosage is 500 mg two or three times daily or 850 mg once or twice daily with or after meals, gradually increased if necessary, at intervals of at least 1 week, to 2 to 3 g daily doses of 3 g daily are associated with an increased incidence of gastrointestinal adverse effects. Gastrointestinal effects are also common on beginning therapy, and the BNF recommends starting therapy more gradually with 500 mg at breakfast for at least 1 week, then increasing to 500 mg twice daily for at least 1 week, with further increases as required, up to a usual maximum of 2 g daily in 3 divided doses with meals. A modified-re-lease preparation is also available, which is given in an initial dose of 500 mg once daily and may be increased in increments of 500 mg, at intervals of at least 1 week, to a maximum of 2 g once daily with the evening meal. If glycaemic control is not adequate the dose may be divided to give 1 g twice daily with meals. If doses above 2 g daily are required, they should be given as the standard preparation. For doses used in children and adolescents, see below.
Metformin is also used as the chlorophenoxyacetate and as the embonate.
Action. A review of the action of metformin considered that although a number of possible mechanisms have been suggested, the major action of metformin lay in increasing glucose transport across the cell membrane in skeletal muscle. There is also some evidence in vitro that it can inhibit the formation of advanced glycosylation end-products.
Administration in children. In children aged 10 years and older with type 2 diabetes mellitus, oral metformin hydrochloride may be used in a starting dose of 500 mg or 850 mg once daily, or 500 mg twice daily, given with or after a meal. It may be gradually increased if needed, at intervals of at least 1 week, to a maximum of 2 g daily given in 2 or 3 divided doses. Modified-release preparations are generally not licensed for use in children.
Although rare, the incidence of type 2 diabetes is increasing in children and adolescents, related in part to the increase in obesity occurring particularly in westernised countries. A small placebo-controlled study of patients aged 10 to 17 years with type 2 diabetes found that metformin improved glycaemic control and that adverse effects were similar to those in adults. In obese children and adolescents with hyperinsulinaemia, who are at risk of developing type 2 diabetes, small studies of metformin use have reported improvements in body composition and fasting insulin concentrations. There has also been some interest in the use of metformin as an adjunct to insulin in adolescents with type 1 diabetes improvements in glycaemic control and reductions in insulin doses have been reported.
Diabetes mellitus. Results of the United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive blood glucose control with metformin reduces the risk of diabetic complications and death in overweight patients with type 2 diabetes.The study also generated some concern regarding intensive therapy with metformin plus a sulfonylurea (see under Interactions) but this was not borne out on further analysis and such combinations are widely used. Metformin is also used with the thiazolidinediones, or with insulin in patients requiring combined or more intensive therapy. Metformin has also been investigated for the prevention of type 2 diabetes in patients at high risk. Although metformin treatment for an average 2.8 years reduced the incidence of type 2 diabetes by 31% in a study of patients with impaired glucose tolerance, intensive lifestyle modification was actually more effective (58% reduction). Lifestyle modification was also more effective than metformin in reducing cardiovascular risk factors and the development of the metabolic syndrome. The durability of these effects is unknown but follow-up of this study is ongoing.
There is some interest in using oral hypoglycaemics as adjuncts to insulin therapy in patients with type 1 diabetes. Short-term results from small studies have suggested that metformin may be beneficial, in this context, in adolescents with pubertal insulin resistance (see also Administration in Children, above) and perhaps in adults who are overweight or otherwise at risk of reduced insulin sensitivity.
Polycystic ovary syndrome. It has been suggested that hyper -insulinism may play a pathogenetic role in stimulating the abnormal androgen production from the ovary seen in women with polycystic ovary syndrome (PCOS). Most early studies ofmetformin in PCOS were small, observational, and of short duration, with mixed results. Although there were reports of reduced insulin levels, increased insulin sensitivity, and improved androgen concentrations, other studies failed to confirm these effects. Later randomised studies were also small, but some were of longer duration. These reported weight reductions of obese patients, reductions in insulin levels and increased sensitivity, improved androgen and other hormonal measures, improved menstrual patterns, and reduced hirsutism, but again, not consistently. Metformin has also been reported to increase the rate of spontaneous ovulation, and may improve the outcome of IVF procedures. Combination ofmetformin with clo-mifene appeared to improve ovulatory response, compared with clomifene alone, in studies of women with PCOS, though there is also a report of no apparent benefit. Furthermore, 2 large, placebo-controlled studies have found that metformin, either alone or with clomifene, did not improve the rate of ovulation, pregnancy, or live births in women with polycystic ovary syndrome.
Some consider that current evidence supports a trial ofmetformin in patients with anovulation, androgen excess, and vascular risk factors, but because of the lack of data on long-term safety such use should be supervised by an endocrinologist or a physician with suitable expertise.
Preparations
British Pharmacopoeia 2008: Metformin Tablets
The United States Pharmacopeia 31, 2008: Glipizide and Metformin Hydrochloride Tablets; Glyburide and Metformin Hydrochloride Tablets; Metformin Hydrochloride Extended-Release Tablets; Metformin Hydrochloride Tablets.
Proprietary Preparations
Argentina: Baligluc DBI AP Diab Dos Glucaminol Glucogood Glucophage Islotin Mectin Medobis Metforal Metfori † Oxemet Redugluc
Australia: Diabex Diaformin Glucohexal Glucomet Glucophage Novomet
Austria: Clonarol Desugar Diabetex Glucomin Glucophage Meglucon Orabet †
Belgium: Glucophage Metformax
Brazil: Diaformin Dimefor Formetf Formyn Glicefor Glifage Glucoformin Metfordin † Metformed Teutoformin
Canada: Glucophage Glumetza Glycon †
Chile: Diaglitab Fintaxim Glafornil Glicenex Glidanil Glifortex Glucophage Hipoglucin Menarini-Metforal †
Czech Republic: Adimet Diaphage Glucomerck Glucophage Gluformin Glumetsan Langerin Metfirex Metfogamma Siofor Stadamet
Denmark: Glucophage Orabet
Finland: Diformin Glucophage Metforem Oramet
France: Diabamyl † Glucophage Stagid
Germany: Biocos Diabesin Diabetase † Espaformin † Glucobon Glucophage Juformin Mediabet Meglucon Mescorit Met Metfodoc Metfogamma Metfor † Metform † MetSurrir Siofor Thiabet
Greece: Glucofree Glucophage Metforil Sukontrol
Hong Kong: CP-Metform Diabetmin Diaformin Glucomet Glucophage Glumet Guamet Melbin
Hungary: Adimet Gluformin Maformin † Meforal Meglucon Merckformin Metfogamma Metrivin † Stadamet
India: Bigomet † Emfor Emnorm Exermet Formin † Glumet Glyciphage Glyree M Insumet Metlong Walaphage X-Met
Indonesia: Benofomin Diabex Eraphage Forbetes Formell Gliformin Glucofor Glucophage Glucotika Gludepatic Glufor Glumin Gradiab Methormyl Methpica Metphar Regius Tudiab Zumamet
Ireland: Glucophage
Israel: Apophage Glucomin Glucophage Glufor
Italy: Glucophage Metbay Metfonorm Metforal Metiguanide
Japan: Glycoran Melbin
Malaysia: Diabemet † Diabetmin Glucomet Glucophage Glumet Riomet Xmet
Mexico: Aglumet Anglucid Apozemia Dabex Debeone Dimefor Dinamel Ficonax Forlucyl Glucophage Glunovag Harbamind Ifor Meglubet Melbexa Mifelar Pharmafet Pre-Dial
The Netherlands: Diabex Dianorm † Finormet † Glucophage Glumeff Niformina
Norway: Glucophage
New Zealand: Glucomet Glucophage † Metomin
Philippines: Diafat Diazen Euform Fornidd Glucare Glucoform Glucomed Glucophage Glumet Glyformin Horsulin Humamet L-Max Insunex Neoform Nidcor Sucranorm Vimetrol Xmet
Poland: Glucophage † Gluformin Metfogamma Metformax Metifor Siofor
Portugal: Diabex Glucophage Mekoll Risidon Stagid
Russia: Bagomet Formin Gliformin Glucophage Metfogamma Siofor
South Africa: Glucophage Metforal
Singapore: Diabetmin Diamin † Glucophage Glycomet Glycoran † Metforal
Spain: Dianben
Sweden: Glucophage
Switzerland: Gluconormine Glucophage Metfin
Thailand: Ammiformin Deson Diamet Formin Gluco Glucoles-500 Glucolyte Glucomet † Glucono Glucophage Gluformin Glustress † Glutabloc Gluzolyte Macromin † Maformin ME-F † Meformed Metfor Metfron Miformin Pocophage Poli-Formin Prophage Serformin Siamformet
Turkey: Glifor Glucophage Gluformin Glukofen
UAE: Dialon
UK: Glucophage Metsol
USA: Fortamet Glucophage Glumetza Riomet
Venezuela: Diaformina DimeforF Glafornil Glucaminol Glucofage
Multi-ingredient
Argentina: Avandamet DBI Duo Glucovance Gludex Plus Isloglib Medobis G Metformin Duo Rosiglit-Met
Australia: Avandamet Glucovance
Belgium: Avandamet Glucovance
Brazil: Glucovance Starform
Canada: Avandamet
Chile: Avandamet Bi-Euglucon M Diaglitab Plus Glifortex-G Glimet Glucovance Glukaut Hipoglucin DA
Czech Republic: Avandamet Competact Eucreas Glibomet Glubrava Glucovance
Denmark: Avandamet
Finland: Avandamet
France: Avandamet Competact Eucreas Glucovance
Germany: Avandamet
Greece: Avandamet Normell
Hong Kong: Avandamet Glucovance
Hungary: Avandamet
India: Betaglim M † Diaforte Diaglip M Exermet GM Exermet GZ Exermet P Gliclamet Glimiprex MF Glimulin-MF † Glinil M Glizid-M Glycigon-M Glycinorm M Glygard M Metaglez P-Glitz M Piomed M Piosafe MF Roglin-M Rosicon MF
Indonesia: Avandamet Glucovance
Ireland: Avandamet
Israel: Avandamet
Italy: Avandamet Bi-Euglucon M Glibomet Gliconorm Glicorest Glucomide Pleiamide Suguan M
Malaysia: Avandamet Glucovance
Mexico: Apometglu Avandamet Bi-Dizalon Bi-Euglucon M Bi-Pradia Duo-Anglucid Glimetal Glucotec Glucovance Imalet Insogen Plus Insusym-Forte Maviglin Mellitron Midaphar-ma Mifelar-C Nadib-M Norfaben M Obinese Sibet-C Sil-Norboral Wadil
The Netherlands: Avandamet Glucovance
Norway: Avandamet
Philippines: Avandamet Euglo Plus Glucovance
Poland: Avandamet
Portugal: Avandamet Competact Glucovance
Russia: Glibomet Glucovance
South Africa: Glucovance
Singapore: Avandamet Glucovance
Spain: Avandamet
Sweden: Avandamet
Switzerland: Avandamet Diabiformine Glucovance
Thailand: Avandamet
UK* Avandamet Competact Eucreas
USA: Actoplus Met Avandamet Diofen Glucovance Glybofen Janumet Metaglip
Venezuela: Avandamet Bi-Euglucon Diaformina Plus Glucovance Starform
The symbol † denotes a preparation no longer actively marketed.
Current Oral Antidiabetic Therapy: Biguanides
Metformin
Drug trade names: Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, Diaformin
Metformin is the only biguanide currently approved for the treatment of type 2 diabetes mellitus. It was originally developed in the 1950s in Europe and has been used there for many years. This agent was approved for use in the United States in 1995. While the mechanism of action is not completely clear at the present time, we do know that metformin is not an insulin secretagogue. It is effective in reducing hepatic and renal gluconeogenesis, thereby lowering fasting blood glucose values. Metformin also is effective in reducing postprandial blood glucose by a mechanism that is thought to involve retardation of gastrointestinal absorption. There also are some data that metformin improves peripheral insulin sensitivity by increasing the expression of glucose transporters and by increasing non-oxidative glucose metabolism.
Metformin usually is given initially as one 500-mg tablet once daily with a meal. One week later, the dose should be increased to 500 mg twice daily and can eventually reach a maximum of 2500 mg/day. Most studies show maximum effect with 2000 mg/day, with no additional efficacy at 2500 mg/day. There also are 850-mg tablets, allowing for convenient twice-daily dosing. Most studies analyzing the effects of metformin show that patients will on average lower HgbA1C by 1.5%-1.9% when it is used as monotherapy.
This agent can be added to a sulfonylurea or insulin therapy (Current Oral Antidiabetic Therapy: A Summary of Oral Therapy), in which case a further decrease in HgbA1C of 1.5% can be expected. Metformin alone is not associated with hypoglycemia, but this can occur when combined with insulin or sulfonylurea therapy. Metformin has the added benefit of reducing triglycerides and inducing mild weight loss in some overweight patients. The use of metformin to achieve glycemic control was studied in a subset of 342 obese diabetic patients in the United Kingdom Prospective Diabetes Study (UKPDS). Although reduction in myocardial infarction endpoints did not quite reach statistical significance (P<.052) in the insulin- and sulfonylurea-intensively treated groups, the obese diabetic patients treated with metformin had significant reductions in myocardial infarction, nonfatal stroke, and all cause mortality. The increased effect of metformin on prevention of macro vascular disease may be related to its known effects on decreasing low-density lipoprotein and triglyceride levels. More information should be available with the release of the UKPDS results concerning lipid profiles.
The main potential complication of metformin use is the risk of lactic acidosis. Unlike its predecessor phenformin, metformin does not strongly inhibit oxidative metabolism of glucose. Due to the absence of this effect, the risk of lactic acidosis is present, but much lower. The incidence of lactic acidosis is quite rare; however, it is recommended to avoid using metformin in patients who are predisposed to lactic acidosis or cannot metabolize lactate. Therefore, patients with a history of hepatic insufficiency, renal insufficiency, severe cardiac or respiratory disease, chronic metabolic acidosis, or alcohol abuse should not take metformin. It also is recommended that metformin should be stopped at the time of any interventional procedures, particularly surgical procedures or those requiring contrast dye. This will prevent a rise in metformin levels should acute renal failure occur. Metformin also should be used with caution in elderly patients secondary to their diminished renal function.
There are no known drug interactions and the most commonly seen side effect from metformin use is gastrointestinal irritation. Administering the tablet with food and beginning with the 500-mg dose usually prevents or ameliorates this side effect. Less than 5% of individuals will actually require cessation of metformin due to gastrointestinal side effects.
Treating Obesity in Patients with type 2 Diabetes: Antidiabetic Treatments and Weight
Approximately 40% of all type 2 diabetics take a drug from the sulfonylurea class (see TABLE 2) — usually glyburide, glipizide, or chlorpropamide. The sulfonylureas cause the beta-cells of the pancreas to increase insulin secretion. Weight gain is common with sulfonylurea use and ranges from 1.8 to 2.8 kg.
|
Table 2. Antidiabetic Drugs Used to Treat Type 2 Diabetes |
|||
| Drug | Mechanism of Action | Effect on Weight During Initiation of Therapy up to One Year | Potential Side Effects |
| Sulfonylureas | Increased insulin secretion by pancreatic beta cells | 1.8 to 2.8 kg weight gain | Weight gain, hypoglycemia |
| Metformin | Decreased hepatic glucose production/enhanced glucosedisposal by skeletal muscle | 0.6 to 0.8 kg weight reduction | Abdominal bloating, nausea, cramping, diarrhea |
| Acarbose | Inhibits alpha-glucosidase and alpha-amylase | None or negligible | Flatulence, diarrhea, abdominal discomfort |
| Troglitazone | Increased glucose disposal in muscle tissue/decreased hepatic glucose production | None to 0.6 kg weight gain | Few reported (jaundice due to idiosyncratic drug reaction) |
| Insulin | Normal physiologic effects | Up to 6.0 kg weight gain | Hypoglycemia |
Metformin (Glucophage) is a biguanide antidiabetic agent that reduces basal hepatic glucose production by altering gluconeogenesis and/or glycogenolysis. Additionally, metformin decreases insulin resistance by promoting insulin-sensitive glucose uptake by muscle cells. Metformin can also reduce triglycerides and low-density lipoprotein (LDL) cholesterol, and increase high-density lipoprotein (HDL) cholesterol. Weight reductions of 0.6 to 0.8 kg have been noted in study subjects taking metformin.When metformin is combined with the sulfonylurea glyburide, however, average weight gains of 0.7 kg have been reported.
Acarbose (Precose) is an alpha-glucosidase inhibitor as well as an inhibitor of pancreatic alpha-amylase. These enzymes are responsible for the hydrolysis of oligosaccharides and related saccharides in the small intestine. Inhibition of these enzymes results in reductions in the rate and extent of carbohydrate digestion and absorption of glucose in the body. Patients treated with acarbose tend to experience no changes in weight or serum lipids.
Troglitazone (Rezulin) belongs to a new class of drugs called thiazolidinediones. It works by decreasing insulin resistance. Its primary actions involve increasing glucose disposal from the blood stream into muscle tissue and decreasing glucose production in the liver. No or very small weight changes in patients taking troglitazone are seen. Decreases in plasma triglyceride and free fatty acid levels have also been reported.
Approximately three-quarters of all the insulin used in the U.S. is taken by people with type 2 diabetes. Exogenous insulin reduces hepatic glucose production in type 2 diabetics. It also increases insulin-stimulated glucose utilization and endogenous insulin secretion. Weight gain is common in patients using insulin and may include gains up to 6.0 kg in a 12-month period.
Two Glitazones for Diabetes
An FDA advisory committee unanimously endorsed approval for marketing of rosiglitazone (Avandia, SmithKline Beecham) and concluded that pioglitazone (Actos, Takeda) is safe (the panel did not review efficacy of pioglitazone). Even though no cases of liver failure or toxicity have been reported with either drug, the panel recommended inclusion of warnings in their labeling that would suggest periodic liver tests because of problems with troglitazone (Rezulin, Parke-Davis).
Separately, SKB strengthened its hand by announcing it would copromote rosiglitazone – likely to be approved for treatment of patients with diabetes type 2 as either monotherapy or with metformin – with Bristol-Myers Squibb, which markets metformin (Glucophage). Since rosiglitazone will probably reach the U.S. market before pioglitazone, the collaboration could be critical in quickly penetrating the insulin-resistance market. Some experts project that pioglitazone will become the market leader in the glitazone class, and Takeda’s previously announced marketing collaboration with Lilly promises to make the competition fierce.