What is a sick day? Any day that you are not feeling well, having trouble eating your usual meals, or are experiencing a medical procedure or extreme emotional upset.

Why are sick days important? Diabetes is affected not only by what you eat and the insulin you take, but also by other hormones in the body. Hormones that work against insulin usually increase during illness or stress, causing the insulin you take to work less effectively. This is why illness and stress cause the blood sugar to rise. Diabetic ketoacidosis is a severe, life-threatening complication of diabetes that commonly occurs during illness or severe stress. This develops due to a lack of adequate insulin to fight the stress-related hormones.

What can I do ? The MOST important thing you can do during a sick day is to take your insulin. Even if you cannot eat, your body needs at least the insulin you take during a usual day, maybe even more. You should adjust your insulin as follows:

• Identify your longest-acting insulin. This is probably either glargine (Lantus), NPH, or Lente. Take your usual dose of this insulin, the same number of times during the day.

• Identify your shortest-acting insulin. This is probably lispro (Humalog), aspart (Novolog), or regular insulin. If you are not eating, do not take your usual doses of the short-acting insulin. Take the short-acting insulin as follows:

Add together your total daily dose of all insulin.

How many units of long-acting and short-acting insulin do I take in a typical day? units

Figure out 15% of this number (with a calculator, multiply your total daily dose x 0.15). If the result is a fraction, round up to the nearest unit. This is your “sick day dose”.

My “sick day dose” is: units of short-acting insulin.

When blood sugar is over 150 mg/dl, take this dose of short-acting insulin, at least 4 hours apart.

What should I eat? If you are able to, eat the way you usually do. If you are unable to eat normally, it is important to make sure you get enough fluid and carbohydrate (sugar).

Drink 4-6 ounces (4 ounces is half a cup) of fluid without calories every 30 minutes.

This fluid could include water, unsweetened hot or cold tea, or diet soft-drinks. This fluid is important to prevent dehydration.

Eat or drink 50 g of carbohydrate every 4 hours. To find the carbohydrate content in food/fluids, look at the nutritional label. Note the serving size, and the total carbohydrate.

For example, one can of (non-diet) soda contains 12 ounces and 43 g of carbohydrate. This carbohydrate (sugar) will provide you with energy to fight your illness, and help to prevent low blood sugar.

What else should I do during a sick day?

• Check your urine for ketones. When the body produces ketones (detectable in the urine) and your blood sugar is high, it means you are not taking enough insulin to stay in control during your illness.

If you have ketone strips, make sure they are not expired

If you do not have ketone strips, get some at the pharmacy (available without a prescription)

Check your urine for ketones several times daily while you are sick. If you are taking enough insulin and fluids, ketone levels should not be more than “small”

• Call your diabetes care provider (primary care physician, nurse practitioner, or diabetes educator) if:

You vomit (throw up) even once; ask for an antinausea medication. Suppositories work best if you are having trouble keeping food down. A prescription may need to be called in to your pharmacy. This could prevent a hospital stay.

You have an obvious infection. You may need an antibiotic.

Your illness lasts longer than 2 days

Your blood sugar is over 400 mg/dl, two times in a row, after you have taken your sick day dose of insulin and it should have had an effect.

You have “moderate” to “large” amounts of ketones in your urine and a blood sugar over 200 mg/dl for more than 8 hours, even after taking your sick day dose of insulin.

You feel very sick or are in pain.

You have abdominal pain, shortness of breath or trouble breathing, your family notices a fruity odor in your breath, or you become extremely sleepy or woozy.

Your diabetes care provider is:

Name:____________________________________________________________________

Office number:_____________________________________________________________

Emergency contact information:________________________________________________

Type 2 Diabetes

What is a sick day? Any day that you are not feeling well, having trouble eating your usual meals, or are experiencing a medical procedure or extreme emotional upset.

Why are sick days important? Diabetes is affected not only by what you eat and the insulin you take, but also by other hormones in the body. Hormones that work against insulin usually increase during illness or stress, causing the insulin you take to work less effectively. This is why illness and stress cause the blood sugar to rise. Severe high blood sugar requiring hospitalization can occur if proper care is not taken during illness.

What can I do? When you are sick, even if you are unable to eat normally, you must take your diabetes medication. If you take only pills for your diabetes, you need these even if you are unable to eat. Metformin (Glucophage), a common diabetes medication, can cause stomach upset if not taken with meals. If this happens to you, stop taking the metformin until you are able to eat again.

If you take insulin (either alone or in combination with diabetes pills), you still need to take it while you are sick. Even if you can not eat, your body needs at least the insulin you take during a usual day, maybe even more. You should adjust your insulin as follows:

• Identify your longest-acting insulin. This is probably either glargine (Lantus), NPH, or Lente. Take your usual dose of this insulin, the same number of times during the day.

• Identify your shortest-acting insulin. This is probably either lispro (Humalog), aspart (Novolog), or regular insulin. If you are not eating, do not take your usual doses of the short-acting insulin. Take the short-acting insulin as follows:

Add together your total daily dose of all insulin.

How many units of long-acting and short-acting insulin do I take in a typical day?_ _units

Figure out 15% of this number (with a calculator, multiply your total daily dose x 0.15). If the result is a fraction, round up to the nearest unit. This is your “sick day dose”.

My “sick day dose” is: _units of short-acting insulin.

When blood sugar is over 150 mg/dl, take this dose of short-acting insulin, at least 4 hours apart.

What should I eat? If you are able to, eat the way you usually do. If you are unable to eat normally, it is important to make sure you get enough fluid and carbohydrate (sugar).

• Drink 4-6 ounces (4 ounces is half a cup) of fluid without calories every 30 minutes. This fluid could include water, unsweetened hot or cold tea, or diet soft-drinks. This fluid is important to prevent dehydration.

• Eat or drink 50 g of carbohydrate every 4 hours. To find the carbohydrate content in food/fluids, look at the nutritional label. Note the serving size, and the total carbohydrate. For example, one can of (non-diet) soda contains 12 ounces and 43 g of carbohydrate. This carbohydrate (sugar) will provide you with energy to fight your illness, and help to prevent low blood sugar.

What else should I do during a sick day?

• If you normally take insulin, check your urine for ketones. When the body produces ketones (detectable in the urine) and your blood sugar is high, it means you are not taking enough insulin to stay in control during your illness.

if:

If you have ketone strips, make sure they are not expired

If you do not have ketone strips, get some at the pharmacy (available without a prescription)

Check your urine for ketones several times daily while you are sick. If you are taking enough insulin and fluids, ketone levels should not be more than “small” Call your diabetes care provider (primary care physician, nurse practitioner, or diabetes educator)

You vomit (throw up) even once; ask for an antinausea medication. Suppositories work best if you are having trouble keeping food down. A prescription may need to be called in to your pharmacy. This could prevent a hospital stay.

You have an obvious infection. You may need an antibiotic.

Your illness lasts longer than 2 days

Your blood sugar is over 400 mg/dl, two times in a row, after you have taken your sick day dose of insulin and it should have had an effect.

You have “moderate” to “large” amounts of ketones in your urine and a blood sugar over 200 mg/dl for more than 8 hours, even after taking your sick day dose of insulin.

You feel very sick or are in pain.

You have abdominal pain, shortness of breath or trouble breathing, your family notices a fruity odor in your breath, or you become extremely sleepy or woozy.

Your diabetes care provider is: Name:___________________

Office number:______________

Emergency contact information:.

TABLE Noninsulin Agents for Treatment of Type 2 Diabetes

TABLE Mechanisms to Lower Blood Glucose by Each Antidiabetic Agent

Note: X, main mechanism; (X) less-clear mechanism.

Sulfonylurea

Sulfonylurea preparations have a long record of safety and effectiveness. They work by stimulating insulin secretion by the pancreatic /3-cell, binding to an adenosine triphosphate-sensitive potassium channel, which results in its depolarization, a subsequent influx of intracellular calcium, and the release of insulin. Sulfonylureas are effective both as monotherapy and in combination with other agents that have different mechanisms of action. A significant percentage of patients (up to 10% per year) who are initially properly managed with sulfonylurea monotherapy lose glycemic control over time. Their main side effects include hypoglycemia and weight gain. Hypoglycemia is a serious adverse effect in the elderly and can trigger serious events such as myocardial infarction and stroke. These drugs must be used cautiously in patients with significant renal and hepatic insufficiency, since the liver is the primary site of metabolism and they are excreted by the kidneys. In these settings, the preferred option may be glipizide, whose metabolites are inactive, or glimepiride, which is substantially excreted through the bile.

A commonly used sulfonylurea in younger populations, glyburide, may have age-related impaired absorption and elimination, and elderly subjects appear to have enhanced insulin responses to the drug as well. This may explain, in part, the age-related exponential increase in the frequency of severe or fatal hypoglycemia with this drug.

TABLE Limiting Factors in the Use of Antidiabetic Agents in the Elderly

May impede ischemic preconditioning Frequent dosing may affect compliance; no long-term experience Risk of lactic acidosis; diarrhea Edema; expensive; no long-term experience Frequent dosing may affect compliance; intestinal gas; expensive Injection; expensive; no long-term experience

Note: X, main side effect; XX, pronounced side effect. Abbreviation: wt, weight.

In addition to the type of sulfonylurea, other potential risk factors for hypoglycemia with these drugs in elderly persons include black race, multiple medications, male sex, renal dysfunction, and ethanol consumption. Sulfonylureas should be considered as first-line therapy in lean elderly patients with diabetes. The result in hemoglobin Ale (HbAlc) lowering is approximately 1% to 2% as monotherapy.

Meglitinides

Meglitinides (repaglinide and nateglinide) are nonsulfonylurea drugs that have a distinct β-cell binding profile and stimulate insulin secretion from the β-cell by a mechanism similar to that of sulfonylureas. The potential advantage of this type of drug is that it has a rapid onset and very short duration of action. Meglitinides have been associated with lower frequency of hypoglycemic events when compared with conventional sulfonylureas, presumably because of their shorter duration of action and the fact that the kinetics are not altered with age. Repaglinide lowers HbAlc by 1% to 2%, a reduction similar to that of the sulfonylureas, whereas the glucose-lowering effect of nateglinide is somewhat less potent. Similar changes in fasting glucose and HbAlc values are seen in middle-aged and elderly subjects, suggesting that there is similar efficacy in each age group. Both repaglinide and nateglinide are extensively metabolized by the liver; therefore, they should be used cautiously in patients with hepatic dysfunction. Meglitinides may be considered as an appropriate strategy for elderly patients who have irregular eating habits or have frequent hypoglycemic events on conventional sulfonylureas. These potential benefits must be balanced against the cost of these newer drugs and the compliance problems that could result from a three-times-a-day dosing schedule, particularly in patients who have impaired memory or take may other drugs.

α-Glucosidase Inhibitors

α-glucosidase inhibitors (miglitol and acarbose) impair the breakdown and limit the absorption of carbohydrates from the gut; therefore their major effect is reduction in postprandial glucose excursions. These drugs are associated with less weight gain and a lower frequency of hypoglycemia than sulfonylureas. The residual carbohydrates in the intestinal lumen cause diarrhea in about 25% of patients taking these drugs. Gradual dose titration is crucial to minimize gastrointestinal side effects and achieve better compliance. Their overall effect on HbAlc concentration is a modest reduction of 0.5% to 1%. In a recent randomized multicenter trial of the a-glucosidase inhibitor acarbose in obese elderly patients with diabetes, acarbose reduced HbAlc by about 0.8% when compared with placebo and also resulted in an improvement in insulin sensitivity. α-glucosidase inhibitors are useful drugs as primary therapy for elderly patients with modest fasting hyperglycemia, especially if they are obese. They can also be used in patients taking other oral agents to enhance glycemic control. Hypoglycemia may occur if these agents are used in combination with sulfonylureas or insulin; consequently, only glucose should be used for prompt treatment of hypoglycemia because the absorption of other carbohydrates is delayed. Acarbose has minimal systemic absorption, yet some hepatic metabolism occurs and because of rare but possible hepatotoxicity, it is contraindicated in patients with advanced liver disease. In contrast, as much as 50% to 90% of the miglitol dose may be absorbed but is not metabolized in the liver but rather eliminated through the kidney. Therefore, miglitol should not be used in patients with renal failure.

Metformin

Metformin is currently the only biguanide available in North America. Its mechanism of action is to improve insulin sensitivity, chiefly by reducing insulin resistance in the liver, thereby decreasing hepatic glucose production. In addition, its glucose-lowering effect is accompanied by a reduction in plasma insulin concentration, and some experts refer to metformin as an insulin sensitizer. Metformin lowers HbAlc by 1% to 2%. Although, the most important side effect associated with biguanides is lactic acidosis, this is rare with metformin; and aging itself does not appear to be a risk factor provided that careful attention is paid to the contraindications for this drug (significant liver, renal, and cardiac disease). Clinical studies suggest that the drug is safe and effective as monotherapy in obese older people. In our view, metformin is an ideal drug for first-line therapy of obese older patients, because it increases insulin sensitivity, assists with weight loss, reduces lipid levels, and does not cause hypoglycemia. The recently published ADA management algorithm suggests the use of metformin, together with lifestyle intervention, as initial monotherapy.

In addition, metformin is a useful adjunct for patients who are inadequately controlled on maximum doses of sulfonylureas. Metformin is contraindicated in older subjects with renal insufficiency, in men with a serum creatinine level of 1.5 mg/dL or higher or women with a serum creatinine level of 1.4 mg/dL or higher. Serum creatinine should be measured at least annually and with any increase in dose of metformin. It should be noted, however, that serum creatinine does not adequately reflect the renal function in the elderly. For those aged 80 years or older or those suspected to have reduced muscle mass, a timed urine collection for creatinine clearance should be obtained. Metformin should be avoided if the value is less than 60 mL/ min. Metformin should be temporarily discontinued during radiographic studies that use iodinated contrast agents, during acute illness, and during most hospitalizations. Clinical situations where tissue perfusion is compromised (sepsis, dehydration, pulmonary disease with hypoxemia, and acute or advanced heart failure) also contraindicate the use of metformin.

Thiazolidinediones

Thiazolidinediones (rosiglitazone and pioglitazone) improve insulin sensitivity primarily in muscles and adipocytes, thereby increasing peripheral uptake and utilization of glucose. They are generally well tolerated and appear to be as effective in older patients as in younger patients, with an approximate 1.5% reduction in HbAlc and with a dose-dependent glucose-lowering effect, which may take four to eight weeks. In addition to benefits of these drugs on cardiovascular and metabolic markers, a recent randomized trial has shown the effect of pioglitazone on the reduction of cardiovascular outcomes in patients with type 2 diabetes. Thiazolidinediones do not lead to hypoglycemia unless they are used in conjunction with secretagogues or insulin. Hepatic toxicity has not been reported in elderly subjects, but liver function tests should be monitored regularly. The incidence of edema and anemia is higher in elderly patients than in middle-aged patients treated, and volume status and blood count need to be carefully monitored. Thiazolidinediones-related fluid retention is a major contributor to increased body weight, typically manifests as peripheral edema, and develops predominantly within the first months of treatment. Thiazolidinediones can be a useful first-line therapy in obese elderly patients, particularly for those patients who cannot tolerate metformin or those who have a contraindication to it. In fact, thiazolidinediones can be safely used in patients with renal impairment provided that the cardiac function is preserved. In addition, they may be a beneficial adjunct therapy in elderly patients who have suboptimal glycemic control, despite insulin requirements of 50 or more units per day.

Controlling your blood sugar levels can be an ongoing challenge. Many different factors affect your blood sugar levels, including diet, activity, stress, and overall health. Knowing how much to eat, how much to exercise, and how much medication and/or insulin to take can be difficult. Keep in mind that your type 2 diabetes care team is available for support.

Making Blood Sugar Control More Manageable

When you have type 2 diabetes, it is easy to get caught up in the day-to-day actions that are required to manage your condition. Sometimes all of the “shoulds” and “should nots” can feel overwhelming. To make your daily efforts more manageable, it may be helpful to think about all your reasons for controlling your blood sugar. You may want to consider posting a list of these reasons where you will see it often.

There are other approaches you can take that might make the steps along the way easier. Try Glucophage XR. For example, if you plan to increase your physical activity, start by taking a 15-minute walk 3 times a week. Then try walking longer or more often. Remember, a big part of the process is learning what works for you. Your healthcare team can help you construct a manageable diabetes care plan.

In addition to exercise, diet, and weight loss, some people with type 2 diabetes need medication to keep their blood sugar levels under control. If you require medication to help control your blood sugar, you may want to ask your doctor or healthcare professional if Glucophage XR may be right for you.

In the ovaries of normal women, progesterone is converted within the theca cells to 17alpha-hydroxyprogesterone, then to androstenedione, and finally to testosterone. Testosterone, in turn, is converted to estradiol in the granulosa cells. In women with polycystic ovaries, there is an increase in the enzyme cytochrome P450c17alpha that converts progesterone to androstenedione. Since androstenedione is rapidly converted into testosterone, the result is increased testosterone production. Some of the excess testosterone causes premature follicular atresia and anovulation, some of the excess reaches the circulation.

What causes the increase in ovarian enzyme activity? It appears that the culprit is insulin, or more to the point, insulin resistance with compensatory hyperinsulinemia. Insulin increases testosterone production by stimulating ovarian function, specifically, by stimulating the activity of cytochrome P450c17alpha. Insulin also decreases serum sex hormone-binding globulin by decreasing the hepatic production of the binding protein; with less binding capacity, there is more free testosterone in the serum. Finally, it appears that insulin increases LH production. Дuteinizing hormone (LH) contributes to POS by stimulating theca-cell growth and thus enhancing testosterone production.

Recently Nestler and Jakubowicz published a report in the New England Journal of Medicine describing the results of their study of an oral hypoglycemic agent – metformin (Glucophage/Bristol Myers Squibb) – on glucose tolerance and serum steroid concentrations in 24 obese women with polycystic ovary syndrome (POS). Metformin is a biguanide that reduces insulin resistance and secondarily inhibits insulin secretion. The subjects were given either placebo or metformin (500 mg three times daily) for 4-8 weeks. Compared with placebo, metformin reduced insulin secretion by about 50% and caused a reduction of approximately 50% in levels of basal and peak serum 17alpha- hydroxyprogesterone and serum free testosterone. Metformin also reduced serum LH about 75% and increased serum sex- binding globulin concentration about 75%. These values remained basically the same in the placebo group.

In some of the study participants, metformin actually induced ovulation. The fact that the reduction in insulin secretion caused a prompt drop in serum basal and stimulated-peak 17alpha-hydroxyprogesterone levels indicates that insulin has a direct effect on cytochrome P450c17alpha, enhancing the production of the hydroxyprogesterone. The effects of insulin on this enzyme are probably heritable, since not all women with insulin resistance and hyperinsulinemia have POS.

In an accompanying editorial in the New England Journal of Medicine, Robert Utiger said that POS is currently treated with weight loss and oral contraceptives and/or an antiandrogen such as spironolactone of cyproterone. The infertility is treated with clomiphene or assisted- reproduction procedures. However, if metformin can reduce androgen production, restore cyclic pituitary-gonadal function, and improve fertility, “it could represent a substantial advance in treatment for women with polycystic ovary syndrome.”

* Extreme thirst

* Frequent urination

* Extreme hunger

* Unexplained weight loss

* Unexplained fatigue

* Blurry vision

* Tingling or numbness in the hands, feet, or legs

* Itchy skin

* Frequent infections of the skin, gums, vagina, or bladder

* Slow healing of cuts and scrapes

If you learn that you have type 2 diabetes and diet and exercise are not enough, treatments are available that may help you control your blood sugar levels. One such treatment is Glucophage XR. Ask your doctor or healthcare professional if Glucophage XR may be right for you.

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.

(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.

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.

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.

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.