Susan has type 2 diabetes and is under the care of diabetes specialist Nancy Bohannon, MD. Like many other type 2s she is also hypertensive, has high cholesterol and suffered a heart attack. She has arthritis, is postmenopausal and is trying to quit smoking as well. To cover all these conditions she is on a list of pharmaceuticals that might have made even Elvis Presley take a step back.
Susan takes insulin, Amaryl and Rezulin for her diabetes; Monopril, an ACE inhibitor, for her hypertension; Pravachol for high cholesterol; Lopid for her high triglycerides; aspirin and the beta-blocker Tenormin to help prevent a second heart attack; Relafen for her arthritis; Zyban and a nicotine patch to help her quit smoking; Fosamax to prevent osteoporosis; and Estratest for estrogen replacement. Obviously, not all of these medications are for her diabetes and its complications, but Susan is a fairly typical type 2 patient.
Before you had diabetes your pancreas reacted to a meal by producing insulin that allowed the glucose broken down from your meal to enter the cells of muscles and other parts of your body. Your liver was also in on the act, releasing glucose during the night and other long periods when you were not eating or producing any insulin.
Then came diabetes.
Often type 2 diabetes is the result of insulin resistant muscles. For years your pancreas was producing insulin that your muscles simply didn’t respond to. Your liver seemed to have the same problem, and continued to release glucose even in the presence of insulin. Both of these reactions increased BGs, and your pancreas fought hard to counteract this by producing more and more insulin. Once it couldn’t keep up the pace, your BGs went up and stayed up – type 2 diabetes had set in. Type 2 diabetes might also be unrelated to insulin resistance and result from your pancreas simply not making a sufficient amount of insulin.
Diet and Exercise
Diet and exercise are still the first line of defense against type 2 diabetes and should be continued even if medications become necessary later on. Developing a healthier diet can improve BG control and decrease your chances of developing many of the secondary complications of diabetes. Exercise can provide you with the same benefits, often with even more pronounced effects.
Every individual has different dietary requirements. It is advisable to meet with a dietitian to develop a diet plan that meets your needs. If this is not possible, your doctor or nurse educator can provide you with some helpful guidelines. It is also a good idea to discuss your intended exercise regimen with your doctor or diabetes educator before you start. This is especially important if you have not been very active recently. Exercise will be most effective if you gradually work your way into increased intensity rather than trying to bite off more than you can chew on the first go-around.
Diet and exercise are especially important because of their impact on cardiovascular risk factors. As was discussed this past July at the International Diabetes Federation meeting in Finland, high fasting (morning) BGs have been proven to significantly increase the chances of death from cardiovascular complications in people with type 1 and type 2 diabetes.
In addition to these benefits, diet and exercise might even help you save a few dollars. According to the Juvenile Diabetes Foundation, approximately 25 percent of type 2s are able to manage their diabetes with diet and exercise alone. These cornerstones of diabetes management could help to keep you off costly oral medications and insulin for longer periods of time, or may help you achieve good BG control with lower doses.
But, if after approximately four to eight weeks of exercise and diet modification your fasting blood glucose levels are consistently 126 mg/dl or higher, you’ll probably find yourself on the way to the pharmacy.
Everyone with diabetes is different and there are many responses to the different oral hypoglycemic agents. By looking at an individual’s overall health, average BG levels, age, eating habits, other medications being used and possible side effects, a doctor will determine which drug and dose schedule is right for each patient.
Four classes of oral medications are now available to help people with type 2 diabetes: sulfonylureas, biguanides, alpha-glucosidase inhibitors and thiazolidinediones. Each class of medication works on a different part of the puzzle of type 2 diabetes (see chart on page 18).
Sulfonylureas (Amaryl, Diabinese, DiaBeta, Glynase PresTab, Micronase, Glucotrol and Glucotrol XL)
Of all the hypoglycemic drugs available, sulfonylureas have been around the longest, long enough to have a second generation of drugs developed with fewer side effects and more powerful hypoglycemic effects leading to an average HbA1c reduction of 1.7%. The sulfonylureas listed in this article, with the exception of Diabinese, are all second generation sulfonylureas.
The best candidates for sulfonylurea therapy are those whose diabetes onset occurred after age 30, have had diagnosed hyperglycemia for less than five years, are normal weight or obese, are willing to follow a dietary program and are not insulin dependent. It is often recommended that sulfonylureas be used after a four-to-eight-week trial of exercise and diet therapy designed to lower BGs. If sulfonylurea therapy becomes necessary, exercise and dietary management should be continued.
The following precautions should be noted when taking sulfonylureas. All sulfonylureas are capable of producing severe hypoglycemia. The elderly, those with adrenal and/or pituitary insufficiency, and those with liver and/or kidney insufficiency are more sensitive to hypoglycemic drugs and more likely to experience hypoglycemia on sulfonylureas.
In addition, the University Group Diabetes Program (UGDP) has shown that the administration of oral hypoglycemic drugs is associated with an increase in cardiovascular mortality compared to diet therapy alone or diet in conjunction with insulin therapy. In this five-to-eight-year study, patients treated with diet and a fixed dose of tolbutamide (a first generation sulfonylurea) were 2.5 times more likely to die from a heart attack than those on diet therapy alone.
While there has been some controversy over the interpretations of the study’s statistics, the Physicians’ Desk Reference (PDR) states that “the findings from the UGDP study provide an adequate basis for this warning.” The PDR also notes that while tolbutamide was the only sulfonylurea used in the study, the similarities between all sulfonylureas make it prudent to consider this warning applicable to all hypoglycemic drugs in this class. Tolbutamide, however, is a first generation sulfonylurea.
For reasons that are not totally understood, some people do not respond to sulfonylureas. Others experience a loss of hypoglycemic effect from sulfonylureas over time and BGs start to run high. This is called secondary failure. When fasting BGs are over 126 mg/dl it is appropriate to make a change in your therapy regimen. You might be switched to a different hypoglycemic agent, or to combination therapy with a sulfonylurea and another hypoglycemic agent.
Metformin, marketed under the name Glucophage, works to lower BGs in a number of ways, but its mechanism of action is not fully understood. Its strongest hypoglycemic effect appears to be its ability to decrease the amount of glucose produced by the liver.
Metformin also appears to increase the rate of glucose uptake in insulin sensitive tissues like muscles. According to Zachary T. Bloomgarden, MD, in “New Therapeutic Approaches to Non-Insulin-Dependent Diabetes Mellitus” in the October 1997 issue of the journal Endocrine Practice, this effect is more pronounced in obese rather than lean type 2s.
In clinical trials the drug decreased BGs by 50 to 100 mg/dl and accounted for an approximate one to two percent drop in HbA1c levels. Similar effects have been reported in patients who have experienced secondary failure on sulfonylureas and have been switched to combination therapy of sulfonylureas and metformin.
In addition to its positive effects on BG control, metformin therapy is also associated with improved blood lipid profiles. According to a study done by Bloomgarden published in Diabetes Care in 1995, “Consistent improvements in triglyceride levels are noted during metformin therapy, and other benefits may be a decrease in low-density lipoprotein and an increase in high-density lipoprotein levels.”
Metformin therapy also appears to have more positive effects on weight gain than sulfonylurea and insulin therapies. The UK Prospective Diabetes Study found that weight gain is greater with insulin and sulfonylureas than with metformin and diet therapies. In the study, fasting insulin levels increased with insulin and sulfonylurea therapies, were stable on diet therapy and decreased on metformin.
The following precautions should be kept in mind when using metformin.
Metformin does not normally cause hypoglycemia, but it may if caloric intake has been insufficient, strenuous exercise has not been countered with adequate food intake, or metformin is being used in conjunction with other hypoglycemic medications like sulfonylureas.
Lactic acidosis is a rare but very serious diabetic complication (up to half of all cases may be fatal) that is made more likely by renal (kidney) insufficiency. The reported incidence of lactic acidosis in patients taking metformin is very low, but because metformin is processed and excreted by the kidneys, regular monitoring of renal function is strongly recommended. Because aging is often associated with decreased kidney function, persons over 80 should not be started on metformin unless tests clearly show that kidney function is not impaired. People who have severe congestive heart failure (requiring pharmacological treatment) should not take metformin as the condition increases the chance of renal insufficiency.
Similar to the risk associated with sulfonylureas, the UGDP found that patients taking phenformin (also a biguanide) had a 2.5 times greater risk of dying from a heart attack than those on diet therapy alone. There has been some controversy regarding these findings, but “The finding provides adequate basis for warning,” reads the Physicians’ Desk Reference. It also notes that even though only one sulfonylurea (tolbutamide) and one biguanide (phenformin) were tested, “It is prudent from a safety standpoint to consider that this warning may also apply to other related oral antidiabetic drugs, in view of the similarities in mode of action and chemical structures.”
For additional considerations and side-effects see page 18.
Alpha-glucosidase Inhibitors (Acarbose/Precose)
Acarbose is marketed in the United States with the name Precose and has a mechanism of action very different from the three other classes of oral type 2 medications. Acarbose slows down the absorption of carbohydrates in the intestines, which limits the increase in after-meal BGs.
As described by Peter J. Nebergall, PhD, in the fall 1997 issue of The Voice of The Diabetic, “More of a management tool than an antidote to insulin shortage, acarbose helps some diabetics keep a more constant blood glucose level.”
Acarbose has become the most frequently prescribed type 2 agent in Germany and has been shown to result in an average HbA1c decrease of 1.5 percent, a 40 mg/dl decrease in fasting BG levels and a 60 to 80 mg/dl decrease in after-meal BGs in 10,000 type 2s. In a recent study presented at the ADA’s 57th Annual Meeting and Scientific Sessions, it was found that African-Americans experience less reduction in HbA1c than their Hispanic, Asian and Caucasian peers when using acarbose.
The following precautions should be kept in mind when using acarbose.
Acarbose alone does not cause hypoglycemia, but may when used in conjunction with other hypoglycemic agents like sulfonylureas.
Gastrointestinal disturbances are the most common side-effect of acarbose treatment. Abdominal pain and diarrhea were the most common problems experienced and tended to return to pretreatment levels over time.
Elevated serum transminase levels (an enzyme that reflects liver function) have also been observed in patients on acarbose. The elevations tend to be dose related, and according to the PDR are, “reversible, more common in females and, in general, were not associated with other evidence of liver dysfunction.”
Rezulin is the first thiazolidinedione, a new class of drug that works primarily as an insulin sensitizer, to be approved for marketing in the United States by the FDA (March 1997). Troglitazone is the only diabetes medication whose primary mechanism of action works at the muscular level, enhancing muscles’ ability to respond to insulin.
Because insulin must be present for troglitazone to work, it was originally approved for use by type 2s who take insulin. As clinical trials continued, it became clear that troglitazone also worked to lower BGs when used alone (with diet and exercise modification) and when used in conjunction with a sulfonylurea. The FDA approved troglitazone for these uses on August 4, 1997.
In one of these clinical trials, 30 percent of those treated with 200 mg of Rezulin and 57 percent of those taking 600 mg had an HbA1c below 8% after six months of treatment while significantly lowering their insulin doses. Only 11 percent of those taking a placebo were able to do the same.
In another trial, insulin-taking type 2s were treated with 200 and 400 mg of troglitazone and their insulin doses were reduced by 41 and 58 percent respectively. Only 14 percent of those taking a placebo were able to do the same. In addition, 15 percent of patients in the 400 mg group and seven percent of those in the 200 mg group were able to discontinue insulin therapy.
In a related study, 41 percent of those taking 400 mg a day were able to go from three daily insulin injections to one.
The following precautions should be noted when taking Rezulin.
Troglitazone alone does not cause hypoglycemia. However, when it is used in conjunction with insulin or a sulfonylurea users may be at risk of developing hypoglycemia. It is recommended that those taking troglitazone in conjunction with another hypoglycemic agent monitor their BGs four to five times a day and keep in close contact with their doctors when they first start on troglitazone, as some patients may need to make substantial decreases in their insulin and/or sulfonylurea doses. Users are advised to learn the symptoms of approaching hypoglycemia and teach friends and family members how to deal with hypoglycemic episodes.
In November of 1997 Parke-Davis, in conjunction with the FDA, announced its plans to change Rezulin’s packaging and prescribing recommendations to reflect the possibility of severe liver damage when using Rezulin. These changes were made in response to 35 reports of “liver dysfunction events” in the approximately 800,000 people using the drug in the United States and Japan.
These “events” ranged from mild to severe increases in transminase levels (an enzyme that reflects liver function) to more severe problems – one patient who required a liver transplant and one death. Within the next month three more deaths were reported in Japan and the total number of adverse events increased to 150 before the labels and prescribing information were changed. Parke-Davis stresses that these events are still very rare, but wants to proceed with caution due to the severity of some of the cases.
Parke-Davis now recommends patients get an initial liver function test before starting the drug, liver function tests once a month for the first six months, tests every other month for the next six to twelve months and periodically thereafter
If transminase levels are greater than three times normal, Rezulin therapy should be discontinued.
Glaxo Wellcome, the company that markets the drug in the United Kingdom, made an independent decision to pull it from the shelves after these reports. The FDA, Parke-Davis and the National Institutes of Health (which is using Rezulin in the Diabetes Prevention Program) have all decided that the benefits outweigh the potential risks.
Parke-Davis notes that its clinical trials for FDA approval revealed that approximately two percent of those taking Rezulin had levels of transminase that were three times above the upper limit of normal, a far greater percentage than the approximate .02 percent of the nearly 800,000 that have recently reported problems.
In addition, using troglitazone while on an oral contraceptive that contains ethinyl estradiol and norethindrone will reduce the concentrations of both medications by approximately 30 percent. This may result in a loss of contraception.
“Take TWO of These and Call Me In the Morning”
It is important to learn as much as possible about the benefits and possible complications of any medication you are taking. However, knowing all about what a medication can do for you won’t do you any good if you don’t take it as directed.
According to the National Association of Chain Drug Stores (NACDS), studies show that by the time patients get to the pharmacy from the doctor’s office they have forgotten half of the doctor’s instructions about a medication. The NACDS also quotes the Forum Drug Utilization Review survey finding that diabetics have one of the highest rates of non-compliance for the use of medications – 40 to 50 percent.
Failing to take a medication as prescribed can have some serious consequences. In fact, medication errors (for all types, not just diabetes) are responsible for 10 percent of all hospital admissions, 25 percent of all hospitalization admissions for the elderly, 23 percent of all nursing home admissions and 20 million lost work days a year. The NACDS estimates that approximately $50 to $100 billion a year is spent on medical problems stemming from taking medications incorrectly.
Taking medication as directed can be especially hard for people with type 2 diabetes. Many type 2s are on several medications at a time, most with different dosing schedules.
Keeping a personal record of the medication you take, the frequency of your doses and special considerations for each medication can help to prevent mistakes. It is advisable to write this information down while you are still in the doctor’s office and ask as many questions as possible. With the answers to these questions in mind (or better yet on paper) and a commitment to follow a healthy diet and exercise regimen, you can start on your path to better BG control and better health.