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The Right Drug at the Right Dose
If you’ve ever compared notes with another person who has diabetes, chances are that your treatment regimens are different, even if you have the same type of diabetes. Why is this?
Health-care practitioners have a large amount of information to take into consideration when deciding on a course of therapy for an individual. They have information on the condition itself and what causes it. They have information on the options for treating it, and, for some conditions, there may be many options. And they have information on the person needing treatment, which can also affect which type of therapy is offered.
This article explores how doctors decide what therapy to recommend and why finding the best therapy for any one individual often takes trial and error.
Diagnosing the problem
Years of research go into determining which tests to use to diagnose a condition, as well as which test results indicate that treatment is needed. In some cases, a test must be repeated one or more times to confirm the first result, or another test must be done to confirm a diagnosis.
However, both the test used to diagnose a condition, and/or the test result at which a diagnosis is made, may change over time, as more research is done, more is learned about a condition, and better tests are devised.
The are currently four types of blood tests that can be used to diagnose diabetes: the HbA1c test (a result of 6.5% or higher means diabetes), the fasting plasma glucose test (a result of 126 mg/dl or higher means diabetes), the oral glucose tolerance test (a two-hour plasma glucose level of 200 mg/dl or higher means diabetes), and the random plasma glucose test (a level of 200 mg/dl or higher means diabetes in a person with symptoms of diabetes). In each case, the practitioner must choose the most appropriate test.
Up until recently, the fasting plasma glucose test was the preferred test for screening people for Type 2 diabetes. In 2010, however, the American Diabetes Association (ADA) began recommending that the HbA1c test be used instead. This is at least in part because it is not necessary to fast before having an HbA1c test, the test does not require drinking a glucose solution, and a person’s HbA1c level is unaffected by stress or illness at the time the blood sample is taken. However, one of the other tests may still be used if a practitioner has reason to believe that one of them would give more meaningful results in a given individual. And when screening pregnant women for gestational diabetes, the oral glucose tolerance test is still the preferred test, but the cut-off values indicating gestational diabetes are different from the cut-off indicating Type 1 or Type 2 diabetes.
There are multiple ways to diagnose many conditions other than diabetes, as well, and the test chosen often depends on the individual. This is because personal characteristics such as sex or the presence of certain medical conditions can affect the accuracy of some medical tests. Being a woman and having diabetes, for example, can influence which tests are used to detect coronary artery disease.
Choosing a treatment
In the United States, treatment guidelines are issued by the National Institutes of Health (NIH), as well as by organizations such as the ADA. Guidelines issued by the NIH can be found online at the Web site of the National Guideline Clearinghouse, www.guideline.gov. They are usually written by experts with comments from outside reviewers as well as public comments prior to their publication. Guidelines written by professional societies are usually written by expert panels composed of members of that society.
Guidelines for the treatment of the various types of diabetes have been published by a number of organizations, including the ADA, the American Association of Clinical Endocrinologists (AACE), the European Association for the Study of Diabetes, the International Diabetes Federation, and others. Such guidelines include not just how the condition is to be treated but what the treatment should accomplish (the “goals” of treatment). However, not all of the organizations recommend the same treatment approach or agree on the goals of treatment. For example, the ADA suggests a goal of an HbA1c level lower than 7% for most adults with diabetes, while the AACE suggests a goal of less than 6.5%. This can lead to differences in the recommendations made by individual practitioners to their patients.
In people with Type 1 diabetes, the goal of treatment is to replace the body’s natural insulin with manufactured insulin so that blood glucose levels stay in a near-normal range. Doctors establish a starting dose, often based on body size, then make dose adjustments based on daily blood glucose monitoring and periodic HbA1c tests. In many cases, the person with Type 1 diabetes is educated to make daily dose adjustments independently.
In people with Type 2 diabetes, the goal is also to lower blood glucose levels to the near-normal range, but treatment may or may not include insulin. In general, changes in lifestyle are included in all Type 2 diabetes treatment recommendations. The drug metformin is usually considered to be the first drug of choice. The ADA then suggests the addition of insulin or a drug in the sulfonylurea class (such as glimepiride, glyburide, or glipizide). Long-acting insulin is often added to supplement oral drugs in people with Type 2 diabetes, although some studies suggest that adding rapid-acting insulin at mealtimes may be equally effective and could be done first. The ADA recommendations also allow for the use of other approved diabetes drugs in selected people.
The AACE’s recommended approach to treating Type 2 diabetes varies based on a person’s HbA1c at diagnosis. It also suggests using some newer drugs, such as those in the class known as DPP-4 inhibitors (such as Januvia) and those known as GLP-1 agonists (such as Byetta) at an earlier stage of treatment.
Both of these approaches to treatment are based on expert committee reviews of the scientific literature, and both encourage adding to or changing the drug regimen quickly — within one to three months — if the current one has not lowered HbA1c level to goal.
In addition to the recommendations of professional medical bodies, doctors also rely on their medical training, their previous experience treating the condition in question, and any continuing education they have received when prescribing treatment.
Narrowing the choices
Allergies. An allergy to a medicine usually prohibits the use of that medicine or sometimes the use of an entire class of medicines. True allergies are due to an immune-based reaction and typically cause such symptoms as skin rashes, itching, wheezing, and tissue swelling. Before prescribing a new drug, doctors ask if a person has any known drug allergies.
Pregnancy or breast-feeding. When a woman is pregnant or breast-feeding, the potential effects of any therapy on the fetus or newborn must be considered. Only medicines that are clearly needed and have an acceptable balance of benefit (to the mother) and risk (to the fetus or newborn) should be prescribed.
The Food and Drug Administration currently classifies drugs in categories A, B, C, D, and X, with A being shown to be safe during pregnancy, and X being a drug that is known to harm human fetuses. Drugs in categories B, C, or D have varying levels of evidence one way or the other. The FDA is currently revising this labeling system to make the information on risks clearer.
The usual blood-glucose-lowering drug of choice during pregnancy is insulin, regardless of the type of diabetes a woman has (Type 1, Type 2, or gestational). However, most retrospective studies and published clinical experiences on the use of oral diabetes medicines during pregnancy have not shown an increased risk of birth defects. Women who currently take oral diabetes drugs and are planning a pregnancy are advised to discuss their options with their doctor.
Other medical conditions. Certain medical conditions can influence drug choices. For example, abnormalities in stomach acidity or small bowel disease may decrease drug absorption, possibly limiting the therapeutic options for people with these conditions.
When a person with diabetes requires treatment for another medical condition, the effect of the treatment on his blood glucose level is an important consideration. Some drugs are known to raise or lower blood glucose levels, or to make the symptoms of low blood glucose less noticeable, and these drugs may need to be avoided or used with caution.
Kidney and liver function. The two major organs involved in drug metabolism are the liver and the kidney, so tests to evaluate how well they are functioning are sometimes done before starting a new drug. Evaluating the kidney’s degree of functioning is commonly done with a serum [blood] creatinine test. Normally, the kidney removes creatinine from the blood, so the higher the blood level of creatinine, the lower the kidney function. There are no good tests to evaluate liver function, but physicians look at blood tests of liver enzymes and bilirubin to get some idea.
It’s worth noting that kidney and liver function can change over time and typically diminish with age. When this happens, these organs cannot process and eliminate drugs from the body the way they once did, and drugs can build up to dangerous levels in the blood (a condition called drug toxicity). This is a common reason people who take insulin start developing hypoglycemia even when they haven’t changed their usual dose of insulin: The kidneys are responsible for eliminating insulin from the body, but when they aren’t working as well, the insulin stays in the body longer, leading to hypoglycemia.
Physical or mental disabilities. Certain drugs such as sedatives and antidepressants may worsen the ability to think clearly or to remember things, or they may cause outright confusion. They would therefore be avoided in people already experiencing thinking or memory problems, such as those believed to have early Alzheimer disease. Many other drugs, including some common over-the-counter therapies may also cause confusion.
Physical disabilities such as low vision, arthritis in the hands, or difficulty swallowing can also affect drug — or drug formulation or packaging — choices. For example, people with low vision who need insulin may find it easier to use an insulin pen than a syringe. People who have difficulty opening pill bottles or manipulating a blood glucose meter because of hand problems may need to seek out alternative pill packaging or devices that help open packages and meters and lancing devices with rubber, “easy-grip” features.
Other drugs already being taken. Drug interactions are a major issue when prescribing a new drug. Drug interactions can produce exaggerated effects when multiple drugs are given to achieve the same goal. It’s also possible for one drug to block the metabolism of another drug, resulting in excessive blood levels of the drug whose metabolism is blocked. In a third possibility, one drug can prevent another drug from doing its job. For example, NSAIDs (such as Motrin) prevent aspirin from inhibiting platelet function when taken at the same time.
Age. Very young age and very old age must be considered when prescribing a drug. That’s because kidney and liver function may be lower or diminished in these age groups, so drugs may not be metabolized at the rate expected. In addition, premature infants have a lower body weight than other newborns, and elderly people may also have a low body weight, meaning they need less of a drug than a heavier person.
Age is also considered when deciding how aggressively to manage certain conditions. For example, the cholesterol goals for a 90-year-old may not need to be as low as for a 50-year-old, and therefore therapy for the 90-year-old is less aggressive.
Body size or weight. For children, drug dosing is often done according to body weight. In adults, many oncology [cancer] drugs are dosed based either on body weight or on body surface area (using an equation that takes height and weight into account). The amount of insulin a person needs can also be affected by weight: When weight is gained, an increased dose may be needed, and if weight is lost, less insulin may be necessary to maintain blood glucose in target range.
Some medical professionals have argued that certain other classes of drugs, such as antibiotics, should also be dosed based on body size for adults, based on data showing that obese people may respond differently to some drugs than people of lower weight.
However, this is a medical issue that has yet to be thoroughly researched.
Profession or daily activities. Many drugs can reduce concentration or cause sleepiness, which can be a big problem for people who need to operate machinery or drive. For these people, doctors attempt to prescribe the least-sedating drugs. For example, to treat allergies, nasal steroids or antihistamines that are less sedating may be prescribed in place of antihistamines such as diphenhydramine (brand name Benadryl), which is known to cause sedation.
Side effects. All drugs have side effects, but sometimes a person develops such severe or intrusive side effects that an alternative must be sought. This can happen soon after a person starts a drug, but in some cases it happens after a person has been using a drug for a long time with no complaints. As noted earlier, a change in kidney or liver function can affect how a person’s body processes a drug, possibly resulting in the onset of side effects. Weight loss can also reduce the amount of a drug a person needs and lead to new side effects if the dose is not reduced. But many times the reason for late-onset side effects is unknown.
Ability to pay. In an ideal world, a person’s ability to pay for a therapy (or his insurance coverage for it) would not be a consideration. Physicians would simply prescribe what is best for the person regardless of cost. But in today’s world, that’s not the way it usually works. To save you out-of-pocket costs, your doctor may prescribe a generic drug or the brand-name drug favored by your health insurance plan. Generic drugs have the same active ingredients as brand-name drugs and should provide equally effective treatment. When no generic is available, your doctor may be able to choose from several drugs in the same class, which have similar effects but may be sold for different prices or require different co-payments.
Once an effective drug and lifestyle regimen has been established, the HbA1c test is used periodically to see whether the regimen continues to be effective. In addition, tests and examinations for long-term diabetes complications such as kidney disease, retinopathy, neuropathy, and cardiovascular disease should be done periodically.
People with diabetes also do their own follow-up in the form of blood glucose self-monitoring. The recommended frequency for monitoring depends on the treatment: People who take insulin are usually advised to monitor more frequently than those who use diet and exercise to lower their blood glucose and those who take pills. Common times to monitor are before meals, two hours after meals, at bedtime, and any time a person has symptoms of hypoglycemia. More frequent monitoring may be necessary during an illness, during pregnancy, or in other special situations.
The advent of continuous glucose monitors has allowed some people to keep even closer tabs on their glucose levels. Continuous glucose monitors measure the glucose level of interstitial fluid — the fluid found between cells — in the fatty layer of tissue just below the skin. They give glucose values every five minutes throughout the day and are particularly useful for showing whether the glucose level is rising or falling. This allows a person to take action before hypoglycemia or very high glucose occurs. Studies with continuous monitors have shown that their use can result in improved diabetes control and a lower HbA1c.
What lies ahead
Genetics. Some day, genetic tests may be used routinely to determine the best drug treatment for the individual. Already, studies have shown that individuals may react differently to certain drugs based on genetic variations, and for some drugs, genetic tests are already available to help physicians determine what dose should be administered or if the drug is safe for the patient.
There’s a long way to go, however. At this point, scientists do not understand many of the functions that genes perform. In addition, medical science still does not know how many drugs cause their therapeutic effects. Much research in both of these areas is needed before DNA analysis can be used on a routine basis to tailor drug therapy.
Therapeutic drug monitoring. Tests to determine the level of drug in the blood and tests to determine if the drug is having its intended action are currently available for some drugs, but they will most likely be used more often in the future. One of the most common of these tests in use today is the INR (which stands for international normalized ratio), which shows how quickly a person’s blood clots. It is used when a person is prescribed the drug warfarin (Coumadin), which is taken to prevent blood clots. At too low a dose, a person’s blood may continue to form unwanted clots, and at too high a dose, the person can bleed to death. The test is done frequently at first, to establish an effective dose, and then less frequently, to make sure the dose is still effective.
An evolving picture
As medical science evolves, new options for diabetes treatment should become available, and it should also become easier to tailor the diabetes regimen to the individual. Ideally, these changes will enable more people than ever before to live longer, healthier lives with diabetes.
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