Absorption
The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, Avandia may be administered with or without food.
Distribution
The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.
Metabolism
Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.
In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.
Excretion
Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [14C]related material ranged from 103 to 158 hours.
Special Populations
Geriatric
Results of the population pharmacokinetic analysis (n = 716 <65 years; n = 331 ?65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.
Pediatric
Pharmacokinetic parameters of rosiglitazone in pediatric patients were established using a population pharmacokinetic analysis with sparse data from 96 pediatric patients in a single pediatric clinical trial including 33 males and 63 females with ages ranging from 10 to 17 years (weights ranging from 35 to 178.3 kg). Population mean CL/F and V/F of rosiglitazone were 3.15 L/hr and 13.5 L, respectively. These estimates of CL/F and V/F were consistent with the typical parameter estimates from a prior adult population analysis.
Gender
Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (n = 405) was approximately 6% lower compared to male patients of the same body weight (n = 642).
As monotherapy and in combination with metformin, Avandia improvedglycemic control in both males and females. In metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response.
In monotherapy studies, a greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target PPAR? is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to Avandia in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.
Race
Results of a population pharmacokinetic analysis including subjects of Caucasian, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.
Renal Insufficiency
There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared to subjects with normal renal function. No dosage adjustment is therefore required in such patients receiving Avandia. Since metformin is contraindicated in patients with renal impairment, coadministration of metformin with Avandia is contraindicated in these patients.
Hepatic Impairment
Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy subjects. As a result, unbound Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects.
Therapy with Avandia should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal) at baseline.
Heart failure. Avandia can cause your body to keep extra fluid (fluid retention), which leads to swelling and weight gain. Extra body fluid can make some heart problems worse or leadto heart failure.
Swelling (edema) from fluid retention. Call your doctor right away if you have symptoms such as:
- swelling or fluid retention, especially in the ankles or legs
- shortness of breath or trouble breathing, especially when you lie down
- an unusually fast increase in weight
- unusual tiredness
Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness or hunger may mean that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you.
Fractures, usually in the hand, upper arm or foot, in females. Talk to your doctor for advice on how to keep your bones healthy.
Weight gain. Avandia can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be a serious problem for people with certain conditions including heart problems. Call your doctor if you have an unusually fast increase in weight.
Low red blood cell count (anemia).
Ovulation (release of egg from an ovary in a woman) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy.
Liver problems. It is important for your liver to be working normally when you take Avandia. Your doctor should do blood tests to check your liver before you start taking Avandia and during treatment as needed.Call your doctor right away if you have unexplained symptoms such as:
- nausea or vomiting
- stomach pain
- unusual or unexplained tiredness
- loss of appetite
- dark urine
- yellowing of your skin or the whites of your eyes.
The most common side effects of Avandia included cold-like symptoms, injury, and headache. What other drugs will affect Avandia (Rosiglitazone)?
You may be more likely to have hyperglycemia (high blood sugar) if you are taking Avandia with other drugs that raise blood sugar. Drugs that can raise blood sugar include:
- isoniazid;
- diuretics (water pills);
- steroids (prednisone and others);
- phenothiazines (Compazine and others);
- thyroid medicine (Synthroid and others);
- birth control pills and other hormones;
- seizure medicines (Dilantin and others); and
- diet pills or medicines to treat asthma, colds or allergies.
You may be more likely to have hypoglycemia (low blood sugar) if you are taking Avandia with other drugs that lower blood sugar. Drugs that can lower blood sugar include:
- nonsteroidal anti-inflammatory drugs (NSAIDs);
- aspirin or other salicylates (including Pepto-Bismol);
- sulfa drugs (Bactrim and others);
- a monoamine oxidase inhibitor (MAOI);
- beta-blockers (Tenormin and others); or
- probenecid (Benemid).
Some medications may interact with Avandia. Tell your doctor if you are using any of the following drugs:
- gemfibrozil (Gemcor); or
- rifampin (Rifater, Rifadin, Rimactane).
If you are using any of these drugs, you may not be able to take Avandia, or you may require a dosage adjustment or special monitoring.
There may be other drugs not listed that can affect Avandia. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. What should I avoid while taking Avandia (Rosiglitazone)?
Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.
Avoid alcohol. It lowers blood sugar and may interfere with your diabetes treatment.
Tell your doctor and dentist that you are taking this medication before you undergo any surgery.
Do not take any over-the-counter cough, cold, allergy, pain, or weight-loss medications without first talking to your doctor.
Contraindications
Initiation of Avandia in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
Avandia is contraindicated in patients with known hypersensitivity to this product or any of its components.
Warnings
Avandia, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered. In combination with insulin, thiazolidinediones may also increase the risk of other cardiovascular adverse events. Avandia should be discontinued if any deterioration in cardiac status occurs.
Patients with congestive heart failure (CHF) NYHA Class I and II treated with Avandia have an increased risk of cardiovascular events.
Patients treated with combination Avandia and insulin should be monitored for cardiovascular adverse events. This combination therapy should be discontinued in patients who do not respond as manifested by a reduction in HbA1c or insulin dose after 4 to 5 months of therapy or who develop any significant adverse events.
Precautions
Due to its mechanism of action, Avandia is active only in the presence of endogenous insulin. Therefore, Avandia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycemia
Patients receiving Avandia in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.
Edema
Avandia should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of Avandia once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Avandia should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure.
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Avandia, and may be dose related. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and Avandia.
Macular Edema
Macular edema has been reported in postmarketing experience in some diabetic patients who were taking Avandia or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient�s underlying medications or other physical findings.
Fractures
In a 4- to 6-year comparative study (ADOPT) of glycemic control with monotherapy in drug-naive patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking Avandia. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for Avandia versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the study. The majority of the fractures in the women who received Avandia occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture rates was observed in men treated with Avandia. The risk of fracture should be considered in the care of patients, especially female patients, treated with Avandia, and attention given to assessing and maintaining bone health according to current standards of care.
Weight Gain
Dose-related weight gain was seen with Avandia alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
Hematologic
Across all controlled clinical studies in adults, decreases in hemoglobin and hematocrit (mean decreases in individual studies ?1.0 gram/dL and ?3.3%, respectively) were observed for Avandia alone and in combination with other hypoglycemic agents. The changes occurred primarily during the first 3 months following initiation of therapy with Avandia or following a dose increase in Avandia. White blood cell counts also decreased slightly in adult patients treated with Avandia. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with Avandia. The observed changes may be related to the increased plasma volume observed with treatment with Avandia and may be dose related.
Ovulation
Therapy with Avandia, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Avandia. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies, the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Avandia should be reviewed.
Hepatic Effects
Another drug of the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death were reported during clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations in liver enzymes (ALT >3X upper limit of normal) compared to placebo. Very rare cases of reversible jaundice were also reported.
Information For Patients
Carcinogenesis/ Mutagenesis/ Impairment of Fertility
A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively).
Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ?1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ?0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.
Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.
Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.
Animal Toxicology
Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments (approximately 5, 22, and 2 times human AUC at the maximum recommended human daily dose, respectively). Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion.
Pregnancy
Pregnancy Category C. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Human Data
Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown. There are no adequate and well controlled studies in pregnant women. Avandia should not be used during pregnancy.
Animal Studies
There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.
Nursing Mothers
Drug-related material was detected in milk from lactating rats. It is not known whether Avandia is excreted in human milk. Because many drugs are excreted in human milk, Avandia should not be administered to a nursing woman.
Pediatric Use
After placebo run-in including diet counseling, children with type 2 diabetes mellitus, aged 10 to 17 years and with a baseline mean body mass index (BMI) of 33 kg/m2, were randomized to treatment with 2 mg twice daily of Avandia (n = 99) or 500 mg twice daily of metformin (n = 101) in a 24-week, double-blind clinical trial. As expected, fasting plasma glucose (FPG) decreased in patients naive to diabetes medication (n = 104) and increased in patients withdrawn from prior medication (usually metformin) (n = 90) during the run-in period. After at least 8 weeks of treatment, 49% of Avandia-treated patients and 55% of metformin-treated patients had their dose doubled if FPG >126 mg/dL. For the overall intent-to-treat population, at week 24, the mean change from baseline in HbA1c was -0.14% with Avandia and -0.49% with metformin. There was an insufficient number of patients in this study to establish statistically whether these observed mean treatment effects were similar or different. Treatment effects differed for patients naive to therapy with antidiabetic drugs and for patients previously treated with antidiabetic therapy.
Geriatric Use
Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older (?65 years) and younger (<65 years) patients were observed.
It seems that not a week goes by before the safety of another popular prescription drug is being questioned. Vioxx and hormone replacement therapy have gone before; the latest is the popular diabetes drug rosiglitazone (Avandia), which is now linked to an increased risk of heart attacks.
This warning comes from a new meta-analysis, reported recently in the New England Journal of Medicine, which found that Avandia raised heart attack risk by 43 percent. The manufacturer of the drug, GlaxoSmithKline, promptly issued a statement strongly disagreeing with the conclusions of the study.
First, let’s place this number of 43 percent in perspective. Prempro (a combination of estrogen and a progestational agent) increased the risk of fatal and non-fatal heart attacks by 23 percent in the postmenopausal women in the Women’s Health Initiative.
And Vioxx, a widely-prescribed anti-inflammatory drug, more than doubled the risk of heart attacks and strokes. In 2004, Merck voluntarily withdrew this drug from the market.
Avandia lowers blood glucose in patients with type 2 diabetes. It belongs to the class of drugs called the thiazolidinediones. The cardiovascular outcomes of another thiazolidinedione, pioglitazone (Actos), have also been examined. It turns out that Actos actually protects against cardiovascular disease.
One possible explanation for the differences between these two drugs from the same class: Avandia raises LDL cholesterol (the so-called “bad cholesterol”) while Actos has a more favorable effect on blood lipids, especially on triglycerides.
The thiazolidinediones are widely prescribed despite common side effects of weight gain, fluid retention, and even heart failure in certain patients at risk.
What should you do if you are taking Avandia? Talk with your doctor about the relative benefits and risks of the drug, and do not stop taking it without your doctor’s approval.
Now the Food and Drug Administration must decide what action to take based on this new information. Avandia is used by millions of people in the United States and many of them may be at risk. However, the authors of the study and an accompanying editorial noted several significant limitations to the results of this meta-analysis.
For example, the total number of heart attacks and cardiovascular deaths in the study was relatively low, so a small change in the numbers could greatly reduce the risk or even indicate that the finding of a greater risk was a chance observation. The FDA will need to review all the available data on the drug before making a final decision.
All of these drug recalls and warnings have led many people to distrust the FDA’s ability to protect us against potentially dangerous medications. The FDA approves a drug if trials show that it is safe and effective in improving certain markers, such as blood pressure, cholesterol, and blood glucose levels.
The assumption is that improving these markers also improves the long-term health of people taking the medications. The authors of the Avandia study, however, question the use of such markers in the approval of a medication. They point out that lowering blood glucose levels with Avandia has never been proven to prevent the complications of diabetes.
I don’t agree that a drug company must prove that a new drug provides long-term benefits in addition to its effect on specific markers before it is approved by the FDA. This requirement would be so costly that companies might never undertake the necessary studies.
As a result, approval of valuable drugs could be delayed, or they might never become available. Blood pressure drugs were approved because they lowered blood pressure, and only later were proven to also prevent heart attacks and strokes. Based on its cholesterol-lowering effect, the FDA approved the first statin drug, lovastatin, in 1987, even though the benefits of the statins on cardiovascular disease were first proven seven years later.
On the other hand, I strongly agree with the authors of the meta-analysis and the editorial who emphasize that the FDA must require drug companies to complete large, long-term clinical trials to evaluate the safety and effectiveness of a medication soon after it has been approved.
One of the operative words is soon; too many years have elapsed since Avandia was approved in 1999, and the recent publication of evidence of its possible cardiovascular dangers.
Posted Thu, May 31, 2007, 5:49 pm PDT
Diabetes prevention: Can Avandia or other drugs prevent diabetes?
![[Image]](http://www.myfamilydrugstore.com/img2/Avandia_1.jpg)
Maria Collazo-Clavell, M.D.
Various medications have been touted as a way to reduce the risk of type 2 diabetes. But are drugs really the silver bullet for diabetes prevention?
Here, Maria Collazo-Clavell, M.D., an endocrinologist specializing in diabetes at Mayo Clinic, Rochester, Minn., answers questions about medications and diabetes prevention.
Who’s at risk of type 2 diabetes?
Being overweight is one of the main risk factors for type 2 diabetes. Inactivity is a concern, too. The less active you are, the greater your risk of type 2 diabetes. The risk also increases as you get older — especially after age 45.
Can medication help prevent type 2 diabetes?
For some people, medication is part of an overall plan for diabetes prevention. Drugs commonly used to treat diabetes — such as metformin (Glucophage) and rosiglitazone (Avandia) — can also help prevent diabetes in people at risk of the disease.
How well do these medications work?
In one study of more than 5,000 people at high risk of developing diabetes, participants took either the medication Avandia or a placebo. After three years, diabetes occurred in 62 percent fewer people taking Avandia than taking a placebo.
In another study, participants taking the drug Glucophage also reduced their risk of developing diabetes — although by less striking percentages.
Is medication the obvious choice for anyone at risk of diabetes?
The makers of Avandia can make powerful claims about the effectiveness of the drug for diabetes prevention. But that’s only part of the story.
Side effects of Avandia may include headache, back pain and fluid retention. Some people taking Avandia gain weight, which only fuels the risk of diabetes. In a few people, Avandia may contribute to swelling in the back of the eye and life-threatening liver failure or heart failure.
Of course, there’s an expense involved as well. And some people argue that prescribing preventive medication is simply treating diabetes earlier in the course of the disease.
So what’s the key to diabetes prevention?
Healthy lifestyle changes remain the most effective — and safest — way to truly prevent disease. It’s not easy, but you can do it.
To keep your weight in a healthy range, focus on permanent changes to your eating and exercise habits. Choose healthy foods low in fat and calories, including plenty of fruits, vegetables and whole grains. Eat smaller portions. Increase your physical activity, even if it’s just parking farther from the door or taking the stairs instead of the elevator. Motivate yourself by remembering the benefits of losing weight, such as a healthier heart, more energy and improved self-esteem.
And even if you don’t lose weight, physical activity still lowers your blood sugar and boosts your sensitivity to insulin — which helps keep your blood sugar within a normal range.
How well do lifestyle changes work?
You might be surprised. In a trial sponsored by the National Institutes of Health, participants who aimed to lose 7 percent of their body weight and exercised 30 minutes a day were nearly 60 percent less likely to develop diabetes than were people who maintained poor eating or exercise habits. Lifestyle changes worked particularly well for participants age 60 and older, who reduced their risk of developing diabetes by more than 70 percent.
Better yet, there’s no risk of side effects and no medication expense. And as long as you continue to exercise and eat healthy foods, you’ll enjoy the benefits of better health.
If you can commit to a healthier lifestyle — even if it’s simply a daily stroll or a healthier afternoon snack — diabetes prevention may become a way of life.
Last Updated: 11/09/2006
Actos beats Avandia in sugar, fat control: study
By Reuters – Wed Sep 19, 11:44 AM PDT
LONDON (Reuters) – Giving patients a starting dose of Takeda Pharmaceutical’s diabetes drug Actos gives better control of blood sugar and lipid levels than using GlaxoSmithKline’s diabetes drug Avandia, according to new clinical trial results.
The findings, presented at a medical meeting in Amsterdam on Wednesday, will add fuel to Takeda’s campaign to prove the superiority of its drug over Avandia, which has been tarnished recently by fears it may increase heart attack risks.
An analysis of data from the first three months of a six-month head-to-head study of the two drugs found a starting dose of 30 milligrams of Actos was more effective than a starting dose of 4 milligrams of Avandia in improving blood sugar levels.
Actos also significantly decreased triglyceride and “bad” LDL cholesterol levels and markedly improved “good” HDL cholesterol.
The research on the two drugs, known generically as pioglitazone and rosiglitazone, was presented at the annual meeting of the European Association for the Study of Diabetes.
“A likely explanation for the different effects on heart attack and strokes between the two drugs could be the favorable effect of pioglitazone in increasing HDL cholesterol without adverse effects on LDL as demonstrated in the… study,” said John Betteridge, professor of endocrinology and metabolism at University College, London.
Avandia approved for combination with insulin in type 2 diabetes treatment
PHILADELPHIA, PA., March 3, 2003 — GlaxoSmithKline announced that the FDA has approved Avandia (rosiglitazone maleate) for use in combination with insulin for the treatment of type 2 diabetes.
As an adjunct to diet and exercise, Avandia now can be used in four therapeutic regimens: as monotherapy or as combination therapy with metformin, sulfonylureas or insulin to improve glycemic control in patients with type 2 diabetes.
“GlaxoSmithKline is very pleased with the new indication for Avandia,” said David Pernock, Senior Vice President, General Pharmaceutical Business Unit at GlaxoSmithKline. “Clearly, people with type 2 diabetes need therapeutic options at each stage of their disease to help ensure tight glucose control. It is our hope that this new indication may help people to better manage their type 2 diabetes.”
The progressive nature of type 2 diabetes
Type 2 diabetes is characterized by high blood sugar levels that occur when the body cannot make enough insulin and/or respond normally to the natural insulin it makes (a condition called insulin resistance). In patients with type 2 diabetes, beta cells (the cells that make and release insulin in the pancreas) generally start to fail over time and produce progressively less insulin. This may lead to increased blood sugar levels and progressive worsening of the disease. When blood sugar levels are elevated over an extended period of time, serious complications may result. To reach blood sugar levels recommended by experts, many people with type 2 diabetes may need to take a combination of therapies, possibly including the addition of insulin.
Avandia in combination with insulin
The approval of Avandia in combination with insulin was based upon data from four 26-week trials in patients with type 2 diabetes. Approximately 1,100 patients participated in clinical studies programs, which included two fixed-dose combination trials, one insulin reduction study and one study in patients with chronic kidney disease. The studies demonstrated the safety and efficacy of Avandia at 4 mg daily in combination with insulin. In fact, in patients receiving Avandia 4 mg daily plus insulin, there was a significant drop in blood sugar levels and approximately 40 percent of patients in the two fixed-dose trials were able to reduce their insulin dose.
Avandia for type 2 diabetes
Avandia is an insulin sensitizer that works by making the cells in the body more sensitive to its own natural insulin. Since the FDA approval of Avandia in May 1999, more than 22 million prescriptions have been written and more than three million patients have been treated in the United States.
Avandia, along with diet and exercise, helps improve blood sugar control. It may be prescribed alone, with metformin, sulfonylureas, or insulin. When taking Avandia with other hypoglycemic agents, like sulfonylureas or insulin, patients may be at risk for low blood sugar. Patients should ask their doctor whether they need to lower their sulfonylurea or insulin dosage.
Some people may experience tiredness, weight gain or swelling
Avandia, like other thiazolidinediones, may cause fluid retention or swelling which could lead to or worsen heart failure, so patients should tell their doctor if they have a history of these conditions. If patients experience an unusually rapid increase in weight, swelling or shortness of breath while taking Avandia, they should talk to their doctor immediately.
In combination with insulin, Avandia may increase the risk of other heart problems. Patients treated with Avandia and insulin should discuss with their doctor important symptoms of which to be aware and whether or not the combination is helping to control their blood sugar. Avandia is not for everyone. Avandia is not recommended for patients with severe heart failure or active liver disease.
Also, blood tests to check for serious liver problems should be conducted before and during Avandia therapy. Patients should tell their doctor if they have liver disease, or if they experience unexplained tiredness, stomach problems, dark urine or yellowing of skin while taking Avandia.
If the patient is nursing, pregnant or thinking about becoming pregnant, or is a premenopausal woman who is not ovulating, she should talk to her doctor before taking Avandia.
Source: GlaxoSmithKline
Avandia Reduces Risk of Progresson from Pre-Diabetes to Type 2 Diabetes by 62 percent
LONDON, September 15, 2006 — In the largest diabetes-prevention trial ever conducted, Avandia (rosiglitazone maleate) reduced the risk of developing type 2 diabetes by 62 percent relative to placebo among people at high risk of developing type 2 diabetes. This highly statistically significant reduction of 62 percent (p<0.0001) was additive to standard counselling on healthy eating and exercise. The results of the landmark study are being reported today both in The Lancet and at the 42nd annual meeting of the European Association for the Study of Diabetes (EASD).1
The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial evaluated the likelihood of progression to type 2 diabetes over a three-year median follow-up period among 5,269 people with a condition known as “pre-diabetes.”1In pre-diabetes, blood sugar levels are higher than normal, but not yet high enough for a diagnosis of type 2 diabetes.3 Patients included in the study were randomised to rosiglitazone (8 mg daily) or placebo and to ramipril (15 mg daily) or placebo and were assessed every six months for three to five years to determine if rosiglitazone or ramipril can reduce the risk of developing type 2 diabetes in pre-diabetic patients, when added to healthy eating and exercise counselling.1 The DREAM study was not designed as a direct comparison between rosiglitazone and ramipril. Results from the ramipril arm of the study, which increased regression to normoglycemia but did not reduce the risk of diabetes or death, are also being reported at EASD and published separately in the New England Journal of Medicine.4
In this study, designed and conducted by the Population Health Research Institute at McMaster University, 10.6 percent of people receiving rosiglitazone progressed to type 2 diabetes versus 25 percent of people treated with placebo.1 In the composite primary endpoint of development of diabetes or death from any cause, rosiglitazone demonstrated a 60 percent risk reduction relative to placebo (p<0.0001).1
“The DREAM findings are particularly significant as we are in the midst of an epidemic of type 2 diabetes with global implications. It is also noteworthy that the damaging complications of type 2 diabetes can often precede the diagnosis of this condition by several years,” said Dr. Bernard Zinman, DREAM Steering Committee Member, director of the Diabetes Centre, Mount Sinai Hospital and professor of medicine, University of Toronto, Canada. “By demonstrating that rosiglitazone significantly reduced the risk of developing type 2 diabetes, these data provide important evidence that it may be possible to alter the course of rising blood sugar levels and its consequences.”
Over the three-year median follow-up period of the trial, 51 percent of the people receiving rosiglitazone returned to normal blood sugar levels compared to 30 percent of people receiving placebo; thus, people taking rosiglitazone were about 70 percent (p<0.0001) more likely than those taking placebo to return to normal blood sugar levels. As might be expected, people in the placebo group with higher Body Mass Index (BMI), an indicator of obesity, were more likely than those with lower BMI to progress to diabetes. However, the risk of developing diabetes did not increase with BMI in the group randomised to rosiglitazone. These findings suggest that rosiglitazone may reduce the increased risk of developing diabetes that is attributable to obesity.1
“GSK is committed to groundbreaking research for the treatment of pre-diabetes and type 2 diabetes in order to improve patient outcomes. We believe the long awaited findings from the DREAM trial will lead to a better understanding of type 2 diabetes and its treatment,” said Dr. Lawson Macartney, senior vice president, Cardiovascular and Metabolic Medicine Development Centre, GlaxoSmithKline. “The DREAM trial is the largest diabetes prevention trial conducted to date and provides the first body of evidence that rosiglitazone can reduce the risk of progression from pre-diabetes to type 2 diabetes in high risk patients.”
In the study, rosiglitazone was generally well tolerated. There was no significant difference between the rosiglitazone and placebo groups in withdrawal from study medication before study end, or in the secondary composite endpoint of cardiovascular (CV) events that included myocardial infarction, stroke, CV death, confirmed heart failure, new angina and revascularisation procedures (2.9 percent in the rosiglitazone group [75 events]; 2.1 percent in the placebo group [55 events], p=0.15). There was a low number of deaths in the trial and no significant difference between the two groups (1.1 percent in the rosiglitazone group [30 deaths] versus 1.3 percent in the placebo group [33 deaths], p=0.7). The most commonly reported CV event in the study was revascularisation procedures. More events of confirmed heart failure were reported in people who received rosiglitazone as compared to those who received placebo (0.5 percent in people randomized to rosiglitazone [14 events] versus 0.1 percent in people randomized to placebo [2 events], p=0.01). Data presented by McMaster University showed that all cases of heart failure were treated effectively during the trial. Information about the potential for heart failure can be found in rosiglitazone prescribing information. At the conclusion of the study, mean bodyweight in the rosiglitazone group had increased slightly (2.2 kg) more than the placebo group.1,5
Rosiglitazone belongs to the thiazolidinedione class of drugs and is an approved treatment for type 2 diabetes that improves blood sugar control, enabling people to reach recommended blood sugar levels. No agent including rosiglitazone is currently approved for the treatment of pre-diabetes.5
About the DREAM Study
DREAM is an international, multi-centre, randomised, double-blind, 2×2 factorial trial involving 5,269 patients from 21 countries with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), also known as pre-diabetes, who are therefore at high risk of developing type 2 diabetes. The DREAM study was conducted by the Population Health Research Institute at the Michael G. DeGroote School of Medicine at McMaster University and Hamilton Health Sciences in Hamilton, Ontario. DREAM was funded by a peer-reviewed grant from the Canadian Institutes of Health Research (CIHR) via the CIHR/Rx&D Collaborative Research Program as well as by GlaxoSmithKline, sanofi-aventis and King Pharmaceuticals.1
About Pre-diabetes and Type 2 Diabetes
The International Diabetes Federation (IDF) estimates a potential increase in pre-diabetes from 300 million people worldwide in 2003 to approximately 500 million by 2025.2 While not everyone with pre-diabetes develops type 2 diabetes, large clinical outcomes trials have demonstrated that without intervention between 29 and 55 percent of people with pre-diabetes develop type 2 diabetes over the course of three years.6-8 As type 2 diabetes naturally progresses, the combined effects of core defects of the disease, namely insulin resistance and beta-cell dysfunction, can make it increasingly difficult for physicians to help patients control blood sugar levels.9
Pre-diabetes is considered a key stage in the development of type 2 diabetes – a chronic, progressive illness often linked to premature death that affects approximately 230 million individuals worldwide and is expected to affect 350 million people globally by 2025.3,10 Complications from diabetes can include eye disease, kidney disease, nerve damage, heart disease, stroke and peripheral vascular disease.11-14 In fact, more than three million people die from diabetes-related causes each year – one death every 10 seconds.15
Most important information about Avandia
More information about AVANDIA (Rosiglitazone):
AVANDIA (Rosiglitazone): What You Should Know
Can Avandia or other drugs prevent diabetes?
Actos beats Avandia in sugar, fat control: study
Avandia approved for combination with insulin in type 2 diabetes treatment
Avandia Reduces Risk of Progresson from Pre-Diabetes to Type 2 Diabetes by 62 percent
GSK Revises US Labeling for Avandia
Data Affirms Avandia (Rosiglitazone maleate) Cardiovascular Safety Profile
Texas Family Sues GlaxoSmithKline (GSK) Over Man’s Heart Attack Death Following Avandia Use
To buy AVANDIA click HERE: My Family Drugstore
![[Image]](http://www.myfamilydrugstore.com/img2/Avandia_f.jpg)