Avandia dream trial

The two studies showed the drug was effective in controlling blood sugar, but Dr. Nissen thought they held signs of cardiovascular problems.

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet ; In DREAM, patients with glucose metabolism abnormalities who had not developed diabetes were randomized to get rosiglitazone or placebo, and followed for three years.

The outcome of interest was the development of diabetes as defined by elevated blood sugar or abnormal results on a glucose tolerance test or death. The differences in rates, however, did not reach statistical significance, and hence could have been due to chance alone. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med ; The outcome of interest was increasing blood sugars leading to the use of another glucose lowering drug.

Patients who received rosiglitazone were numerically more likely to have a cardiovascular adverse event, including myocardial infarction, congestive heart failure, and stroke. Nissen wrote to GlaxoSmithKline in early January, asking for more data. The company offered to collaborate with him, but said it wanted to crunch the numbers itself.

Nissen countered that the Cleveland Clinic needed full access to all the raw information and the right to publish as it pleased. Talks over the matter were inconclusive. In mid-April, he found online the FDA document detailing the agency's original review of the drug. Then, in a Google search, Dr. Nissen found the online database of Glaxo study results.

Many of the trial summaries included heart-attack data. Dr Nissen and statistician Kathy Wolski used the on-line data in a meta-analysis of 42 trials of rosiglitazone. The meta-analysis suggested that the drug was associated with a higher risk of myocardial infarctin odds ratio 1. Because Avandia is now so widely used, Nissen's and Wolski's study has gotten a lot of press and caused a lot of consternation.

Nonetheless, the first big question is why Avandia become so popular in the first place? When I have taught evidence-based medicine using the venerable " Users' Guides " approach, we came back to the key question to be answered when deciding about what therapy to use: do the benefits of therapy outweigh the potential harms?

Rosiglitazone and cardiovascular risk. N Engl J Med ; , available here ] suggested: Physicians who chose to prescribe rosiglitazone perhaps focused on the single dimension of glycemic control. The underlying assumption represents a kind of linear 'physiological' argument: high levels of glycated hemoglobin increase risk, so a reduction in glycated hemoglobin will automatically translate into improved health outcomes for patients. Many physicians did not require proof of health benefits as a criterion for selecting rosiglitazone as a therapy for type 2 diabetes.

Had practicing physicians required this higher standard, they would have been at a loss for evidence from large, long-term trials. Rosiglitazone was approved on the basis of short-term studies of the surrogate end point of glycemic control. So it appears that the first lesson from this case reiterates the approach used in the "Users Guides. The consternation currently being caused by the results of the meta-analysis by Nissen and Wolski indicates how far many of us have departed from these principles.

But it gets worse, Dr. Nissen made another discovery in scrolling through the Web site. The company itself had done a meta-analysis similar to the one he was attempting, and quietly posted the result. The rate for people taking Avandia was 1. So, One issue coming under congressional scrutiny is whether the Food and Drug Administration should have acted faster to alert the public about possible risk from Avandia. Glaxo performed its own meta-analysis, which also showed a potential danger.

It shared an early version of it with the FDA in September and a more complete one in August The findings weren't reflected on the U. Robert Meyer, head of the FDA office that oversees diabetes drugs, said the agency is still working on its analysis.

Meyer, although he called the meta-analyses 'a signal of concern. Thus, the next big question is if both GSK and the FDA had data suggesting rosiglitazone may be associated with increased cardiovascular risks and again, in the absence of any data that the drug has clinical benefits that could outweigh these risks , why didn't they act on, or at least publicize this data?

Well, there is one obvious explanation why GSK may have not been in a hurry to act. But the FDA does not have to worry about sales or share prices.

Its job is supposed to be to protect the public's health and safety. Why didn't it act? Has its funding by users' fees made FDA officials feel they are responsible first to the drug, device, and biotechnology companies that pay these fees? The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med ; Has its dependence on advisory panels often populated by people who have financial arrangements with drug, device and biotechnology companies made it more used to these companies' interests than any others?

See this post and its links. We can hope that the Avandia story will mark the tipping point on the way to reinvigorated FDA that sees itself as responsible first and foremost to the public, not specific commercial interests.

See also comments on GoozNews , and on PharmaGossip. American citizens might advocate these suggested ways to reinvigorate the FDA to their members of congress: 1. End financing by "user fees" that incorrectly suggest that the FDA's clients are drug and device manufacturers, not the public at large.

Ban people with conflicts of interest from FDA advisory panels. Make the FDA explicitly responsible for safety of drugs that are on the market, and give it the resources and tools to uphold that responsibility.

Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed following treatment with AVANDIA compared to placebo during the week study.

See Table 1. Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of AVANDIA is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDIA during this acute phase should be considered.

A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials mean duration 6 months. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls.

Myocardial ischemic events included angina pectoris, angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, and coronary artery disorder.

An increased risk of myocardial ischemic events with AVANDIA was observed in the placebo-controlled studies, but not in the active-controlled studies. See Figure 1. Figure 1. Most of the nitrate users had established coronary heart disease. Among patients with known coronary heart disease who were not on nitrate therapy, an increased risk of myocardial ischemic events for AVANDIA versus comparator was not demonstrated.

Data from 3 other large, long-term, prospective, randomized, controlled clinical trials of AVANDIA were assessed separately from the meta-analysis. Duration of follow-up exceeded 3 years in each study.

Interim results have been published 3 for RECORD Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes , an ongoing open-label, 6-year cardiovascular outcomes study in patients with type 2 diabetes with an average treatment duration of 3. Figure 2. In preliminary analyses of the DREAM trial, the incidence of cardiovascular events was higher among subjects who received AVANDIA in combination with ramipril than among subjects who received ramipril alone, as illustrated in Figure 2.

In their entirety, the available data on the risk of myocardial ischemia are inconclusive. Definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AVANDIA or any other oral antidiabetic drug. See Table 2. In five, week, controlled, randomized, double-blind trials which were included in the meta-analysis [see Warnings and Precautions 5.

These trials included patients with long-standing diabetes median duration of 12 years and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure.

The total number of patients with emergent congestive heart failure was 21 2. The total number of patients with emergent myocardial ischemia was 24 2. Although the event rate for congestive heart failure and myocardial ischemia was low in the studied population, consistently the event rate was 2-fold or higher with coadministration of AVANDIA and insulin.

Patients with edema requiring pharmacologic therapy and those with congestive heart failure were excluded at baseline and during the run-in period. No myocardial ischemia was observed in the insulin group, and no congestive heart failure was reported in either treatment group. 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 [see Boxed Warning, Warnings and Precautions 5.

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 were more likely to have adverse events associated with edema if started on combination therapy with insulin and AVANDIA [see Adverse Reactions 6.

The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials.

Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning]. In a 4- to 6-year, monotherapy, comparative trial ADOPT in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication [see Clinical Studies Liver enzymes should be measured prior to the initiation of therapy with AVANDIA in all patients and periodically thereafter per the clinical judgment of the healthcare professional.

Initiation of, or continuation of, therapy with AVANDIA in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. The decision whether to continue the patient on therapy with AVANDIA should be guided by clinical judgment pending laboratory evaluations.

If jaundice is observed, drug therapy should be discontinued. 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. Over the 4- to 6-year period, the incidence of bone fracture in females was 9. This increased incidence was noted after the first year of treatment and persisted during the course of the study.

These sites of fracture are different from those usually associated with postmenopausal osteoporosis e. 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.

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. Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response.

Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies; therefore, the frequency of this occurrence is not known.

Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with AVANDIA.

In double-blind studies, anemia was reported in 1. In clinical trials, edema was reported in 4. Edema was reported in In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Hypoglycemia was the most frequently reported adverse event in the fixed-dose insulin combination trials, although few patients withdrew for hypoglycemia 4 of for AVANDIA plus insulin and 1 of for insulin alone.

Table 5 presents adverse reactions without regard to causality; rates are expressed per patient-years PY exposure to account for the differences in exposure to study medication across the 3 treatment groups.

The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. In this study, one case of diabetic ketoacidosis was reported in the metformin group. Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA mean decreases in individual studies as much as 1.

Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. In a single study in pediatric patients, decreases in hemoglobin and hematocrit mean decreases of 0. In pre-approval clinical studies in 4, patients treated with AVANDIA 3, patient-years of exposure and in a long-term 4- to 6-year study in 1, patients treated with AVANDIA 4, patient-years exposure , there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0. Hyperbilirubinemia was found in 0. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of AVANDIA.

Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure. In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion e.

There are postmarketing reports with AVANDIA of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established. There are postmarketing reports with AVANDIA of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome, and new onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions 5. An inhibitor of CYP2C8 e.

Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. 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. 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. 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.

Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose. There was no effect on pre- or post-natal survival or growth.

Drug-related material was detected in milk from lactating rats. For the overall intent-to-treat population, at week 24, the mean change from baseline in HbA1c was There was an insufficient number of patients in this study to establish statistically whether these observed mean treatment effects were similar or different. The median weight gain was 2. Figure 3. Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see Clinical Pharmacology Therefore, no dosage adjustments are required for the elderly.

In controlled clinical trials, no overall differences in safety and effectiveness between older greater than or equal to 65 years and younger less than 65 years patients were observed. Limited data are available with regard to overdosage in humans. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors.

The pKa values of rosiglitazone maleate are 6. It might still be appropriate to approve drug X even if it is less effective than metformin, particularly if it represents a novel mechanism of action and raises no safety concerns. The FDA does not have the authority to require that a new drug be superior to existing drugs.

On the other hand, the FDA is not required to have proof that a new drug is unsafe to deny approval and should set a high standard for drugs that offer no advantage over existing therapy. Even for a novel agent, a few cases of a rare but life-threatening event, such as agranulocytosis, may be sufficient to prevent approval. New drugs should be labeled for treatment of hyperglycemia in patients with type 2 diabetes, but no claim for reducing the risk of complications should be allowed unless directly supported by data.

There should be no distinction between first- and second-line therapy or between monotherapy and combination therapy. Data from pivotal trials should be shown in the label to provide insight into what clinical effects can be expected under what conditions.

Gaps, uncertainties, or inconsistencies should be acknowledged, such as lack of information in certain populations. In some circumstances, sponsors should be required to perform postmarketing trials to address remaining issues. Failure to complete these trials should be posted on the FDA Web site. From the clinical review and action letter posted by the FDA on its Web site, professional organizations can develop recommendations about how a new drug should be used in relation to other approved agents.

Table 1 is a summary of a suggested paradigm for clinical trials to develop new drugs for type 2 diabetes. With better knowledge and experience, this paradigm may need to change. But the goal should remain the same.

New drugs should continue to be developed to reduce the global burden of diabetes and its complications. Regulators should set high standards but should also be pragmatic. Fear of uncertainty should not be allowed to stifle innovation. The opinions expressed in this article represent those of the author and do not necessarily reflect the official position of the Food and Drug Administration.

The costs of publication of this article were defrayed in part by the payment of page charges. Section solely to indicate this fact. Sign In or Create an Account. Advanced Search. User Tools. Sign In. Skip Nav Destination Article Navigation. Close mobile search navigation Article navigation. Volume 30, Issue Previous Article Next Article.

Lessons from the Avandia controversy. New paradigm for the development of drugs to treat type 2 diabetes. Looking ahead. Article Navigation. Misbin, MD Robert I. Misbin, MD. This Site.

Google Scholar. Address correspondence and reprint requests to Robert I. Misbin, MD, Schindler Dr. E-mail: robert. Diabetes Care ;30 12 — Article history Received:. Get Permissions. Table 1— Paradigm for development of new drugs to treat type 2 diabetes.

Primary end point can be A1C, fasting, postprandial, or mean daily glucose depending on the circumstances. Trial B 6- to month active comparator trial in patients to study effects of two or more doses of drug X versus metformin.

Primary end point is A1C. Events related to cardiac ischemia should be adjudicated. Trial C 6- to month add-on trial in patients on metformin to study effects of two or more doses of drug X versus placebo. Trial D 6- to month add-on trial in patients on insulin to study effects of one or more doses of new drug versus placebo.

Dose of insulin is titrated according to the standard of practice. Primary end point is reporting of serious adverse events. Patients on placebo are started on metformin. Rescue due to hyperglycemia with insulin secretagogue, insulin sensitizer, or insulin as appropriate depending on the nature of drug X. Trial B Patients on drug X are continued on drug X. Patients on metformin are continued on metformin.

Rescue with insulin secretagogue, insulin sensitizer, or insulin as appropriate depending on the nature of drug X. Trial C Patients on drug X are continued on drug X. Patients on placebo are started on insulin secretagog or insulin sensitizer as appropriate depending on the nature of drug X. Rescue with insulin. Trial D Patients on drug X are continued on drug X. Patients on placebo are continued on placebo. Insulin is given as needed for glycemic control. Patients who cannot achieve adequate control are withdrawn.

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