A potential new treatment for type 2 diabetes, dapagliflozin, recently failed to gain approval from the FDA. What makes this rejection noteworthy is that the new medication works by a completely new mechanism causing the kidney to excrete sugar from the blood into the urine. Reasons for the rejection were the increased risk of bladde and breast cancer in those taking the medication, increased urine and genital infections and possible liver toxicity. That list of problems seems pretty convincing to me. This is unfortunate because the drug appears to cause weight loss and does not cause low blood sugar (hypoglycemia). However, a drug that works by “poisoning” the kidney so that it dumps sugar into the urine strikes me as a drug that is going to cause a lot of other problems.
The other established diabetes medication generating new warnings is Actos (pioglitazone). I have written a number of articles on the sister drug Avandia, defending its usefulness despite possible cardiovascular risks, but the cancer warning for Actos is a new angle on this class of drugs (thiazolidinediones). Actos has been withdrawn in France due to concerns that it may cause bladder cancer but no such action has been taken in the U.S. The FDA this month did issue a warning that individuals with bladder cancer or at risk for bladder cancer, should be advised not to use Actos. If Actos is hit hard by these actions this whole class of diabetes drugs will have been eliminated from use.
A sure sign of trouble for Actos is that a “google search” for Actos is now showing lawyer websites as the first 5 citations.
Being sick is dangerous. Treating illness also has dangers. I am concerned that our cultural zeal for uncovering scandals and for pursuing litigation will lead us to sterile treatment options and doctors who are unwilling to risk helping.
Gary Pepper, M.D.
Editor in Chief, metabolism.com
(I donâ€™t think so, and hereâ€™s why.)
The FDA just announced its approval of linagliptin (Tradjenta), a new diabetes medication developed by Eli Lilly and Company and Boehringer Inglheim. Linagliptin is the third drug to be approved in the class of medications commonly known as gliptins (scientifically known as dipeptidyl peptidase-4 (DPP-4) inhibitors) which block the destruction of a glucose controlling hormone, GLP-1. Januvia, developed by Merck and Company, was the first of the gliptins to be approved in 2006. Three years later in 2009, Onglyza, developed by AstraZeneca was approved while two other similar drugs were withdrawn from the approval process in the meantime.
Diabetes drugs are evaluated by the FDA for safety and for their ability to combat diabetes by lowering blood sugar. Assuming the drug being evaluated is safe then we will want to know how effectively the new medicine lowers the blood sugar. The glycohemoglobin A1c blood test represents the average blood sugar for the prior 3 months, and is the most concise way of assessing an individuals over all blood sugar control. By determining the ability of a medicine to lower the â€œglycoA1câ€ we can get a very accurate idea of the strength of the medicine for diabetes treatment. In general, physicians set a glycoA1c goal of 7% or less for their diabetic patients which equates to an average blood sugar level of 154 mg/dl or 8.6 mmol/L.
Linagliptin passed the FDAâ€™s strigent safety review. Several large studies sponsored by the drug developers show the linagliptin lowers glycohemoglobin A1c by about 0.5. For example, if a person has a glycoA1c of 7.5 % before starting linagliptin, they can anticipate it will be 7.0% when on the medication. This translates to an average blood sugar of 169 mg/dl dropping to 154. This is virtually the same effect found with Januvia and Onglyza, the other medicines in this group.This amount of blood sugar lowering seems feeble but the benefit is even worse then that. Hereâ€™s why.
Blood tests are accurate enough for the clinical purposes of physicianâ€™s diagnosing and treating their patients. â€œClinical purposesâ€ allow for some fuzziness in measurements. Does it matter to a patientâ€™s health if the blood sugar is 200 or 210? Not really. In general, a variation of 10% is acceptable for clinical blood tests, meaning that if a result is given as 100, a repeat measurement of the same blood sample could read between 95 and 105. For the glycohemoglobin A1c test a variation of 0.5 is common with standard laboratory techniques. For an individual on linagliptin there is virtually no way to determine if the change in glycoA1c is due to the medication or is simply within the variation of the blood test. Not very impressive is it?
How much is the average person going to pay for this unimpressive effect? I researched the retail cost of Januvia, the sister drug to linagliptin. Drugstore.com lists a price of $216 for 30 pills after a 18% saving. $7 per pill….wow!! I assume linagliptin will be priced competitively. Compare this to the price of $13 for a monthâ€™s supply of metformin, currently the most prescribed oral agent for treating diabetes. In contrast, metformin shows a 1.5% to 2% drop in glycohemoglobin A1c, more than three times that of the gliptins such as linagliptin.
I have used both Januvia and Onglyza in my medical practice. As advertised, I havenâ€™t encountered significant side effects. Also, as advertised the effect of these medicines to lower blood sugar has been disappointing and complaints by patients about the cost has been a constant theme. At the same time my email inbox is stuffed with invitations to join online symposiums with paid experts inevitably focusing on how to ramp up my use of these drugs. The sales pitch is given in inflated marketing lingo as a â€œchange in the treatment paradigmâ€ for treating diabetes. Buyer beware, is my advice for the health care consumer starting a new medication for treating type 2 diabetes.
Gary Pepper, M.D.
New Diabetes Treatment Guidelines Lack Credibility:
Recently the American Academy of Clinical Endocrinologists issued new treatment guidelines for treating Type 2 Diabetes. Complex medical guidelines are often referred to as a treatment algorithm. One of the stated goals of the AACE algorithm is to focus primarily on the theoretical ability of the diabetic medications to control blood sugar while ignoring the cost of the medication. The rationale to this approach is that controlling blood sugar with more expensive drugs will cost less in the long run since patients will be healthier and have less complications due better control of the blood sugar. On the surface this philosophy seems sound but digging beneath the surface reveals dangerous flaws in this thinking.
1. The first assumption, that newer medications for diabetes are better than older drugs is unsubstantiated. In fact there is ample evidence that newer diabetic drugs are no better than the older drugs for controlling blood sugar. The latest study finding no benefit of the newer diabetes medications is the FIELD study conducted outside of the U.S. This study showed that 5 years of treatment with the older diabetic drugs (sulfonylureas, metformin and insulin) resulted in adequate and prolonged control of blood sugar. In 2007 researchers from Johns Hopkins Bloomberg School of Public Health summarized the results of major studies using older and newer anti-diabetic medications and found no significant benefit of the newer medications.
2. The next assumption, that cost is not a key factor in treatment success contradicts most clinicians’ experience in diabetes care. It is clear to me, that patients are far less likely to comply with using expensive drugs than medications they can more easily afford. Looking at the numbers reveals the vast cost differences between the older (generic) versus the newer (brand) medications. Using figures provided by a local pharmacy I found that the retail cost of a typical two drug therapy for diabetes using older drugs is $59 per month. The retail cost of using two of the new drugs for a month ranges from $481 to $570. In more severe diabetes three drugs per day may be needed. The low cost alternative amounts to $185 per month while the high end alternative with new drugs is $610 per month. Looking at the cost of using insulin shows a similar vast cost difference between the older and newer drugs. Older forms of insulin may cost $100 for a month’s supply while a similar course of therapy with the newer insulin preparations will cost almost $250 per month. How many people will be willing and able to afford the new versus the old drugs, particularly knowing that there may be no health benefit to the more expensive drug combination?
The end result of not being able to afford these prices is non-compliance with medications and the result of non-compliance is higher costs passed on to the medical system. The Medco study from 2005 showed that the least compliant patients were more than twice as likely to be hospitalized compared to the most compliant, and that the yearly cost of caring for non-compliant patients is double that of compliant patients.
3. My next point is possibly the most contentious. The AACE guidelines were produced by a committee of physicians chaired by two distinguished endocrinologists, Dr. Paul Jellinger and Dr. Helena Rodbard. Both doctors are highly respected and accomplished. They are also both highly compensated consultants to the pharmaceutical companies which market the newest generation of diabetes medications. In the disclaimer attached to the committee’s recommendations, both Dr. Jellinger and Dr. Rodbard admit to consulting arrangements with virtually every one of the pharmaceutical companies whose interests are effected by their committee’s findings. I too am a consultant to many of these same companies (at least, until now), but I am not responsible for developing national guidelines for diabetes care. In my opinion the close association of both committee chairmen to the pharmaceutical companies detracts heavily from the credibility of their recommendations. The need for credibility is even more important when the AACE committee advises physicians to avoid using sulfonylureas, the only class of drugs not marketed by any of the big pharma companies. and which also happens to be the cheapest drug class, the drugs with the longest history of use, and the class of drugs many regard as the most effective at lowering blood sugar levels. The sulfonylurea class of drugs is so effective at lowering blood sugar, in fact, they are used as the gold standard by which the effectiveness of all new diabetic medications are compared.
4. In contrast with the AACE, the American Diabetes Association (ADA) has issued more conservative guidelines for diabetic therapy, preserving the role of the older generic drugs. My recommendation is that AACE go back to their committee and reconsider the way they have produced their algorithm. Appointing new leadership whose credentials do not lend themselves so readily to skepticism, would be an important first step in that process.
Gary Pepper, M.D.
This post is the third in a series under the title: 2009. Another Troubled Year for Endocrinologists.
This year the FDA has instituted new standards for diabetes drugs coming up for approval. These new standards require that each new drug prior to approval must demonstrate the lack of any negative impact on cardiovascular (heart and blood vessel) health. While this may seem a legitimate requirement, in reality it requires thousands of patients be treated for many more years in research settings to acquire this information. So far three new diabetes medications from Takeda Pharmaceuticals, Novo Nordisk and Bristol Myers have all been put in limbo due to delays on their approval based on the new requirements.
I would point to the case of Avandia as an example of how difficult it is to prove that a drug has negative cardiovascular effects. In 2007 an alarm was sounded by several outspoken critics, whose analysis pointed to increased cardiovascular risk from Avandia. At that time Avandia was a key diabetes medication on the market for over 5 years with millions of individuals treated. Although the diabetes community remained split on the truth of these assertions major medical organizations such as the American Diabetes Association placed a virtual ban on the use of this medication and the FDA placed its highest “black box” level warning on Avandia use. At that time the FDA was criticized widely for allowing this supposed public danger to go unrecognized for so long. Many think that it is in response to this criticism that the FDA was forced to add the new much more stringent requirements on new drug approval.
Since 2007 however, a large V.A. study (the VADT study) and the 2009 RECORD study both found no evidence of cardiovascular risk with Avandia use. The belief is growing that the FDA was initially correct in allowing Avandia to come to market, although so much negative publicity has hurt the use of Avandia and led the FDA to take a highly defensive approach to new drug approval.
Some pharmaceutical executives believe the new FDA requirements will double the cost of bringing a new drug to market. Approval of several promising new diabetes treatments has already been stalled and the companies developing new medical therapies are beginning to move diabetes treatment to the back-burner. It is likely that it will takes years to reverse this trend, if a reversal is possible at all.
Gary Pepper, M.D. Editor-in-Chief, Metabolism.com
Two of the newest diabetes treatments suffered major set-backs this week. Endocrinologists across the U.S. received a notice today that Exubera, the inhaled form of insulin, would soon become unavailable. This is because Pfizer, the pharmaceutical giant which has sole rights for marketing Exubera has decided to end its role in selling this drug. This will effectively end the availability of Exubera and patients taking this medication will have to be switched to something else.
The reason for Pfizer’s abandonment of Exubera appears to be slow sales due to the lack of interest by consumers in using inhaled insulin. Physicians were also slow to recommend this treatment due to the difficulties in teaching patients how to use the inhaler device, and restrictions on using inhaled insulin in patients with minor lung disorders.
The second drug running into trouble this week is Byetta (highlighted in an article at metabolism.com when it first became available). Thirty cases of pancreatitis, a potentially fatal inflammation of the pancreas, have been reported in Byetta users. Of these, 7 cases seem to be linked to higher doses of Byetta while the others had other risk factors for pancreatitis. Most patients improved when Byetta use was discontinued. The FDA is requiring that a warning regarding pancreatitis be added to Byetta’s labelling. At this time it is difficult to say what restrictions will have to be placed on Byetta because of this new development, or how it will effect Byetta sales.
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