by Gary Pepper, M.D.
“New is not always better.” This caution seems reasonable when considering the value of the recently approved medications for treatment of Type 2 (adult type) diabetes. Â These drugs include three new classes of medication referred to as GLP-1 analogs, DPP-4 inhibitors and most recently SGLT-2 inhibitors. The focus of this discussion will be the most widely prescribed of the newcomers, the DPP-4 inhibitors.
The first thing consumers will notice about the new diabetes medications are their TV commercial friendly names, Â Januvia, Onglyza, Tradjenta, and Nesina. Â Mix these newcomer drugs together into a single pill with the venerable low cost generic metformin and the names becomes Janumet, Kombiglyze, Jentadueto, and Kazano.
The next thing a consumer will notice is the price tag. At the local pharmacy in Jupiter, Florida the retail prices of a 3 month supply of Januvia, Onglyza or Tradjenta are all about $1100. Â A three month supply of the established generic drug, glipizide, is $9.99 and metformin is between zero and $41. (more…)
In my last article on the newest generation of diabetes pills (the DPP-4 inhibitors), I basically said that their benefits were not impressive and the costs were too high. I stand by those comments, but I need to add some clarifying thoughts. I continue to use drugs like Januvia, Onglyza and Trajenta because certain individuals seem to get a better effect from them than I generally expect. If, for instance, a diabetic is on maximum dose of the older (and cheaper) diabetic medications and the glucose control is not good, instead of going directly to insulin as the next step, I will try the DPP-4 inhibitors (gliptins). If the glycohemoglobin A1c level drops by a percentage point (e.g from 9% to 8%) I will continue the new drug therapy. If the change is minor (less than a percentage point) then there is little reason to continue spending my patients’ money on a therapy which has failed. In these cases, insulin needs to be started. The nice thing about insulin treatment is that it almost always results in a swift and dramatic improvement in blood sugar. Few of my patients willingly accept insulin at the beginning and are glad they were given one more chance to stay on pill therapy, even if it is just a temporary reprieve.
These comments are for educational purposes only and do not constitute medical advice.
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.
It seems obvious that cutting away part of the stomach and intestine should cause weight loss. With a smaller stomach and less intestine fewer calories can be absorbed per day causing weight loss. Surgeons who perform gastric by-pass were puzzled however, by how fast their patients showed metabolic improvement after undergoing this procedure. They noticed many of their diabetic patients could be taken off diabetic medication immediately after surgery before weight had been lost. Scientists looking into this phenomena discovered unsuspected ways gastric by-pass improved metabolism.
The intestines produce hormones which regulate blood sugar and appetite. GLP-1 is among the best known of these intestinal hormones. GLP-1 is the basis of a whole new generation of medications used to treat diabetes such as Byetta, Victoza, Januvia and Onglyza. GLP-1 lowers blood sugar, stimulates the pancreas and reduces appetite. After gastric by-pass increased amounts of GLP-1 are produced by the remaining intestine. In a study published in the Journal of Clinical Endocrinology and Metabolism (95:4072-4076, 2010), researchers at St. Lukeâ€™s Hospital in New York discovered that levels of oxyntomodulin, another intestinal hormone that suppresses appetite and acts like GLP-1 on blood sugar levels, is doubled after gastric by-pass.
These exciting discoveries help explain why obese diabetics can often be sent home without any medication to control blood sugar immediately after undergoing gastric by-pass surgery. Although most insurance plans do not cover gastric by-pass surgery, dramatic improvements in patients after the procedure with greatly reduced medication costs may convince insurance companies that paying for the procedure will result in better outcomes and save them money in the long run.
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.