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Updated September 17, 2013

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Byetta and kidney disease |Erectile Dysfunction Products | Weight Loss Pills |Insulin and cancer | Plavix | Benicar |Tradjenta| Simvastatin| Bydureon | Tekturna |

Bydureon™ (by-du-re-on) is a new form of Byetta (exenatide). The exenatide has been formulated to an “extended release” form. The major advantage over the other GLP-1 products (Byetta™, Victoza™) is that it is injected only once a week.

There are at least three questions we should ask of any drug:

  1. Does it work for me?
    1. Bydureon (exenatide ER) has been shown to be at least as effective as the twice daily Byetta (Exenatide), in some cases even slightly more effective in A1c reduction. It may not be quite as effective in reducing the fasting blood sugar according to Abstract: 107-OR American diabetes Association, 2008. Average A1c Reduction was -1.9 percentage points vs. -1.5 for twice daily Byetta. Weight loss was about 9 pounds for each. Bydureon may require up to six weeks to reach “steady state” and be fully effective.
  2. Is it safe for me?
    1. The most frequent side effects occur in the G.I. tract. Most commonly nausea. A partial list of other reactions reported include: abdominal distension, abdominal pain, acute pancreatitis (including hemorrhagic and necrotizing), alopecia, anaphylactic reaction, and angioedema. There are Black Box warnings, see below.
  3. Is the cost OK for me?
    1. According to the New York Times, the wholesale price of Bydureon would be $323.44 for four doses (one month supply), or about $4,200 a year. There is a discount card that could save $50/month in co-pay (Call 1-877-700-7365). I don't know how well it will be covered by insurance plans. The wholesale cost of twice daily Byetta is about $340 per month. That is covered by some plans. It seems logical that Bydureon will be covered as well. But logic like whiskey loses its beneficial effect when taken in large quantities, John Dunsany.

Things to be aware of:
It has been shown to cause a type of thyroid cancer in rats. “Exenatide extended-release causes thyroid C-cell tumors at clinically relevant exposures in rats. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies.” Bydureon prescribing information.
According to the prescribing information, Bydureon should not be given to patients with a personal or family history of medullary thyroid cancer.
Extended-release exenatide has been associated with pancreatitis.
Extended-release exenatide should not be given to patients with severe renal (kidney) impairment.

Bydureon is dispensed in a powder form (preloaded on a vial) and must be mixed with liquid (preloaded in a syringe).
Cost: like most new products, it is expensive. According to the New York Times, the wholesale price of Bydureon would be $323.44 for four doses (one month supply), or about $4,200 a year. There is a discount card that could save $50/month in co-pay. Call 1-877-700-7365

Zocor® (simvastatin). An important drug warning was issued by the manufacturer(s) of Zocor® (simvastatin), Vytorin® (simvastatin plus ezetimbe [Zetia®]), and Simcor® (simvaststin and niacin) on June 8, 2011. The warning was a result of a study that showed an increase in serious muscle damage and kidney problems in patients taking large doses of simvastatin. The drug warning states: "The use of the 80 mg dose of simvastatin should be restricted to patients who have been taking that dose chronically (e.g., for 12 months or more) without evidence of muscle toxicity." In addition, because there was a possibility of drug interactions, the use of certain drugs with any available dose of simvastatin was considered CONTRAINDICATED. The list of drugs but is quite extensive. Some common ones, frequently taken by patients with diabetes include antibiotics erythromycin, clarithromycin (Biaxin®), telithromycin (Ketek®). Several antifungal agents are also included in this group including ketoconazole, possible, so, itraconazole and certain drugs used for HIV infections.

Other medications should not be administered with certain doses of simvastatin due to potential drug interactions. These include many common medications used by people with diabetes. Examples are amiodarone, verapamil, amlodipine (Norvasc®) and diltiazem.  It is recommended that the dose not exceed 10 mg of simvastatin daily if taking amiodarone, verapamil or diltiazem and should not exceed 20 mg daily if the patient is taking amlodipine (Norvasc®)  or Ranolazine.

Links for further information:
http://www.simvastatininfocenter.com/
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000911/
http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf

Tradjenta ™(linagliptin) is a DPP4 (Dipeptidyl peptidase-4 inhibitor) product. It is very similar to other DPP4 drugs, Januvia™ (sitagliptin) and Onglyza™ (saxagliptin). The effectiveness of DPP4 products is similar. There are subtle differences. Dose reduction is recommended for Januvia and Onglyza if there is significant kidney damage (dailymed.nlm.nih.gov). There is no such recommendation for Tradjenta. There are reports of pancreatitis with Januvia and Tradjenta but none (to my knowledge) so far with Onglyza. There are more reports of side effects with Januvia than the others, likely because it has been around longer. With time we will likely see more side effects with the newer DPP4 drugs. COSTS: Revenue from Januvia was 1.4 billion in 2009 according to Wikinvest. The makers of Onglyza and Tradjenta offer co-pay reduction cards for those with private insurance (large market). These discount cards are good for one to two years and don't work for people with Medicaid and/or Medicare. Discount cards are generally available from your physician. There are some available on the web, Onglyza cards here and Tradjenta here. There is also a site that has links to many other discount deals, click here.

BENICAR. Two clinical studies show increased risk of death (heart attack, stroke or sudden death) in patients with diabetes who took Benicar ® (olmesartan).  Benicar ® is a widely used drug for hypertension (high blood pressure), it has not been removed from the market by the FDA but is still undergoing review.
FACTS:
-Most of us with diabetes will die from some kind of heart of blood vessel disease. There is an increased risk in all with diabetes.
-Benicar belongs to a class of hypertension drugs called ARBs (Angiotensin II Receptor Blockers). Others in the class include Atacand®, Teveten®,  Avapro®,  Cozaar®, Micardis®, Diovan®.
-The studies being reviewed by the FDA compared Benicar ® to placebo (a sham pill). It is not known if other blood pressure pills in this class have the same risk. It is also not known if this risk exists for blood pressure medicine in other classes.
WHAT TO DO:
If taking Benicar®, consult your physician. DO NOT STOP THE DRUG. The risk of problems from uncontrolled blood pressure far far outweighs the risk cited by the FDA. Click here for the FDA warning.

Plavix®(clopidogrel). What’s all the noise about? The FDA notified healthcare professionals and patients on 3/12/2010 that a Boxed Warning has been added to the prescribing information for Plavix®. This medication is widely prescribed to retard the clumping of a type of blood cell (platelets) involved in the blood clotting mechanism. It is therefore useful (and approved by the FDA) for patients with a history of recent heart attack (myocardial infarction) stroke, or known obstruction of arteries in the legs (peripheral artery disease). It has been shown to reduce the likelihood of an additional stroke or heart attack.  Click here for the FDA release. Click here for detailed information on Plavix®


The major complications of diabetes involve blood vessels, increasing the risk of heart attack, stroke and peripheral artery disease (among others). The result is that many patients with diabetes are prescribed anti-platelet drugs such as Plavix®. The “Boxed Warning” relates to the fact that it does not work well in some people, because of genetic differences. Plavix® (clopidogrel) is not an active drug in itself. It must the converted by a liver enzyme (CYP2C19) to the active compound.  Some people are genetically different and have slow acting CYP2C19, therefore they do not convert Plavix® very well to the active component and the desired effect is lost.


Genetics will have a major role in determining drug prescriptions and doses in the future. One study of “poor metabolizers” found the genetic difference in 23% of Japanese; 39% of Filipinos; 32% of Chinese-Taiwanese; 15% of Saudi Arabians; 13% of European-Americans; and 25% of African Americans from North Carolina. A sizable body of people will therefore likely not respond well to Plavix®. One must, however be careful of predicting a metabolic outcome based on perceived ethnicity. It has been stated that 75% of African Americans have European or Native American ancestry (wiki.answers.com). Testing is available to detect the CYP2C19 genetic difference.


Plavix is certainly not the only drug affected by the CYP2C19 enzyme system. The list is extensive and includes such common products as oral contraceptives, isoniazid, Prilosec®, fluconazole and Provigil. A detailed explanation can be found by clicking here. A detailed list of drugs involving the CYP enzyme system can be found by clicking here.


Some other available anti-platelet drugs include:
Aspirin - has been shown to increase the activity of CYP2C19 significantly, there should therefore be no decrease in activity by “slow metabolizers”.
Effient® (prasugrel hydrochloride) – metabolized by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The effect of Effient in those of African or Hispanic descent is similar to that in Caucasians. The active metabolite has been found to be approximately 19% higher in Chinese, Japanese, and Korean subjects than in Caucasian subjects. It also has a “Boxed Warning”. Click here.

Sources:
Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, Evans DA. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics. 1997 Feb;7(1):59-64.
Daily Med  http://dailymed.nlm.nih.gov/.
Nature  http://www.nature.com/clpt/journal/v73/n3/abs/clpt2003387a.html
FDA  http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm204256.htm

Byetta ® linked to kidney disease?

The FDA announced to physicians that 62 cases of acute kidney failure and 16 cases of reduced renal function have been reported between April 2005 and October 2008 in patients taking Byetta® (exenatide). Some patients already had kidney disease. Diabetes , particularly if uncontrolled, is associated intimately with kidney problems, so there is increased risk in those of us with the disease.

According to Reuters, Byetta ® is now FDA approved for diabetes treatment as a single agent. Previously it was FDA approved "...as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, but have not achieved adequate glycemic control." (From the NIH web site)

A spokesperson form the manufacturing companies indicated there "no evidence from pre clinical and clinical studies that Byetta has any direct toxic effect on the kidney" and noted that diabetes itself is the leading cause of kidney failure. Reuters.

At the Diabetes Control Center, we are not recommending that our patients taking Byetta stop it based on this news. When it was placed on the market, there were warnings about Byetta® use in patients with decreased kidney function. We recommend regular checks of kidney function in all patients with diabetes and especially in those taking certain medications, including Byetta®.

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Erectile Dysfunction Products

Over the Counter (OTC) products for ED (Erectile Dysfunction) - NOT A GOOD IDEA. Many OTC products are unregulated by the FDA. This means manufacturers place substances in products labeled “herbal”, “dietary supplement”  or “natural” that may not be listed in the ingredients and that may be lethal. For instance FDA alerted consumers and healthcare professionals not to buy or use Xiadafil VIP Tablets sold in bottles of 8 tablets (Lot #6K029) or blister cards of 2 tablets (Lot# 6K029-SEI). The product is marketed as a dietary supplement and is promoted and sold over the internet for sexual enhancement and to treat erectile dysfunction (ED). The product contains a potentially harmful, undeclared ingredient that may dangerously affect a person's blood pressure and can cause other life-threatening side effects. Xiadafil VIP Tablets contain hydroxyhomosildenafil, an analog of sildenafil, the active ingredient in Viagra, an FDA approved prescription drug for ED. The undeclared ingredient may interact with nitrates found in some prescription drugs and can lower blood pressure to life-threatening levels           FDA alerted consumers and healthcare professionals not to buy or use Xiadafil VIP.  Another such product is Viril-ity Power (VIP), or tablets. Source FDA News, May 27, 2008

. Charles H. Raine, III, M.D.

Click here for FDA news on these products.

Click here for FDA Consumer Health Information publication (pdf) : Hidden Risks of Erectile Dysfunction “Treatments” Sold Online.

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Weight loss pills.


If something appears too good to be true, it probably is!!  Several weight loss pills containing sibutramine and /or rimonabant are marketed online.  Sibutramine may be habit-forming with long-term use, cause headaches, rapid heart beat, etc. The initial drug in the rimonabant class was withdrawn because of severe depression in some studies.


FDA alerted consumers nationwide not to purchase or consume more than 25 different products marketed for weight loss because they contain undeclared, active pharmaceutical ingredients that may put consumers' health at risk. The undeclared active pharmaceutical ingredients in some of these products include sibutramine (a controlled substance), rimonabant ( a drug not approved for marketing in the United States), phenytoin ( an anti-seizure medication), and phenolphthalein (a solution used in chemical experiments and a suspected cancer causing agent). The weight loss products, some of which are marked as "dietary supplements," are promoted and sold on various web sites and in some retail stores.


FDA advises consumers who use the products to stop taking them and consult their healthcare professional immediately as the health risks posed by these products can be serious (for example, high blood pressure, seizures, tachycardia, palpitations, heart attack or stroke). FDA also encourages consumers to seek guidance from healthcare professional before purchasing weight loss products. See the FDA News Release for a listing of the names of the 25 referenced products. Source, FDA Consumer update released March 27, 2009.
Read the MedWatch 2008 safety summary, including links to the News Release and Questions and Answers, at:
http://www.fda.gov/medwatch/safety/2008/safety08.htm#Weight
Charles H. Raine, III, M.D.

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Does insulin cause cancer?

June 28, 2009

Insulin is known to have a mitogenic (promoting multiplication of cells) effect.  Cancer results from uncontrolled cell multiplication. EASD (European Association for the Study of Diabetes) recently released several observational studies, some indicating an increased cancer risk with several insulins, especially glargine (Lantus®). The studies will be published shortly in Diabetologia, EASD’s major journal.
After reading the several articles, these are my conclusions:

  1. The studies are observational – the weakest of scientific data.
  2. The studies, all done in Europe, had varying design and results.
  3. The cardiovascular (heart attack and stroke, kidney failure, amputation and eye disease) risks from uncontrolled diabetes far, far outweigh cancer risk from insulin.
  4. Type 2 diabetes is associated with three of the five leading causes of cancer death in the US (regardless of type of treatment for diabetes), according to an editorial in Diabetologia accompanying the articles.
    1. The increased risk of cancer of the colon in people with diabetes is 30%
    2. Pancreas 50%
    3. Breast 20%
  5. In all of the studies the patients taking glargine (Lantus®)  alone had more risk factors for cancer than others, i.e. older, more overweight and hypertensive.
  6. The current evidence is not grounds for changing from insulin therapy, e.g. Lantus ®

Specifics from the studies
The Swedish Study:

  1. There was no statistically significant difference in cancer incidence between, those on insulins other than insulin glargine (Lantus ®) and those on insulin glargine plus other insulins.
  2. Those on glargine alone had a higher risk of breast cancer than those on insulins other than glargine with a relative risk if 1.99 (about twice the risk).
  3. The risk of all other cancers was about equal.
  4. The number of breast cancers was relatively low, 25 (of 5,970 individuals), on insulin glargine VS 183 (88,555 individuals) on other insulins.

The Scottish Study:

  1. Patients taking insulin glargine alone had a higher overall cancer rate that those taking the older human insulin, risk about 1.64 times higher. Breast cancer was about 1.66 times higher.
  2. Patients taking glargine alone or with other insulin had a lower rate of progression of any cancer, about 34% lower.

The United Kingdom Study

  1. There was no statistically significant difference in cancer incidence, regardless of the insulin taken.  The number of patients in the study was small (2,286 on insulin glargine alone, 1,262 on NPH insulin).
  2. Metformin seemed to have a protective effect.

The German Study:

  1. Insulin glargine carried a significantly lower cancer risk than those on older human insulin, if insulin dose was not considered.
  2. When dose was considered, the risk of cancer was 1.13 times higher if taking 50u of insulin glargine VS 50u of older human insulin.

In summary, there are studies and there are studies. Old and new information indicate that the patient with diabetes is at peril of any number of maladies. The best approach is to follow the advice of your doctor. Take medication as prescribed and follow guidelines for immunizations, cancer screening (mammogram, PAP smears, colonoscopy, etc.) and other health promoting procedures. Charles H. Raine, III, M.D. Reference Diabetologia.org

Click here for EASD news release.

Click here for statement from Sanofi Aventis maker of glargine (Lantus®)

Click here for EASD statement for patients.

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