Sitagliptin With Simvastatin (JUVISYNC): A New Drug Combination to Avoid

Taking advantage of an increasingly common means of getting new patents and increasing drug sales, drug manufacturer Merck has combined the antidiabetic drug sitagliptin (JANUVIA) and the cholesterol-lowering drug simvastatin (ZOCOR) into one pill: JUVISYNC. And on Oct. 7, 2011, the Food and Drug Administration (FDA) approved this new drug combination.

The FDA has not posted any reviews of this new drug combination. The only information on sitagliptin with simvastatin available to the public is the FDA’s letter of approval and the drug label. A review of the warning information on both drug labels reveals many possible side effects, from potential liver toxicity to acute renal failure to skeletal muscle toxicity.

Public Citizen has categorized the combination of sitagliptin with simvastatin as a “Do Not Use” drug because there is no clinical evidence of its safety and effectiveness and because of the adverse reactions possible with use of each drug in the combination. The FDA-approved labeling for the drug fails to discuss any clinical trial in which the effectiveness of the combination was compared with that of the individual drugs.

Sitagliptin: adverse effects and FDA response

The article in the March 2012 Worst Pills, Best Pills News, “A Review of the ‘Gliptin’ Diabetes Drugs,” gives an overview of pancreatitis concerns and allergic reactions to sitagliptin. Since the FDA approved the drug in October 2006, however, there have been numerous warnings of other adverse effects.

These adverse effects must be considered with the knowledge that “[t]here have been no clinical studies establishing conclusive evidence of macrovascular risk [heart attack and stroke] reduction with Januvia or any other anti-diabetic drug” (from the drug’s product label, added in July 2008). Since macrovascular risk is the main risk for diabetics, it is hard to see what benefits could outweigh the risks discussed below.

By 2008, two years after the approval of sitagliptin, two warnings had been added to the drug’s label, prompting Public Citizen to classify sitagliptin as a “Do Not Use” drug.

The first warnings of adverse effects came only a year after approval (October 2007). They included the potential for serious hypersensitivity reactions (patches of red, swollen skin or hives) and hypoglycemia (low blood sugar) and were added to the “Warnings and Precautions” section of the product label.

In October 2008, another adverse event was added to the post-marketing section of the “Adverse Reactions” section of the drug label: increase in hepatic (liver) enzymes. The increase in these enzymes is a signal of liver toxicity. When the liver is damaged, enzymes leak out of cells and can be measured in the blood.

The reporting of new types of adverse events continued. In September 2009, the FDA alerted physicians that it had received 88 post-marketing cases of acute pancreatitis, including two of the most severe forms (hemorrhagic or necrotizing). This adverse event was added to the top of the “Warnings and Precautions” section of the product label.

Five months later, in February 2010, the FDA became so concerned about the risks of sitagliptin that it required Merck to submit a Risk Evaluation and Mitigation Strategy (REMS) and create a Medication Guide, a safety information brochure to be issued each time a prescription is filled. The REMS process allows the FDA to require the drug manufacturer to provide enough safety information for doctors and patients to ensure that a drug’s benefits outweigh its risks. Increasingly, for drugs with significant risks and unclear benefits, Public Citizen has questioned whether it is possible to effectively manage the risk without withdrawing the drug from the market.

As further evidence of its concern, the FDA required a study of pancreatic safety in a diabetic rodent model, a study that was to have been completed by June 2011. We do not know if this study was actually performed and submitted to the FDA, because no such information has been provided to the public.

In a September 2010 letter, the FDA, apparently still concerned about the number of pancreatitis cases being reported, required Merck to add to the drug’s label the incidence of pancreatitis in the controlled clinical trials (not just post-marketing cases).

To artificially make the incidence of pancreatitis appear lower than it actually was, Merck pooled all double-blind trials without regard to study length, dosage or patient characteristics. Consequently, the length of exposure could have been anywhere from five to 52 weeks. It was not surprising that the findings showed a very low incidence of pancreatitis for both the sitagliptin group and the control group, a very questionable result based on the number of cases that continue to be reported.

In the same September 2010 letter, the FDA added another series of adverse events to both the label and Medication Guide: constipation, headache and vomiting had been turning up in post-marketing reports. That same year, sitagliptin sales exceeded $1.2 billion, with almost 6 million prescriptions sold.

Another safety concern for patients came from the FDA on April 14, 2011, with a letter to Merck and an FDA Drug Safety Alert. The agency requested that “worsening renal function, including acute renal failure (sometimes requiring dialysis)” be added to the product label and Medication Guide. In this same letter, the FDA agreed to Merck’s request to eliminate the REMS, which had been in place for only a little more than a year.

Thus far, we have not seen any explanation as to why the FDA eliminated the REMS. The FDA should provide the reasoning behind its removal of the REMS after such a short time because sitagliptin is certainly far from being a safe drug to use.

Simvastatin: adverse effects and drug interactions

Simvastatin’s main adverse reactions concern skeletal muscle and the liver. Skeletal muscle toxicity is manifested by pain and, if left to progress, can cause kidney damage. We have discussed these effects in the June 2007 and June 2008 issues of Worst Pills, Best Pills News. There is also a potential for drug interactions: Many drugs taken with simvastatin increase the risk of muscle damage.

In November 2009, the U.K. updated warnings for patients taking any statin drug. The advisory stated that patients should be aware of the possibility of depression, sleep disturbances, memory loss and sexual dysfunction, as well as the possibility of interstitial lung disease. The safety warnings concluded that there was “sufficient evidence to support a possible causal relationship between statin use and the above adverse reactions.”

In May 2010, the FDA issued a warning concerning the risk of myopathy when taking simvastatin at an 80-milligram (mg) dose. People at higher risk of myopathy (those over 65 years of age; women; and patients with renal impairment, hypothyroidism or previous muscle problems) may still be in jeopardy of suffering this effect at the 40-mg dose.

Most recently, in January 2012, the U.K. issued a warning concerning the risk of hyperglycemia (high blood glucose) and new onset diabetes in patients taking statins. There does not appear to be information on how this affects those who already are diabetic.

Drug combination doubles the toxicity

What is the net effect from trying to lower glucose with one drug that is combined with another drug that can raise it? Since there is no evidence from the drug label that any clinical studies were done to compare the effectiveness of the combination with that of the individual drugs, this question cannot be answered.

However, the combination of sitagliptin with simvastatin presents the certainty of adverse effects from each of the two drugs as well as the possibility of further adverse effects from drug interactions between the two.

What You Can Do

Do not use the drug combination sitagliptin with simvastatin. The drug has not been shown to be safe and effective in high-quality research studies. Public Citizen has also classified sitagliptin alone as a “Do Not Use” drug.

You should consult your physician about other drugs to treat high cholesterol and diabetes and use the lowest doses of well-tested, safe drugs.

Consumers may report serious adverse events with drugs or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.

• Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088