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Sitagliptin (JANUVIA) for Type-2 Diabetes: DO NOT USE for Seven Years (Until 2014)

Worst Pills Best Pills News article June, 2007

Editor’s note: The following article introduces Worst Pills, Best Pills News readers to a new drug, sitagliptin, that will probably receive a substantial amount of public attention. It compiles the most important information, alternative treatments for the drug’s indication, and our recommendation for use of this drug in an easy-to-read format that we hope will allow you to make better choices when faced with new drug decisions in the future.  

What is sitagliptin?
Sitagliptin was approved by the Food and Drug Administration (FDA) in October 2006 to improve blood sugar control in patients with type-2 diabetes. The drug is approved for use alone or in combination with other drugs to treat type-2 diabetes, along with a healthy diet and exercise.  

Sitagliptin should not be used in patients with type-1 diabetes or patients with a serious complication of diabetes known as diabetic ketoacidosis.  

Clinical studies have not yet determined whether sitagliptin is safe for children. This could mean that the drug has not been tested in children or that it has been tested in children and found to be ineffective.  

Sitagliptin has not been shown to reduce the risk of death in patients with type-2 diabetes.

Sitagliptin is manufactured by Merck & Co. Inc., located in Whitehouse Station, N.J.

What is type-2 diabetes?
Type-2 diabetes, the most common form of diabetes, is often related to diet. This form is sometimes referred to as adult-onset diabetes or noninsulin-dependent diabetes. Despite the name, people can develop type-2 diabetes at any age – even during childhood. This form of diabetes usually begins with insulin resistance, a condition in which fat, muscle and liver cells do not use insulin properly. At first, the pancreas keeps up with the added demand by producing more insulin. In time, however, it loses the ability to secrete enough insulin in response to meals. Being overweight and inactive increases the chances of developing type-2 diabetes. Treatment includes healthy diet, being physically active, taking aspirin daily, controlling blood pressure and cholesterol, and, if still necessary, using diabetes medicines.

Can type-2 diabetes be prevented?
Yes. There is no longer any question that lifestyle changes that result in weight loss can prevent or delay type-2 diabetes in those at risk of developing the disease. Lifestyle change, including daily exercise and health-conscious food choices, in addition to weight loss, is the treatment of choice for type-2 diabetes prevention. This is both the safest and the most permanent treatment.  

An editorial published in the March 20 Annals of Internal Medicine said “... a long-term follow-up study of patients randomly assigned to a four-year lifestyle intervention has demonstrated that the beneficial effects of lifestyle intervention on diabetes development last for up to seven years.”

What is known about the safety of sitagliptin?
The long-term safety of sitagliptin is largely unknown.

Very few patients have used sitagliptin long-term. About 2,650 patients were exposed to sitagliptin in pre-approval clinical studies conducted by the drug manufacturer and, of those, about 2,400 patients received 100 milligrams or higher of the drug. Four hundred forty-four patients were given at least 100 milligrams of sitagliptin for periods up to one year; 164 of these patients received the drug for more than two years. This very small pool of patients over only two years is the longest clinical trial of this drug.

Because sitagliptin is the first in a new family of drugs that works in a new way, it is possible that unknown and unpredictable adverse effects may occur after the drug is used in large numbers of patients.

Does the FDA have safety concerns with sitagliptin?
Yes, the FDA medical director in charge of the drug’s review did express concern about sitagliptin.

Clinical study participants who took the drug experienced an increase in creatinine, a chemical found in blood. Elevations in creatinine are often an early indicator of kidney problems.

The medical director recommended that doctors periodically monitor the kidney function of their patients who are taking the drug, because the drug dosage would need to be reduced in patients with diminished kidney function.  

However, the FDA decided not to include a recommendation to routinely monitor creatinine levels in sitagliptin’s professional product labeling (also known as a package insert).

What are the most common side effects seen with sitagliptin in the clinical trials?
The table below lists the most common side effects associated with sitagliptin. These problems occurred two percent more often in patients taking sitagliptin than in those not taking the drug.

The most common adverse effect was nausea. Surprisingly, 13 patients (3 percent) reported depression when they used the drug. Some, but not all, of these patients were reported to have pre-existing depression.

  Adverse Events – Incidence With Sitagliptin Greater Than 2% More Than Those Not Taking Sitagliptin
Adverse Effect
Sitagliptin 100 milligrams –
Number (%)
Sitagliptin 200 milligrams –
Number (%)
No Sitagliptin Number (%)
Nausea
21 (4.9%)
3 (11.1%)
3 (1.9%)
Swelling (peripheral edema)
20 (4.7%)
1 (3.7%)
3 (1.9%)
Bronchitis
24 (5.6%)
0
1 (0.6%)
Inflammation of Nose, Pharynx (nasopharyngitis)
40 (9.3%)
1 (3.7%)
8 (5.2%)
Upper Respiratory Tract Infection
49 (11.4%)
4 (14.8%)
11 (7.1%)
Muscle Pain (myalgia)
17 (4.0%)
1 (3.7%)
3 (1.9%)
Pain in Extremity
19 (4.4%)
0
3 (1.9%)
Depression
13 (3.0%)
0
0
Cough
17 (4.0%)
0
4 (2.6%)

What evidence did the FDA use to approve sitagliptin?
The approval of sitagliptin for use not in combination with any other drug was based on two clinical trials, one lasting 24 weeks and the other 18 weeks. These trials compared the drug to a placebo (no treatment at all).  

Studies were also conducted evaluating sitagliptin in combination with metformin (GLUCOPHAGE) and pioglitazone (ACTOS). Sitagliptin is approved for use in combination with these drugs.

How was the effectiveness of sitagliptin measured?
In the clinical trials submitted to the FDA, a laboratory test that measures how well sitagliptin controls blood sugar levels over time was used as the main measure of effectiveness of sitagliptin. This test is called the hemoglobin A1c (HgbA1c).

HgbA1c is called a surrogate, or intermediate, endpoint, and it is not known if improving HgbA1c with sitagliptin translates into a reduction in the chances of cardiovascular disease or improved survival in those taking the drug.

How effective was sitagliptin in these clinical trails?
The FDA medical officer for sitagliptin wrote that sitagliptin’s effect on lowering HbgA1c was “fairly modest.”

The table below summarizes the effect of sitagliptin in lowering HgbA1c in the two clinical trials that supported the approval of the drug by itself compared to a placebo. The minus sign (-) indicates a decrease in HgbA1c levels and the plus sign (+) indicates an increase. In both studies and in both doses tested, the improvement in HgbA1c was less than 1 percent.

The American Diabetes Association (ADA) recommends a HgbA1c target level of 7 percent or lower. In these two trials, 41 percent of the patients in Study 1 and 36 percent of the patients in Study 2 achieved the ADA target HgbA1c level.

The two studies referred to above compared sitagliptin to the older drug glipizide (GLUCOTROL). In these studies, sitagliptin lowered HgbA1c levels by about 0.5 to 0.6 percent, while glipizide lowered the levels by about 1 percent.

The Effect Of Sitagliptin When Used Alone On HgbA1c Levels
Amount of Medication Change in HgbA1c Level from the Start of the Study to the End of the Study
STUDY 1 – Lasting 24 weeks
Sitagliptin 100 milligrams
-0.62%
Sitagliptin 200 milligrams
-0.78%
Placebo
+0.17%
STUDY 2 - Lasting 18 weeks
Sitagliptin 100 milligrams
-0.46%
Sitagliptin 200 milligrams
-0.34%
Placebo
+0.16%

Are there other treatments available to treat type-2 diabetes?
Yes. Other FDA-approved drug treatments for type-2 diabetes include insulin and eight other families of drugs. These drugs are listed in the table below.

Newly marketed drugs such as sitagliptin are generally no more potent, and in some cases less effective, in lowering blood sugar levels than the three oldest families of drugs: insulin, the sulfonylureas and the biguanides.

Drugs Approved for Type-2 Diabetes
 Family  Generic Name (BRAND NAME)
 Insulin  Many preparations
 Sulfonylureas  acetohexamide (DYMELOR)
 chlorpropamide (DIABINESE)
 
 tolazamide (TOLINASE)
 tolbutamide (ORINASE)
 glimepiride (AMARYL)
 glipizide (GLUCOTROL)
 glyburide (DIABETA)
 Biguanides  metformin (GLUCOPHAGE)
 Alpha-glycosidase inhibitors  acarbose (PRECOSE)
 miglitol (GLYSET)
 Thiazolidinediones or “glitazones”  pioglitazone (ACTOS)
 rosiglitazone (AVANDIA)
 Meglitinides  nateglinide (STARLIX)
 repaglinide (PRANDIN)
 Incretin mimetic  exenatide (BYETTA)
 Amylin analog  pramlintide (SYMLIN)
 Dipeptidyl peptidase 4 inhibitor  sitagliptin (JANUVIA)

What is Public Citizen’s recommendation for the use of sitagliptin?
Public Citizen urges people to refrain from using sitagliptin until 2014, seven years from the date of approval.

In general, people should wait at least seven years from the date of FDA approval to take any new drug unless it is one of those rare “breakthrough” drugs that offers a documented therapeutic advantage over older, proven drugs.

New drugs are tested in a relatively small number of people before being released, and serious side effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people.

We call this our “Seven Year Rule,” and it is based on a study we co-authored in the May 1, 2002, Journal of the American Medical Association. This study found that one-half of all new drug safety withdrawals occurred within two years of their FDA approval. One-half of all black box warnings, the strongest type of safety warning the FDA can request, and drug safety withdrawals combined occurred within seven years of new drug approvals – thus the Seven Year Rule.

 


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