The Dangerous Diabetes Drug Pramlintide: Do Not Use

In 2005, the Food and Drug Administration (FDA) approved a diabetes drug that works in a different way than any other diabetes drug on the market.[1] The drug, pramlintide (SYMLIN, SYMLINPEN), is injected at mealtime along with insulin for patients with type 1 or type 2 diabetes for whom mealtime insulin alone has not lowered blood sugar levels sufficiently.[2]

Pramlintide is a synthetic version of a naturally occurring hormone called amylin, which is produced by the same cells in the pancreas that make insulin. Like amylin, pramlintide is thought to lower blood sugar by slowing the rate at which food empties from the stomach; blocking the release of glucagon, another pancreatic hormone that raises blood sugar levels; and suppressing the appetite, thereby decreasing food intake.[3]

The drug provides only minimal benefits for controlling blood sugar levels, with no evidence that it prevents or slows the progression of any diabetes-related illnesses, such as cardiovascular, kidney or eye disease.[4],[5] Additionally, pramlintide can be toxic and has serious adverse effects. For these reasons, the FDA initially rejected the drug and later approved it only with unusually stringent restrictions on its marketing and prescribing. For the same reasons, Public Citizen’s Health Research Group designates pramlintide as a Do Not Use drug.

Limited benefit and significant harm

Pramlintide’s original manufacturer, Amylin Pharmaceuticals, applied for FDA approval of the drug in 2000.[6] At an FDA advisory committee meeting convened to consider the application, we testified against approval of the drug and noted that it has only marginal benefit, lowering hemoglobin A1c levels (a measure of how well a patient’s blood sugar has been controlled during the previous two to three months) on average by just 0.3%, from 9% to 8.7%, compared with a placebo.[7]

Additionally, pramlintide is associated with serious harms. Most significantly, clinical trials of the drug demonstrated that it can cause dangerously low blood sugar levels, which in some cases were linked to confusion while driving and serious car crashes. Pramlintide also increases the risk of convulsions, coma and nausea.

Pramlintide cannot safely be mixed with insulin in the same syringe. As a result, patients who are prescribed pramlintide must double the number of injections that they give themselves daily.

Finally, because pramlintide can slow emptying of the stomach, the absorption of certain oral medications may be delayed if taken within an hour before or two hours after injecting the drug.[8]

Delayed approval with strict requirements

Pramlintide’s tendency to cause severely low blood sugar levels prompted the FDA to reject the company’s 2000 application to market the drug as well as another application filed a few years later.[9] When the FDA finally approved the drug in 2005 for use with insulin in patients with type 1 or type 2 diabetes for whom mealtime insulin alone has not lowered blood sugar levels sufficiently, it required the company to take the following unusually strict steps:[10],[11]

• Inserting a black-box warning (the most serious type of warning required by the FDA) in the drug’s label notifying health care professionals and patients of the danger of severely low blood sugar levels;
• Abiding by a prohibition on advertising the drug directly to consumers;
• Waiting a year after putting the drug on the market before advertising in medical or other journals;
• Only advertising the drug to physicians specializing in diabetes management and supported by certified diabetes educators;
• Gradually introducing pramlintide into the market, with close evaluation and reporting to the FDA of which health care professionals prescribe the drug;
• Conducting a post-approval observational study to further evaluate the risk of low blood sugar levels resulting from pramlintide administration;
• Reporting severe hypoglycemia adverse events associated with pramlintide to the FDA in an expedited manner for the first two years after the drug’s approval or until the observational study was completed; and
• Setting up a 24-hour/7-day call center to assist patients and physicians in the use of pramlintide.

The FDA-required post-approval observational study was conducted by the drugmaker from 2005 to 2008 and measured the frequency of severely low blood sugar levels in approximately 1,300 patients newly started on pramlintide.[12] Approximately 5 percent of patients with type 1 diabetes and 3 percent of patients with type 2 diabetes experienced such an adverse event in the first three months after starting pramlintide, with the risk declining thereafter.

In 2010, because of ongoing concerns about the risk of severely low blood sugar levels, the FDA notified the company that it would need to implement a risk evaluation and mitigation strategy (REMS) for pramlintide that required it to, among other things, inform health care professionals about the adverse effects of pramlintide and to evaluate their understanding of this information. In 2017, this REMS requirement was terminated,[13] despite the lack of new evidence from large, long-term trials showing that pramlintide is any safer or more effective than when it was approved 12 years earlier.

What You Can Do

Do not use pramlintide. If you have type 1 diabetes, insulin is a necessary and effective treatment; the dose, formulation and time of administration should be adjusted to achieve optimal blood sugar levels. If you have type 2 diabetes, you should begin treatment with diet and exercise and, if your blood sugar levels are not optimal, also take metformin (FORTAMET, GLUCOPHAGE). For our complete guide to type 2 diabetes treatment, see our article “Type 2 Diabetes: A Guide to Prevention and Treatment” in the May 2014 issue of Worst Pills, Best Pills News.[14]

References

[1] Dungan K, Hirsch IB, Mulder JE. Amylin analogs for the treatment of diabetes mellitus. UpToDate. October 6, 2017. https://www.uptodate.com/contents/amylin-analogs-for-the-treatment-of-diabetes-mellitus?source=search_result&search=amylin%20agonists&selectedTitle=1~150. Accessed September 28, 2017.

[2] AstraZeneca Pharmaceuticals. Label: pramlintide (SYMLINPEN,). April 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=4aea30ff-eb0d-45c1-b114-3127966328ff&type=pdf&name=4aea30ff-eb0d-45c1-b114-3127966328ff. Accessed October 6, 2017.

[3] Dungan K, Hirsch IB, Mulder JE. Amylin analogs for the treatment of diabetes mellitus. UpToDate. September 11, 2017. https://www.uptodate.com/contents/amylin-analogs-for-the-treatment-of-diabetes-mellitus?source=search_result&search=amylin%20agonists&selectedTitle=1~150. Accessed October 6, 2017.

[4] Jonas D, Van Scoyoc E, Gerrald K, et al. Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations: Final Original Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Feb. Drug Class Reviews.

[5] The different classes of antidiabetic drugs. Prescrire Int. 2007;16(92):229.

[6] Food and Drug Administration. Letter to Amylin Pharmaceuticals, Inc. on the approval of pramlintide. March 16, 2005. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021332ltr.pdf. Accessed September 28, 2017.

[7] Public Citizen. Testimony on pramlintide (Symlin). July 26, 2001. https://www.citizen.org/our-work/health-and-safety/testimony-pramlintide-symlin. Accessed September 28, 2017.

[8] AstraZeneca Pharmaceuticals. Label: pramlintide (SYMLINPEN,). April 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=4aea30ff-eb0d-45c1-b114-3127966328ff&type=pdf&name=4aea30ff-eb0d-45c1-b114-3127966328ff. Accessed October 6, 2017.

[9] Food and Drug Administration. Medical review: NDA 21-332, pramlintide. 2005. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21-332_Symlin%20Injection_medr.PDF. Accessed October 6, 2017.

[10] Food and Drug Administration. Letter to Amylin Pharmaceuticals, Inc. regarding the approval of pramlintide. March 16, 2005. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021332ltr.pdf. Accessed September 28, 2017.

[11] Amylin Pharmaceuticals, Inc. Label: pramlintide (SYMLIN). March 14, 2005. href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021332lbl.pdf. Accessed October 6, 2017.

[12] Pencek R, Roddy T, Peters Y. Safety of pramlintide added to mealtime insulin in patients with type 1 or type 2 diabetes: a large observational study. Diabetes Obes Metab. 2010;12(6):548-551.

[13] Food and Drug Administration. Letter to AstraZeneca AB regarding supplemental approval of pramlitnide. March 8, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/021332Orig1s026ltr.pdf. Accessed September 28, 2017.

[14] Type 2 diabetes: A guide to prevention and treatment. Worst Pills Best Pills News. May 2014. . Accessed September 28, 2017.