The latest FDA drug-approval disaster suggests doctors should consider omega-3s for diabetes
by Craig Weatherby
A series of blunders involving approval of marginally useful “me-too” drugs by the Food and Drug Administration (FDA)—drugs that soon proved more dangerous than useful—exposed the all-too-cozy relationships between drug companies, regulators at the FDA, and the medical advisory boards that wield great influence over the agency’s drug-approval decisions.
The negative outcomes of this rather incestuous network were underscored by fiascos involving the arthritis pain drugs Vioxx® and Celebrex®, and were preceded by ill-advised approval of the dangerous weight control drugs Phen-Fen® and Redux®.
Last month, the FDA blew their safety assessment of a proposed new diabetes drug called muraglitazar, jointly marketed as Pargluva® by Merck and Bristol-Myers Squibb. The agency was set to approve it before independent researchers who examined the very same clinical data discovered that muraglitazar increases the risk of strokes and heart attacks substantially.
As we’ll explain later, omega-3s may offer a viable alternative or complement to muraglitazar and other “PPAR-activator” diabetes drugs. This is because PPAR drugs are designed to mimic the effects of dietary polyunsaturated fatty acids, including omega-3s.
PPARs: a key acronym in diabetes care
Muraglitazar was expected to introduce a new class of diabetes drugs called glitizars, reported to reduce insulin resistance—the dysfunction that underlies adult onset (“type II”) diabetes—and lower the elevated blood levels of sugar and blood fats that accompany the disease.
Glitizar-type drugs act on cell-surface receptors called peroxisome proliferator–activated receptors (PPARs). Nuclear receptors—also known as nuclear transcription factors—enable cells to adapt to signals alerting them to bodily conditions by modifying the expression levels of relevant genes. Among other things, PPARs act as genetic “switches” to regulate lipid (fat) metabolism.
The body uses omega-3 and omega-6 polyunsaturated fatty acids—and the ephemeral messenger chemicals called prostaglandins they generate—to bind to and hence “activate” PPAR receptors. Synthetic PPAR-activating drugs are designed to fit into specific PPAR receptors, to produce certain desired results.
Two kinds of PPAR-activating drugs are currently approved in the United States:
- PPAR-alpha activator drugs like gemfibrozil and fenofibrate lower blood triglyceride levels and modestly increase blood levels of HDL (“good”) cholesterol, and have been available for several decades;
- PPAR-gamma activator drugs increase insulin sensitivity and are used for glycemic control in patients with type II diabetes: they include rosiglitazone, pioglitazone, and troglitazone, which was withdrawn from the market because it can damage the liver.
Drugs that activate both kinds of PPARs—so-called “dual PPAR” agents—have been a holy grail of diabetes care, since they could treat two main symptoms of diabetes—hyperglycemia (elevated blood sugar levels) and dyslipidemia (imbalanced blood-fat levels)—simultaneously. Muraglitazar was expected to be the first “dual-PPAR” drug to come to market.
While drug companies cannot patent or profit from them, omega-3s offer effects comparable to those of synthetic dual-PPAR drugs (see “Omega-3s versus PPAR drugs”, below).
FDA call for comments brings bad news
In September of this year, a scientific panel appointed by the FDA voted 8-1 to recommend approval of muraglitazar as the first dual PPAR drug.
However, when the FDA issued a letter on October 18 calling for comment, it got more than it expected. A team at the renowned Cleveland Clinic cardiovascular center, led by Steven E. Nissen, M.D., published an article in the Journal of the American Medical Association, in which they analyzed the same data the FDA expert panel examined. To the agency’s chagrin, they found glaring problems the FDA and its expert panel managed to miss.
Specifically, they found that muraglitazar (Pargluva®) doubles the risk of heart attack and stroke, and likely raise the risk of cancer.
The findings were particularly alarming because some of the increased risks appeared within six months of starting on the drug. As the authors concluded, “Muraglitazar appears to increase the risk for morbidity and mortality in diabetic patients during relatively short-term treatment.… The consistency of these RRs [relative risks] suggests that this result is not due to chance. Accordingly, muraglitazar should not be used or approved to treat patients with diabetes until an appropriate dedicated trial to assess cardiovascular outcomes is performed.”
In other words, millions of diabetes patients came very close to taking a drug that could have inured or killed thousands of them. While they did solicit comments and consequently catch their error before releasing the drug, it seems that the FDA and its expert panels are still in need of serious scrutiny.
Omega-3s versus PPAR drugs
We’ve reported in the past on the anti-diabetic powers of omega-3s (click here to read Fish, Omega-3s, and Diabetes,” from the November 12, 2004 edition of Vital Choices.) Now it appears that they present serious alternatives or complements to prescription PPAR drugs.
Omega-3s and PPAR-alpha drugs
Like PPAR-alpha activators (e.g., gemfibrozil and fenofibrate), omega-3s lower blood triglyceride levels and increase blood levels of HDL (“good”) cholesterol. Like the drugs, omega-3s produce these benefits by activating PPAR-alpha, but omega-3s also work to lower blood triglyceride levels by inhibiting a different transcription factor, called SREBP-1. Although one large trial showed that omega-3s raise blood levels of HDL (”good”) cholesterol in men to a modest extent, omega-3s do not raise HDL blood levels in men or women as high or as reliably as PPAR drugs do.
Omega-3s and PPAR-gamma drugs
The results of recent animal research indicate that fish oil may be more effective than current PPAR-gamma drugs at stabilizing blood sugar levels. Japanese researchers found that when the mice metabolize DHA—the long-chain omega-3 found only in fish—their bodies produce chemicals more effective for glycemic control than the widely prescribed PPAR-gamma drug pioglitazone.
The Japanese researchers involved came to this encouraging conclusion: “…metabolites of docosahexaenoic acid (DHA) are strong PPAR-gamma activators and potential anti-diabetic agents.… The efficacy of 5E-4-hydroxy-DHA 2a [a DHA metabolite] as a PPAR-gamma activator was about fourfold stronger than that of pioglitazone. Furthermore, the 4-keto derivative (10b) [another DHA metabolite] showed anti-diabetic activity in animal models without producing undesirable effects such as obesity and hepatotoxicity [liver damage].”
Note: This was an animal study whose results may not translate to humans, so people shouldn’t rush to replace their diabetes medicines with omega-3s. But these intriguing results suggest that omega-3s may offer a very viable alternative or complementary therapy.
Unlike existing PPAR-gamma drugs, omega-3s do not enhance insulin sensitivity substantially, but, as the authors of a recent literature review noted, fish oil “…reduces insulin response to oral glucose without altering the glycemic response.” In other words, the omega-3s in fish oil stabilize blood sugar levels, which is the key purpose of PPAR-gamma drugs, but they do it by still-uncertain means other than insulin sensitization.
In cases where PPAR-gamma drugs do not work so well or produce uncomfortable side effects, diabetes patients could discuss with their doctor the feasibility of trying omega-3 supplements, which offer broad related health benefits. It goes without saying that any such experiment must take place under close medical supervision.
- Nissen SE, Wolski K, Topol EJ. Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus. JAMA. 2005 Oct 20; [Epub ahead of print]
- Rodriguez-Cruz M, Tovar AR, del Prado M, Torres N. [Molecular mechanisms of action and health benefits of polyunsaturated fatty acids]. Rev Invest Clin. 2005 May-Jun;57(3):457-72. Review. Spanish.
- Yamamoto K, Itoh T, Abe D, Shimizu M, Kanda T, Koyama T, Nishikawa M, Tamai T, Ooizumi H, Yamada S. Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents. Bioorg Med Chem Lett. 2005 Feb 1;15(3):517-22.
- Delarue J, LeFoll C, Corporeau C, Lucas D. N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? Reprod Nutr Dev. 2004 May-Jun;44(3):289-99. Review.
- Campbell IW. The clinical significance of PPAR gamma agonism. Curr Mol Med. 2005;5:349-363.
- Devasthale PV, Chen S, Jeon Y, et al. Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl] methyl]glycine [Muraglitazar/BMS-298585], a novel peroxisome proliferator-activated receptor alpha/gamma dual agonist with efficacious glucose and lipid-lowering activities. J Med Chem. 2005;48:2248-2250.
- Endocrinologic and Metabolic Drugs Advisory Committee Meeting. FDA Web site. Available at: http://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4169M2.pdf. September 9, 2005.
- Table of contents. Endocrinologic and Metabolic Drugs Advisory Committee. FDA Web site. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B2_02_00-FDA-TOC.htm.
- Advisory Committee briefing document: Pargluva (muraglitazar, BMS-298585). FDA Web site. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B2_01_01-BMS-Pargluva.pdf.
- Buse JB, Rubin CJ, Frederich R, et al. Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin Ther. 2005;27:1181-1195. MEDLINE
- Vu-Dac N, Schoonjans K, Kosykh V, et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest. 1995;96:741-750.
- Despres JP, Lemieux I, Robins SJ. Role of fibric acid derivatives in the management of risk factors for coronary heart disease. Drugs. 2004;64:2177-2198.
- Molavi B, Rasouli N, Mehta JL. Peroxisome proliferator-activated receptor ligands as antiatherogenic agents: panacea or another Pandora's box? J Cardiovasc Pharmacol Ther. 2002;7:1-8.
- Okuda N, Ueshima H, Okayama A, Saitoh S, Nakagawa H, Rodriguez BL, Sakata K, Choudhury SR, Curb JD, Stamler J; INTERLIPID Research Group. Relation of long chain n-3 polyunsaturated fatty acid intake to serum high density lipoprotein cholesterol among Japanese men in Japan and Japanese-American men in Hawaii: the INTERLIPID study. Atherosclerosis. 2005 Feb;178(2):371-9.