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Drug May Help Prevent Diabetes but Omega-3s Offer Comparable Effects
2/24/2011
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Scientific skeptics decry rush to prescribe costly drug, advise lifestyle and diet changes first 
by Craig Weatherby 


A recent headline in The International Herald Tribuneseemed to trumpet a dream come true: “Drug Can Prevent Diabetes in Many at High Risk, Study Suggests.”

 

It referred to the results of the so-called “DREAM” study, which were published in the in The Lancet last month and created big waves in the diabetes world. (DREAM is an acronym for “Diabetes REduction Assessment with ramipril and rosiglitazone Medication Trial”.)


Key Points


  • Drug used to treat diabetes may enhance preventive effects of lifestyle changes.
  • Related drug was withdrawn last year due to increased heart and cancer risks.
  • Drug in new prevention study is designed to mimic the effects of omega-3s, which yield similar effects and end results.

As the Tribune story said, “…people in high-risk categories who took the drug rosiglitazone for three years reduced their chance of developing diabetes by two-thirds. The study involved about 5,000 people in 21 countries.”

 

Diabetes afflicts one in 20 adults worldwide. In addition, researchers estimate that nearly one in ten of non-diabetic adults do not process sugar efficiently and are at high risk for developing the disease.

 

Rosiglitazone (Avandia), the drug tested successfully in the DREAM study, is now prescribed to treat adult-onset or type II diabetes. Drug makers would reap huge windfalls should doctors begin prescribing rosiglitazone and other glitizar-class drugs to prevent diabetes.

 

But omega-3s may offer these drugs stiff competition in diabetes prevention while bringing people many ancillary health benefits and offering superior safety (see “Why omega-3s may offer a serious alternative”, below).

 

And some independent scientists and advocacy groups decried the hoopla surrounding release of the DREAM study results.

 

  • Cathy Moulton, care adviser for Diabetes UK in London told the Tribune, “We’ve looked carefully at the data and it’s just hard to know how many people would benefit and at what cost. We’re worried that people may think there’s a quick fix, when what is proved to work is lifestyle changes. For the moment, we don’t think we can solve this epidemic with a pill.”
  • Jaakko Tuomilehto, M.D., Professor of Public Health at the University ofHelsinki penned an online editorial in The Lancet in which he said that “intensive lifestyle changes” seem a safer, equally effective approach.

Dr. Tuomilehto estimated that 544 people would have to be treated with medicine for three years to avoid one death from 
cardiovascular disease. Interestingly, the DREAM study participants were advised to make the kinds of lifestyle and diet changes he recommends (The group that got the drug did better, hence the headlines).

 

These drugs would be costly to take over a lifetime, and could produce as yet unknown long-term risks. In fact, two other glitizar drugs (troglitazone and muraglitazar) have been associated with increased health risks; see “FDA Drug Cops Fumble in Diabetes Fiasco”.

 

Why omega-3s may help: The role of PPARs in diabetes

While we lack clear proof that diets high in marine omega-3s can prevent or treat diabetes, there is some animal evidence that omega-3s help control blood sugar and ample evidence that omega-3s reduce risk factors for the heart disease that often develops in response to chronic diabetes (see “Fish, Omega-3s, and Diabetes”). And it’s a fact that people who eat a lot of fish—like the Japanese and Greenland’s Inuit Eskimos—enjoy lower rates of diabetes.

 

But recent research puts omega-3s in an even more promising light. So-called “PPAR-activator” drugs are designed to mimic the effects of dietary polyunsaturated fatty acids, including omega-3s, and they are the leading treatments for adult onset diabetes.

 

Like omega-3s, rosiglitazone and other glitizar-type drugs act on cellular “nuclear receptors” called Peroxisome Proliferator–Activated Receptors (PPARs), which 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 made from them (prostaglandins)—to activate PPAR receptors. Synthetic PPAR-activating drugs are designed to fit into specific PPAR receptors, to produce the same desirable results.

 

Omega-3s exert effects comparable to those seen with the two kinds of PPAR-activating drugs currently approved in the United States, which have different, complementary actions:

 

Omega-3s versus 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. And, 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 versus PPAR-gamma drugs

The results of recent animal research indicate that fish oil may be more effective than current PPAR-gamma drugs (e.g., rosiglitazone and pioglitazone) 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. While we don't yet know whether the results of this animal study will translate fully to humans, they suggest that omega-3s may offer a 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 (Delarue J et al 2004) 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. It’s just that they do it by means other than re-sensitizing cells to insulin.

 

Omega-3s: the original “dual PPAR” agents

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.

 

A drug called muraglitazar was expected to be the first dual-PPAR agent to come to market. But soon after the FDA approved it, muraglitazar was found to double the risk of heart attack and stroke and likely raise the risk of cancer.

 

And as we’ve just seen omega-3s yield the end results sought from both kinds of PPAR drugs: perhaps not as quickly or powerfully, but more safely. Omega-3s can destabilize blood sugar control in the short term.  This effect seems to be a temporary, self-correcting phenomenon, and it goes without saying thatsupplementation should take place under expert medical supervision.

 

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 many other health benefits at the same time.

 

 

Sources

  • DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006 Sep 23;368(9541):1096-105.
  • 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 inHawaii: the INTERLIPID study. Atherosclerosis. 2005 Feb;178(2):371-9. 

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