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From the Townsend Letter
April 2014

briefed by Jule Klotter
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Doctors can once again prescribe Avandia and other rosiglitazone-containing diabetes medications to patients without having to enroll them in the US Food and Drug Administration's Rosiglitazone Risk Evaluation and Mitigation Strategy (REMS) program. Avandia use was restricted to patients who did not respond to other diabetes medications in 2010, following the recommendation of a FDA expert panel. Clinical evidence, including an independent meta-analysis of placebo-controlled, randomized studies, showed that patients who used rosiglitazone, an insulin sensitizer, were more likely to have a heart attack or other cardiovascular event.
A new FDA expert panel, convened in 2013, used REMS data and a reanalysis of the Rosiglitazone Evaluated for Cardiovascular Outcomes & Regulation of Glycemia in Diabetes (RECORD) clinical trial as the basis for reversing most of the 2010 restrictions. The RECORD study, funded by GlaxoSmithKline and published in the Lancet (June 20, 2009), has been the subject of much criticism. The open-label study investigated cardiovascular outcomes and rosiglitazone (Avandia) use. It compared patients using rosiglitazone in combination with metformin or a sulfonylurea with patients using a combination of metformin and sulfonylurea, the approved treatment for type 2 diabetes. The study's authors did notice an increased risk of heart failure and fractures in rosiglitazone users, especially in women. They did not, however, find an increased risk of cardiovascular events, stating in their conclusion: "Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs." The accuracy of this conclusion, however, is questionable; both the study's design and execution are flawed.
Because RECORD was an open-label study, participating doctors, patients, and manufacturer GlaxoSmithKline researchers knew who was taking which combination. Data could be easily manipulated. During a partial examination of the study's data, FDA reviewer Dr. Thomas Marciniak identified "a dozen instances in which people taking Avandia appeared to suffer serious heart problems that were not counted in the study's tally of adverse events," according to a New York Times article by Gardiner Harris (July 9, 2010). Such findings raise serious questions about the study's quality.
Dr. Steven Nissen believes that the reanalysis of the flawed RECORD study was instigated by leadership of the FDA's Center for Drug Evaluation & Research (CDER), which is responsible for drug regulation. Nissen, Cleveland Clinic's Chairman of the Department of Cardiovascular Medicine, and colleague Kathy Wolski wrote the May 2007 meta-analysis that showed a 43% increase of heart attack in Avandia users. At the time, neither realized that the CDER and Avandia manufacturer GlaxoSmithKline (GSK) had found similar results in a 2005 study. "In Congressional testimony, CDER officials acknowledged that FDA statisticians had confirmed our findings, reporting a 40% increase in the risk of heart attack," Nissen states in an opinion article for Forbes. CDER and GSK agreed to conceal the hazard from practitioners and patients. Publication of the Nissen-Wolski meta-analysis made it impossible to continue hiding Avandia's cardiovascular risks. "In 2012, GSK pled guilty to criminal misconduct," Nissen writes, "related in part to concealing the hazards of Avandia and paid a $3 billion fine, one of the largest in US history."
A commentary in Pharmacist's Letter/Prescriber's Letter (January 2014) says, "… experts warn that reanalyzing a flawed study doesn't make it valid … and other studies DO suggest Avandia increases CV risk." The publication suggests using pioglitazone, instead of rosiglitazone, if a glitazone is needed. Like rosiglitazone, however, pioglitazone increases the risks of weight gain, peripheral and macular edema, heart failure, and fractures. Pioglitazone has also been associated with increased risk of bladder cancer.

FDA to lift some Avandia (rosiglitazone) prescribing/dispensing restrictions. Pharmacists Lett/Prescribers Lett. Therapeutic Research Center; Stockton, CA. PL Detail-Document #300105. January 2014.

Harris G. Caustic government report deals blow to diabetes drug. New York Times. July 9, 2010. Available at Accessed December 31, 2013.

Home PD, Pocock SJ, Beck-Nielsen H et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomized, open label trial [abstract]. Lancet. June 26, 2009;373(9681):2125–2135. Available at Accessed December 31, 2013.

Nissen S. The hidden agenda behind the FDA's new Avandia hearings. Forbes. May 23, 2013. Available at Accessed January 27, 2014.

US Food and Drug Administration. FDA requires removal of certain restrictions on the diabetes drug Avandia [online press release]. November 25, 2013. Accessed December 27, 2013.

Fructose Metabolism and Metabolic Syndrome
Fructose has been identified as a cause of metabolic syndrome and weight gain, according to animal research, epidemiological studies, and a few clinical experiments. This nonessential sugar is present in fruit, high-fructose corn syrup, and table sugar (sucrose). Until recently, the assumption has been that consuming large amounts of fructose directly leads to a greater risk of metabolic syndrome. However, the location of fructose metabolism (the organs in which the sugar breaks down) has an even greater effect on metabolic syndrome development, according to a 2012 experiment conducted by T. Ishimoto and colleagues.
Fructose is metabolized by fructokinase, an enzyme that has two isoforms: fructokinase A and fructokinase C. "Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion," the authors explain. "In contrast, fructokinase A is widely distributed [in these and other organs especially skeletal muscle], has low affinity for fructose, and has less dramatic effects on ATP levels."
The researchers developed mice that lacked the genetic ability to make fructokinase A and mice that were unable to make both A and C. Unlike wild-type mice, the mice that lacked both A and C (meaning that they did not metabolize fructose) failed to develop the symptoms of metabolic syndrome when fed high amounts of fructose. These mice excreted the fructose in their urine. The mice that produced just the C isoform, however, fared worse than the A-C knockout mice or the wild-type mice. At 25 weeks, these fructokinase A knockout mice had significantly higher epididymal fat mass, serum insulin, serum leptin, and intrahepatic triglycerides, and more severe hepatic steatosis than the wild-type mice. Even though fructokinase A does not have as strong an affinity for fructose as isoform C, A is found throughout the body, including skeletal muscle, and can break fructose down before it reaches the liver. The researchers say, "By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome."
The presence of fructokinase A in skeletal muscle may help explain Luc Tappy's observation that plasma triglyceride concentrations do not increase in people with high fructose consumption who also exercise daily. He says, "For athletes, a high fructose intake may even be beneficial, as it has been shown that fructose can be metabolized during exercise, and increase performance."

Alegret M, Laguna JC. Opposite fates of fructose in the development of metabolic syndrome. World J Gastroenterol. September 7, 2012; 18(33): 4478–4480. Available at Accessed December 27, 2013.

Ishimoto T, Lanaspa MA, Le MT, et al. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. PNAS. March 13, 2012; 109(11): 4320–4325. Available at Access December 27,2013.

Tappy L. Q&A: 'Toxic' effects of sugar: should we be afraid of fructose? BMC Biology. 2012;10(42). Available at Access December 27, 2013.

Jamun Fruit, Anthocyanins, and the Liver
Eugenia jambolana (jamun) fruit reduces liver injury due to cholestasis (obstructed liver bile flow), according to a 2012 study. When bile acid concentrations rise, free radical production and inflammation also increase, damaging and killing liver cells. Eventually, hepatic bile obstruction can cause hepatic fibrosis and cirrhosis. Ajay C. Donepudi and colleagues with the US Department of Agriculture chose Jamun fruit because of its use in Ayurvedic medicine and because of its high anthocyanin content. Anthocyanins are antioxidant compounds that give plants their blue, purple, and red colors. For this study, Donepudi and colleagues performed bile-duct ligation (obstructing bile flow) or sham surgery on male mice. Twenty-four hours later, the mice orally received the first of 10 daily treatments: a Jamun fruit pulp extract (100 mg/kg of body weight) or placebo. Twenty-four hours after the last treatment, researchers euthanized the mice and collected blood samples and the animals' livers. Mice in the ligation group had 10 times the serum ALT activity (indicating liver damage) seen in the sham surgery mice. Jamun fruit extract lowered the high serum ALT levels in bile duct ligation (BDL) mice by 60%. Collagen deposition (fibrosis formation) was also reduced in BDL mice treated with the extract. In addition, the extract decreased reactive oxygen substances, nitric oxide production, macrophage infiltration, and pro-inflammatory cytokine expression in BDL mice.
Jamun fruit is by no means the only rich source of anthocyanins. In 2006, USDA researchers screened over 100 common store-bought foods for anthocyanins, including fresh and dried fruits, vegetables, nuts, spices, breakfast cereals, baby foods, chocolate, and juices. Fresh chokeberries, elderberries, black raspberries, blueberries (particularly wild varieties), and black currants had the highest anthocyanin content among tested foods. Anthocyanins were rarely detected in processed foods, including breads, cereals, and baby foods.
Over 600 anthocyanins have been identified so far. Determining their bioavailability, health effects, and responses to processing is an ongoing project.

Donepudi AC, Aleksunes LM, Driscoll MV, Seeram NP, Slitt AL. The traditional Ayurvedic medicine, Eugenia Jambolana (Jamun Fruit) decreases liver inflammation, injury, and fibrosis during cholestasis. Liver Int. April 2012;32(4):560–573. Available at Accessed December 27, 2013.

Wu X, Beecher GR, Holden JM, Haytowitz DB, Gebhardt SE, Prior RL. Concentrations of anthocyanins in common foods in the United States and estimation of normal consumption. J Agric Food Chem. 2006;54:4069–4075. Available at Accessed December 27, 2013.

Metabolic Syndrome, Gut Bacteria, and Probiotics
Feng-Ching Hsieh and colleagues in Taiwan have developed a strain of Lactobacillus reuteri GMNL-263 (Lr263) that decreases insulin resistance and lessens hepatic steatosis in rats on a high-fructose diet. High fructose consumption causes many symptoms of metabolic syndrome as well as increasing fat deposits in the liver in both rodents and humans. In this experiment, the researchers fed two groups of rats a high-fructose diet for 14 weeks; one group also received Lr263. A control group ate a standard diet (instead of high-fructose diet) without the probiotic. At study's end, serum glucose, insulin, leptin, C-peptide, glycated hemoglobin, GLP-1, liver injury markers, and lipid profile measures in serum and liver were significantly higher in high-fructose-fed rats, who did not receive the probiotic, compared with controls. In the Lr263 group, these same measures were similar to the control mice eating a standard diet.
Feng-Ching Hsieh and colleagues also tracked bacterial content in stool samples. Both groups on the high-fructose diet had an increase in clostridia (considered harmful), compared with controls. The Lr263 group, however, had a 2.5 ± 4.9% increase while the group without Lr263 had a 30.1 ± 5.9% increase in clostridia. As expected, the Lr263 group had considerably more lactobacillithan the control (35.4 ± 7.8); but the bifidobacteriumlevel was also higher (26.7 ± 3.4%). Lactobacillusand bifidobacteriumlevels in the high-glucose group without Lr263 were similar to the control group's.
Lr263 is not the only probiotic to show therapeutic promise for treating type 2 diabetes and metabolic syndrome. Two review articles – one by K. Naydenov and colleagues and the other by Yong Zhang and Heping Zhang – cite research concerning imbalances in gut microflora that contribute to diabetes and obesity. Like Lr263, Lactobacillus acidophilus and Lactobacillus casei have shown antidiabetes effects, according to Naydenov et al. They propose that yogurt, containing lactobacilli and other beneficial bacteria, may be useful in treating diabetic and prediabetic conditions. (Consumers need to be aware that many commercial yogurts – especially those with sweeteners and gelatin or thickening agents – have few, if any, live probiotic bacteria.) In addition to yogurt and/or probiotics, Zhang and Zhang point out that some botanicals – such as berberine in Coptis chinensis – "have anti-diabetic effect through modulating microbiota composition. … " What we eat – for good or bad – can change gastrointestinal microflora and, in turn, increase or decrease the risk of developing metabolic syndrome and diabetes.
Normally, the human gut contains as many as 1000 different microbial species that provide a large variety of metabolic and immune-enhancing services. Researchers are just beginning to understand the complex relationships between these microbes and our health. What if the microbes living within us, our own personal ecology, hold the key to preventing diabetes and other chronic illnesses?

Hsieh F-C, Lee C-L, Chai C-Y, Chen W-T, Lu Y-C, Wu C-S. Oral administration of Lactobacillus reuteri GMNL-263 improves insulin resistance and ameliorates hepatic steatosis in high fructose-fed rats. Nutr Metab. 2013;10(35). Available at Accessed December 27, 2013.

Naydenov K, Anastasov A, Avramova M, et al. Probiotics and diabetes mellitus. Trakia J Sci. 2012;10(Suppl. 1):300–306. Available at Accessed December 31, 2013.

Zhang Y, Zhang H. Microbiota associated with type 2 diabetes and its related complications. Food Sci Hum Wellness. 2013. Accessed December 31, 2013.


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