Primecuts: This Week In The Journals

June 7, 2010

By Todd Cutler, MD

Faculty Peer Reviewed

Summer is here and the only thing hotter than the weather is this week’s edition of Primecuts. In an early online publication this week in Lancet [1], the authors of the CANOE (Canadian Normoglycemia Outcomes Evaluation) study evaluated the efficacy of rosiglitazone and metformin in preventing progression to type 2 diabetes in patients with impaired glucose tolerance. In previous studies, both drugs had individually been shown to be effective in preventing progression to diabetes in high-risk patients, however, when used at standard doses, both agents were associated with significant toxicities. In this trial, patients were randomized to a low dose combination of rosiglitazone and metformin (n=103) or placebo (n=104) and followed for a median of 3.9 years. The primary endpoint, progression to type 2 diabetes as measured by an oral glucose tolerance test or by persistently elevated fasting glucose, was significantly decreased in the treatment group (14%) compared to placebo (39%) with a relative risk reduction of 66% and an absolute risk reduction of 26%. The authors noted no significant difference in metabolic toxicities typically associated with thiazolidinediones although the treatment group reported significantly more episodes of diarrhea and tended to have more adverse gastrointestinal symptoms.

While the design of the study has been generally viewed favorably, the significance of the findings has been the subject of some debate and skepticism. Dr. Victor Montori, an endocrinologist at the Mayo Clinic, disputed the claim [2] that treatment with oral hypoglycemic agents prevents diabetes but instead argued that such patient are treated as diabetics earlier in their lives – a limitation acknowledged by the authors. GlaxoSmithKline, the manufacturer of rosiglitazone (Avandia) and funder of the CANOE study, has been heavily criticized since a 2007 study reported that rosiglitazone increases the risk of cardiovascular events [3]. Dr. Steven Nissen, the lead author of that study, questioned the significance of the results and found the timing of the publication’s release “puzzling [4].” This week, facing accusations that rosiglitazone causes heart attacks and strokes, GlaxoSmithKline settled their first class action lawsuit [5] and next month the FDA plans to review the safety of rosiglitazone. In defense, the lead author, Dr. Bernard Zinman of the University of Toronto, argued that the results would have likely been the same if pioglitazone (Actos) had been evaluated in place of rosiglitazone [2]. Political controversies aside, what shouldn’t be overlooked is that this study raises an intriguing question as to whether patients at high risk for developing diabetes should receive pharmacotherapy before their diagnosis. Further studies should evaluate whether this approach would have an effect on clinically significant endpoints.

This week in JAMA [6], current approaches to inpatient management of heart failure were scrutinized in a robust Medicare database evaluation of almost seven million hospital admissions for CHF exacerbations between 1993 and 2006. Over 13 years, the length of hospitalization for CHF exacerbations decreased from 8.81 to 6.33 days, respectively and in-hospital mortality fell from 8.5% to 4.3% as did overall 30-day mortality. Additionally, fewer patients were discharged home while more patients were ultimately discharged to skilled nursing facilities. More surprising were statistically significant increases in outpatient 30-day mortality and readmission rates after discharge. The authors argue that, in the absence of drastic medical advances in acute CHF management, any relatively short-term changes are likely attributable to financial incentives that reward minimizing inpatient costs without penalizing for poor post-discharge outcomes. Most regrettable is that, following the law of unintended consequences, efforts to decrease inpatient costs may ultimately result in worse patient outcomes and even greater overall costs.

Over the past decade, advances in the field of immunology have spurred research into the development of protective vaccines against cancer. Most studies are founded on the notion that cancer cells express altered versions of normal proteins, termed “self-antigens,” that serve as the potential targets of an anti-tumor immune response. A caveat of this approach is the potential development of autoimmunity instigated by immune cells primed to react against proteins expressed by non-cancerous tissue. For example, in some human trials, the activation of the immune system against melanoma antigens has led to the development of vitiligo, a response that serves as an indirect marker of effective immunogenicity.

In a fascinating study published this week in Nature Medicine [7], immunization against the self-antigen, a-lactalbumin, provided complete protection against the development in breast cancer in genetically susceptible mice. a-lactalbumin is a unique vaccine target in that, while highly expressed in most breast carcinomas, breast epithelial cells otherwise only produce it during lactation. This was evidenced in the study by the absence of inflammation in the breast tissue of non-lactating mice. In contrast, the breast tissue of lactating mice showed extensive infiltration by reactive T-cells along with the production of high concentrations of pro-inflammatory cytokines and ultimate breast failure as indicated, lamentably, by pups demonstrating failure to thrive. As the authors point out, the conditional expression of a-lactalbumin exclusively by breast carcinoma and actively lactating breast tissue makes it an ideal target of a prophylactic anti-tumor vaccine without the risk of developing autoimmunity in women past their childbearing years, the population at greatest risk for the development of breast cancer.

Lastly, this week the FDA approved [8] the twice-yearly injectable drug denosumab, manufactured by Amgen and marketed as Prolia, for the prevention of fractures in women with osteoporosis. In the FREEDOM trial[9], published last year, denosumab was reported to decrease fractures in postmenopausal women with osteoporosis. The first approved drug in its class, denosumab is a human monoclonal antibody that inhibits the receptor activator of nuclear factor-kB ligand (RANKL), an important molecule in the regulation of osteoclasts and may prove to be an important addition to the armamentarium available to women at high risk for osteoporotic fractures.

Dr. Cutler is a first year resident at NYU Langone Medical Center

Peer reviewed by Cara Litvin, MD, Executive Editor, Clinical Correlations

 References:

[1] Zinman B, Harris SB, Neuman J. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. The Lancet. 2010 Jun 3. [Epub ahead of print] Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960746-5/fulltext

[2] The Canadian Press. Diabetes prevention tackled with half-dose drugs [Internet]. CBC News; 2010 Jun 3. Available from: “http://www.cbc.ca/health/story/2010/06/03/diabetes-avert-avandia-actos.html

[3] Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007 Jun 14;356(24):2457-71.  http://content.nejm.org/cgi/content/short/356/24/2457

[4] Wood S. “Puzzling” Lancet paper posits low-dose rosiglitazone/metformin for diabetes prevention [Internet]. TheHeart.org; 2010 Jun 2. Available from: http://www.theheart.org/article/1085027.do

[5] Stovall S. GlaxoSmithKline Settles First Avandia Case in US [Internet]. The Wall Street Journal; 2010 Jun 2. Available from: http://online.wsj.com/article/BT-CO-20100602-705019.html?mod=WSJ_World_MIDDLEHeadlinesEurope

[6] Bueno H, Ross JS, Wang Y. Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993-2006. JAMA. 2010 Jun 2;303(21):2141-7. http://jama.ama-assn.org/cgi/content/full/303/21/2141

[7] Jaini R, Kesaraju P, Johnson J. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med. 2010 May 30. [Epub ahead of print] Available from: http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2161.html

[8] Berkrot B, Beasley D. FDA approves Amgen osteoporosis drug [Internet]. Reuters; 2010 Jun 1. Available from: http://www.reuters.com/article/idUSTRE6506NB20100601

[9] Cummings SR, San Martin J, McClung MR. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. http://content.nejm.org/cgi/content/short/361/8/756

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