Primecuts – This Week In The Journals

January 3, 2011

By Ely Felker, MD

Faculty Peer Reviewed

Another holiday season has come and gone.  As the ball dropped in Times Square, end-of-the-year celebration gave way to New Year’s resolutions and self-recriminations; because as sure as the holidays are a time of joy and cheer, they are also a time of indulgences, especially dietary indulgences.  Since so many resolutions this year will center on diet and weight loss, this week’s Primecuts will highlight some recent developments in the war against obesity and its health consequences. 

 On Dec 7, 2010, the FDA gave a positive endorsement to Contrave, a potential new weight-loss drug.  If ultimately approved, it will be the first new anti-obesity drug in over 10 years.  A combination of bupropion, an anti-depressant, and naltrexone, an opioid antagonist, Contrave is thought to counteract obesity through its effects on the reward pathway.  In an editorial in The Lancet [1], at least one author had serious reservations about Contrave, citing modest benefits (only a 5% decrease in body weight) and serious potential risks with bupropion, including lowered seizure threshold and cardiovascular effects.  No adverse events were reported in phase-3 clinical trials (including COR-1, published in The Lancet [2]), but future studies designed to address cardiovascular risk specifically will likely take place after the drug has been approved and released. 

 A recent JAMA editorial titled, “Reexamining the Physical Examination for Obese Patients” [3] suggested that at least part of the undue morbidity and mortality burden of this patient population may be related to incomplete or poor quality physical examinations in the physician’s office.  As a recent medical school graduate, I can attest to the lack of emphasis placed on developing specific examination skills for obese patients.  The authors of the editorial cited, as an example, the association between increasing BMI and later stage breast cancer at the time of diagnosis.  The authors speculate that physicians may be reluctant to perform thorough breast and pelvic examinations on obese patients, feeling these exams are “difficult” and “inadequate” [3].  The editorial did provide a guide to some useful examination techniques in an obese patient.  Two I found particularly useful were “asking the recumbent patient to raise his arms above his head to spread out chest-wall soft tissue” while auscultating the heart; and “performing a thorough skin examination with special attention directed toward the intertriginous folds” [3].  As the prevalence of obesity continues to rise in this country, developing—and teaching—effective physical exam techniques for this patient population will be paramount.   

 The Annals of Internal Medicine published results of a prospective, cohort study [4] designed to determine whether trans-palmitoleate, a fatty acid predominantly found in dairy products, was independently linked to lower metabolic risk and incidence of type II diabetes mellitus (DM2).  Multivariate-adjusted models were used to investigate how trans-palmitoleate related to major metabolic risk factors and new-onset DM2.  Trans-palmitoleate was associated with a significantly lower incidence of DM2, with hazard ratios of 0.41 (95% CI, 0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62), in quintiles 4 and 5, respectively, compared with quintile 1 (P<0.001).  Higher levels of trans­-palmitoleate, conversely, were statistically significantly associated with:  higher HDL (1.9% across quintiles; P = 0.04), lower triglycerides (-19%; P < 0.001), and lower insulin resistance (-16.7%; P <0.001).   Findings may explain the previously observed metabolic benefits of dairy consumption. 

 Also from The Annals of Internal Medicine, results of a randomized, double-blinded, placebo-controlled trial [5], designed to test whether twice-daily exenatide injections reduce HbA1c levels more than placebo in people receiving insulin glargine, are now available.  Exenatide is a GLP-1 agonist, which exerts myriad metabolic effects, including increasing glucose-dependent insulin secretion.  The study population consisted of adults with DM2 with a HbA1c between 7.1% and 10.5%, who were receiving insulin glargine +/- metformin or pioglitazone (or both).  Patients in the treatment arm received 10 µg exenatide sq twice daily for 30 weeks.  The primary outcome was change in HbA1c level.  Results showed that HbA1c level decreased by 1.74% in the treatment arm vs. 1.01% in the placebo arm (P <0.001).  Weight decreased by 1.74 kg in the treatment arm compared with a 1.0 kg increase in weight in the placebo group.  13 pts (9.4%) receiving exenatide withdrew from the study due to adverse events and one patient (0.8%) receiving placebo withdrew due to adverse events.  Adverse events in the exenatide arm included: nausea, vomiting, diarrhea, constipation, and headache.  Concomitant use of exenatide with insulin had not been studied previously; results of this trial suggest that addition of twice-daily exenatide to an insulin-containing DM2 regimen can improve glycemic control, and do so without conferring additional risk of hypoglycermia or weight gain. 

 While we’re on the topic of DM2 medications, The NEJM [6] just reported findings from  Choi et al., [7] from a paper published earlier this year in Nature, which suggest a potential new therapeutic target in the treatment of DM2.  PPARγ, a transcription factor which regulates expression of thousands of genes related to adipogenesis—and the target of the drug class thiazolidinediones (TZD)—has a serine residue at position 273, which Choi and colleagues discovered is phosphorylated by cyclin dependent kinase 5 (CDK5).  So what, you wonder?  Well, it turns out that phosphorylation at this position alters transcriptional activity of the gene, resulting in reduced expression of several genes with favorable metabolic effects.  Therefore, activating CDK5 lessens the beneficial effects realized with PPARγ activation.  Rosiglitazone, the TZD studied, was shown not only to activate PPARγ, but also to inhibit CDK5; an exciting finding because it suggests that perhaps the insulin-sensitizing effects of the TZD class are due not to their activation of PPARγ, but rather to their inhibition of CDK5.  If this is borne out in future studies it could allow for more targeted DM2 therapies that could hopefully avoid some of the adverse effects of the TZD class, such as weight gain, edema, and heart failure. 

 That’s all for this week’s edition of Primecuts.  Wishing everyone a happy, safe, and slim New Year.    

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

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

Image courtesy of Wikimedia Commons.

References

 [1] Horton R, editor. New obesity pill: new hopes, old fears. The Lancet. 2010 Dec 18;376(9758): 2042.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62281-7/fulltext?rss=yes

 [2] Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim DD, Dunayevich E.  Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-1): a multicenter, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2010 Aug 21;376(9741):595-605. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60888-4/abstract

 [3] Silk AW, McTigue KM. Reexamining the Physical Examination for Obese Patients. JAMA. Forthcoming 2010. http://jama.ama-assn.org/content/early/2010/12/28/jama.2010.1950.extract

 [4] Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS, Hotamisligil GS. Trans-Palmitoleic Acid, Metabolic Risk Factors, and New-Onset Diabetes in U.S. Adults. Ann Intern Med. 2010 Dec 20;153(12):790-799. http://www.annals.org/content/153/12/790.abstract

 [5] Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, Hoogwerf BJ, Rosenstock J. Use of Twice-Daily Exenatide in Basal Insulin-Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial. Ann Intern Med. Forthcoming 2010. http://www.ncbi.nlm.nih.gov/pubmed/21138825

 [6] Kahn BB, McGraw TE. Rosiglitazone, PPARγ, and Type 2 Diabetes. N Engl J Med. Forthcoming 2011. http://www.nejm.org/doi/full/10.1056/NEJMcibr1012075

 [7] Choi JH, Banks AS, Estall JL, Kajimura S, Laznik D, Ruas JL, Chalmers MJ, Kamenecka TM, Bluher M, Griffin PR, Spiegelman BM. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature. 2010 Jun 24;466:451-456. http://www.nature.com/nature/journal/v466/n7305/abs/nature09291.html

 

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