Primecuts – This Week In The Journals

March 7, 2011

By Daniel Eiras, MD

Faculty Peer Reviewed

In world news this week, we witnessed continued violence in Northern Africa as intense fighting between Libyan rebels and pro-Gadhafi troops in the Libyan cities of Zawiyah and Misrata saw 60 people killed, raising the confirmed number of dead to more than 300 since protests began in Libya on February 17th. [1]  The true death toll is unknown, however, and some authorities including the Human Rights League believe that the accurate estimate of people killed during the fighting over the last 3 weeks is closer to six thousand. [2]

 In the health press, Roni Rabin of the New York Times reported on a recently published article in the American Journal of Emergency Medicine regarding the increasing number of Emergency Department visits attributed to the overdose of illegal and prescription drugs. [3,4] Collecting data from 970 emergency departments in 27 states, the researchers extrapolated that 700,000 Americans are brought to the hospital on a yearly basis after drug ingestions, costing approximately $1.4billion a year.  The researchers went on to say that 44% of the prescription drug overdoses in their study were due to antidepressants and pain medications such as oxycodone and hydrocodone. 

 In the March 2nd edition of the USA Today, Mary Marcus discussed a new study printed in the journal Neurology which proposes that non-steroidal anti-inflammatory drugs may be neuroprotective against Parkinson’s Disease. [5]  The study followed 140,000 health professionals over the course of 6 years and determined that those people who took NSAIDS at least twice a week were 38% less likely to develop Parkinson’s Disease over the time period studied. [6] This study lends further evidence to the role of inflammation in the development of Parkinson’s Disease, but falls short of recommending ibuprofen as primary prophylaxis before further studies are done into the relationship.

 A number of medical journals published articles on different aspects of diabetes this week.  Since the American Diabetes Association included the use of the hemoglobin A1c (HbA1c) as an appropriate diagnostic test for the diagnosis of diabetes in 2010, there has been ongoing debate that as to the validity of the test between racial groups.  Observational evidence has shown that HbA1c values are typically higher among black diabetic patients, and it has been argued that there may be biochemical differences that lead to differences in the glycation of hemoglobin between blacks and whites, therefore necessitating separate race-specific cut off values when interpreting a patient’s HbA1c.  A cross-sectional study in the Annals of Internal Medicine this week attempted to answer this question by demonstrating that blacks diabetics indeed have a higher HbA1c than whites, (7.25 vs. 6.45 in this study), but this difference also paralleled other glycemic markers (including glycated albumin, fructosamine, and 1,5-anhydroglucitol). [7] These data argue that it is not racial differences in hemoglobin glycation that account for elevated HbA1c levels among blacks, but instead that there may be dietary and other social factors that lead to higher levels of fasting glycemia. 

 The ACCORD Trial, a large multi-center study which looked at the long-term consequences of intensive glycemic control among patients with type 2 diabetes, published an article in the New England Journal of Medicine this week as a culmination of their 5-year follow-up of patients enrolled in their study. [8] The initial paper was published after the study was terminated 3.7 years into the follow-up period when it was shown that intensive glycemic control (defined as a target HbA1c less than 6%) increased the risk of mortality among patients with a high risk for cardiovascular disease.  After the intensive-therapy arm was terminated, all patients were placed on standard therapy (defined as a target HbA1c between 7 and 7.9%) and were continued to be followed for the remainder of the trial period 17 months later.  In the original publication it was found that patients in the intensive-therapy group did not have different rates of nonfatal myocardial infarctions, nonfatal strokes, or death from cardiovascular causes, but had an increased rate of cardiovascular death (hazard ratio of 1.21). The study published this week showed that these trends continued over the following 17 months, even though rates of severe hypoglycemia and other adverse events were similar between the two groups. The extended study period gives the ACCORD Trial an even stronger basis of proof to the increased risk of death in intensive glycemic control among diabetics.

 Two studies this week attempted to elucidate the genetic nature of diabetes. It is well known that family history is a major risk factor for the development of type 2 diabetes, but the genetic causes of insulin resistance have not yet been determined.  Prior studies have identified the insulin receptor INSR glycoprotein as a pivotal role-player in the response to insulin management within target tissues, and the architectural transcription factor HMGA1 has been shown to function as a key regulator of INSR gene expression.  In an article published in JAMA this week, researchers hypothesized that variations of HMGA1 action may play a role in predisposing patients to developing type 2 diabetes. [9]  They analyzed the DNA of diabetic and non-diabetic patients in Italy, France and the United States for HMGA1 gene variants, and found four genetically defective variants which were found in 9.8% of diabetics, versus 0.6% of the non-diabetic controls.  The significance of this finding is that these variants could serve as early predictive markers for diabetes, and may predict an individual patient’s response to therapy.

 Another European study looked at markers of inflammation as potential predictors of the development of type 2 diabetes.  It is known that cytokines, in particular interleukin-1 (IL-1), play an important role in metabolic dysregulation, and IL-1 receptor antagonist protein (IL-1Ra) levels have been shown to increase in patients up to 6 years prior to their diagnosis of diabetes.  Using data from two prospective studies of patients without diabetes at baseline, researchers confirmed in their article in the Journal of Internal Medicine this week that rising levels of IL-1Ra were a significant independent predictor for the development of diabetes. [10]  The study went on to look at the relationship of genetic variants of the IL-1 locus on the development of diabetes, but was unable to identify variants that were significant for both men and women. 

 Switching gears a bit away from diabetes and towards another disease treated in the primary care setting, Dr. Ronald Victor and NYU’s own Dr. Joseph Ravenell published an article in the Archives of Internal Medicine outreach methods focused on blood pressure control in the black male population, a group which traditionally has a higher rate of uncontrolled hypertension than their female or white counterparts. [11] The study’s innovative design involved the use of 17 black-owned barbershops in the Dallas area as the setting for the intervention.  The barbershops involved in the study were split into two arms, the control group which involved handing out health pamphlets to patrons, and the experimental arm which offered blood pressure checks and referrals for physician follow-up.  The study found that over a 2 ½ year follow up period, a significantly greater percentage of the hypertensive patrons in the experimental arm had controlled blood pressure readings versus the control arm (19.9% versus 11.1%).  This study demonstrates an interesting and innovative approach of utilizing and empowering community members as health educators in the effort to control a growing hypertension epidemic.

 A meta-analysis in the British Medical Journal this week looked at the risk of recurrent venous thromboembolism in men and women. [12] The analysis combined data from seven prospective studies which followed patients with thromboembolism, and found that men had a higher risk of recurrence than women both at one year after initial event (5.3% in women versus 9.5% in men) and at the three year mark (9.1% in women versus 19.9% in men).  When subgroup analyses were performed on patients who were found to have provoked venous thromboembolism, there was no difference in risk of recurrence between men and women. This study may suggest that recommendations regarding the long-term treatment of patients with venous thromboembolism may need to be gender-based, and a greater weight should be placed on lifelong therapy for men with unprovoked thromboembolism.

 In two related articles published in PLOS Medicine this week, one set in Burkina Faso and one in Mali, researchers looked at the use of a novel treatment strategy for the prevention of malaria in children. [13,14]  It has already been shown that the use of long-lasting insecticide-treated bednets confer partial protection against the transmission of malaria, but the rate of clinical malaria remains at approximately 45% even with the proper adherence to the use of the bednets.  Researchers from the London School of Hygiene and Tropical Medicine looked at the use of empiric prophylaxis during the months of highest malaria transmission as a means of adding further protection against clinical malaria among children.  In their randomized, double-blinded, placebo-controlled trial, the experimental arm was treated with sulphadoxine pyrimethamine plus amodiaquine during the three months of highest rates of transmission (August to October).  The data showed that while both experimental and placebo groups had virtually no drug-related adverse events, the incidence rate of malaria infection declined by 85% in the experimental arm in Mali and by 69% in Burkina Faso.  The treatment arm was also noted to have a decreased prevalence of severe anemia, of being underweight, and of all-cause hospital admissions.  This study demonstrates the effectiveness of a novel approach to malaria control that may benefit regions with seasonal malaria epidemics.

 Lastly, in the Lancet this week, the ZEUS Study published an article which evaluated the use of everolimus as part of a non-nephrotoxic immunosuppressive therapy in patients with kidney transplants. [15]  Immunosuppression has been shown to result in higher rates of survival in the first year after renal transplantation, and this has typically been done using calcineurin inhibitors such as ciclosporin and tacrolimus.  The side effect of calcineurin inhibitors, however, is that they are associated with acute and chronic nephrotoxicity, and are known to aggravate cardiovascular risk factors.  Because of these side effects, another pathway of immunosuppression using rapamycin inhibition has been studied as a means for leading to longer survival and better outcomes.  In this phase II safety trial, the rapamycin-inhibitor everolimus was studied as an addition to the typical immunosuppressive therapy in patients undergoing de novo kidney transplants.  Five hundred and three patients were randomized to receive either the control regimen of ciclosporin, mycophenolate and corticosteroids, or to the experimental arm which received everolimus along with mycophenolate and corticosteroids.  At one year after transplantation, the main study outcome of GFR was noted to be significantly better in the everolimus group than the ciclosporin group (71.8mL/min versus 61.9mL/min).  The everolimus group was noted to have slightly high rates of certain side effects including higher serum lipid concentrations, increased urinary protein excretion, lower hemoglobin concentrations, higher rate of thrombocytopenia, and diarrhea.  This study shows that the use of everolimus in the overall immunosuppression strategy may help protect long term renal function and improve outcome in patients undergoing renal transplantation.

Dr. Eiras is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Neil Shapiro, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1.  Maria Golovnina. “Rebels in Libyan city repel repeated attacks.” Reuters. Mar 5, 2011. <http://www.reuters.com/article/2011/03/05/us-libya-zawiyah-idUSTRE7242IL20110305>

2.  “Rights groups say 6,000 killed in Libya.” Press TV.  Mar 2, 2011. <http://www.presstv.ir/detail/167886.html>

3.  Rabin, Roni. “Hazards: Misuse of Drugs Crowds Emergency Rooms.” The New York Times. Mar 3, 2011. <http://www.nytimes.com/2011/03/08/health/research/08hazards.html?ref=health>

4.  Xiang Y, Zhao W, Xiang H, Smith GA. ED visits for drug-related poisoning in the United States, 2007. Am J Emerg Med. 2011 Feb 28. [Epub ahead of print] <http://www.ajemjournal.com/article/S0735-6757(10)00583-8/pdf>

5.  Marcus, Mary. “Ibuprofen may reduce risk of getting Parkinson’s disease.” USA Today.  Mar 2, 2011. >http://yourlife.usatoday.com/health/medical/story/2011/03/Ibuprofen-may-reduce-risk-of-getting-Parkinsons-disease-/44420904/1>

6.  Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 2. [Epub ahead of print] <http://www.neurology.org/content/early/2011/03/01/WNL.0b013e31820f2d79.full.pdf+html>

7.  Selvin E, Steffes MW, Ballantyne CM, Hoogeveen RC, Coresh J, Brancati FL. Racial Differences in Glycemic Markers: A Cross-sectional Analysis of Community-Based Data. Ann Intern Med. 2011 Mar 1;154(5):303-9. <http://www.annals.org/content/154/5/303.long>

8.  Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT [ACCORD Study Group]. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011 Mar 3;364(9):818-28. <http://www.nejm.org/doi/full/10.1056/NEJMoa1006524>

9.  Chiefari E, Tanyolaç S, Paonessa F, Pullinger CR, Capula C, Iiritano S, Mazza T, Forlin M, Fusco A, Durlach V, Durlach A, Malloy MJ, Kane JP, Heiner SW, Filocamo M, Foti DP, Goldfine ID, Brunetti A. Functional variants of the HMGA1 gene and type 2 diabetes mellitus. JAMA. 2011 Mar 2;305(9):903-12. <http://jama.ama-assn.org/content/305/9/903.long>

10.  Luotola K, Pietilä A, Zeller T, Moilanen L, Kähönen M, Nieminen MS, Kesäniemi YA, Blankenberg S, Jula A, Perola M, Salomaa V; for the Health 2000 and FINRISK97 Studies. Associations between interleukin-1 (IL-1) gene variations or IL-1 receptor antagonist levels and the development of type 2 diabetes. J Intern Med. 2011 Mar;269(3):322-332. doi: 10.1111/j.1365-2796.2010.02294.x. <http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02294.x/abstract>

11.  Victor RG, Ravenell JE, Freeman A, Leonard D, Bhat DG, Shafiq M, Knowles P, Storm JS, Adhikari E, Bibbins-Domingo K, Coxson PG, Pletcher MJ, Hannan P, Haley RW. Effectiveness of a Barber-Based Intervention for Improving Hypertension Control in Black Men: The BARBER-1 Study: A Cluster Randomized Trial. Arch Intern Med. 2011 Feb 28;171(4):342-50. Epub 2010 Oct 25. <http://archinte.ama-assn.org/cgi/content/full/171/4/342>

12.  Douketis J, Tosetto A, Marcucci M, Baglin T, Cosmi B, Cushman M, Kyrle P, Poli D, Tait RC, Iorio A. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. BMJ. 2011 Feb 24;342:d813. doi: 10.1136/bmj.d813. <http://www.bmj.com/content/342/bmj.d813.long>

13.  Konaté AT, Yaro JB, Ouédraogo AZ, Diarra A, Gansané A, Soulama I, Kangoyé DT, Kaboré Y, Ouédraogo E, Ouédraogo A, Tiono AB, Ouédraogo IN, Chandramohan D, Cousens S, Milligan PJ, Sirima SB, Greenwood B, Diallo DA. Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Burkina Faso: A Randomised, Double-Blind, Placebo-Controlled Trial. PLoS Med. 2011 Feb 1;8(2):e1000408. <http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000408> 

14.  Dicko A, Diallo AI, Tembine I, Dicko Y, Dara N, Sidibe Y, Santara G, Diawara H, Conaré T, Djimde A, Chandramohan D, Cousens S, Milligan PJ, Diallo DA, Doumbo OK, Greenwood B. Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali: A Randomised, Double-Blind, Placebo-Controlled Trial. PLoS Med. 2011 Feb 1;8(2):e1000407. <http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000407

15.  Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, Fischer W, Gschaidmeier H, Pietruck F; on behalf of the ZEUS Study Investigators. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011 Feb 18. [Epub ahead of print] <http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62318-5/fulltext

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