By Joshua Palmer
Faculty Peer Reviewed
Facts on the Tip of My Tongue
There are three notable things about November 14th. It is the birthday of Frederick Banting (the discoverer of insulin), it is World Diabetes Day and um…uh…Banting and Diabetes Day um… well I forgot the third…sorry…oops. Oh yeah, this year’s diabetes slogan is “Act on Diabetes. Now” [1,4]. All joking and Rick-Perry-memory lapses aside, this week was notable. The United States Department of Health and Human Services put out a new 2010-2020 set of “health metrics” for tracking obesity, nutrition and access to health care in the United States [2]. In a similar release, Pediatrics set new screening guidelines for diabetes and heart disease. An expert panel gathered by the National Heart, Lung and Blood Institute and endorsed by the American Academy of Pediatrics produced surprising consensus points: every child should have cholesterol and diabetes tests starting at age 9, yearly blood pressure tests should start at age 3, anti-smoking advice should start between ages 5-9, and BMI tracking should start at age 2 [3,4].
For Real This Time: The Fountain of Youth Found?
In Nature this week, the Mayo Clinic expanded our picture of how to retain a healthy body [11]. It was back in 2005 in Cell, when senescent cells were vogue in the study of aging, and senescent cells were found to build up in various tissues as you age [10]. Mayo researchers hypothesized that through secreted products it was this group of cells that contribute to chronic disease and cancer. To test this hypothesis, they created and characterized a strain of INK-ATTAC transgenic mice with the ability to destroy only cells with the p16ink4a biomarker and thus able to selectively destroy senescent cells. They monitored fat, skeletal muscle and eye tissues where p16ink4a contributes to age-related disorders. They found significant decreases in the biomarker after drug administration (AP20187), meaning the drug worked in destroying the cells in vivo. They tested the theory by comparing the transgenic mice and untreated cohort mice and found that the treated mice developed fewer cataracts, had larger muscles, could exercise longer and had more fat stores than their age-matched cohort—essentially, the aging process was delayed. When the transgenic mouse was treated later in life cataracts had already matured and did not regress but exercise tolerance, fat stores and skeletal muscle had significantly improved compared to its age-matched cohort [11]. They were able to restore a youthful phenotype in mice that had begun the aging process, a significant breakthrough in extending a healthy life [13].
Who Needs Jenny Craig Anymore?
In an astounding animal prototype trial conducted at M.D Anderson and published by Science Translational Medicine, a new peptidomimetic, adipotide, has been shown to be selectively anti-angiogenic for white fat (binding ANXA2 and prohibitin causing apoptosis of blood vessels), the type of fat found in adipose tissue of mammals. Obese Old World monkeys lost 11% of their body weight in 28 days, which was selectively fat; their BMI improved and they became less insulin resistant. This effect on body weight was not shown in lean monkeys. The major side effect after four weeks was a decrease in their GFR which improved after the short period of administration. The drug is to be trialed in humans early next year and due to Ablaris’ original contract with M.D. Anderson, the first group to be studied is obese males with prostate cancer due to the link of humoral growth factors produced by adipose tissue and prostate cancer progression (6). After the close of the initial trial, the drug will then be administered as a weight reduction therapy in larger groups of human trials [12].
A New Era for Acute Coronary Syndrome?
To coincide with the American Heart Association Scientific Sessions, a series of 4 articles were published on the new oral factor Xa, direct thrombin inhibitors or thrombin receptor antagonists (PAR-1). Three of the articles failed to show any benefit and in some cases had more adverse events–Abciximab and heparin in NSTEMI, Vorapaxar in ACS and apixiban vs lovenox in thromboprophylaxis[8,9,10]. However, just when you thought the ship had sailed, the Rivaroxaban in ACS or ATLAS trial held its weight and showed some benefit [7].
The randomized, double blind, placebo controlled ATLAS ACS 2—TIMI 51 trial accrued 15,526 hospitalized patients with Acute Coronary syndrome and assigned them to either one of two doses of Rivaroxaban or placebo. The primary endpoint was death from cardiovascular causes, MI or stroke, secondarily death from any cause and bleeding events were recorded. Rivaroxaban significantly reduced the primary endpoint compared to placebo, with respective rates of 8.9% and 10.7%. When taken separately, both doses were efficacious for the primary endpoint but only the lower 2.5mg BID dosing was efficacious in lowering risk of cardiovascular death and death from any cause, lowered from about 4.5% to 3%. The risk of bleeding was increased considerably in the experimental group. Major bleeds occurred 4x and intracranial hemorrhages 3x that of the placebo controls. There was no significant change in the number of fatal bleeds and the lower dose seems safer. The results of this trial highlight the developing role of weighing the risk of bleeding with the ischemic benefits of treatment [7]. The role of this agent seems to be less in younger, healthier patients but further elucidation of high risk sub-groups and analysis with other newer agents may help stratify which groups of patients benefit from a more rigorous regimen [5].
Let’s Increase the Intensity on Diabetes
Diabetes is one of the leading causes of End-Stage Renal Disease (ESRD) but what is not well known is if intensive glycemic control will lessen the microvascular complications. The Diabetes Control and Complication Trial (DCCT)/Epidemiology Diabetes Interventions and Complications (EDIC) Research Group tested the theory that complications are less with intense therapy. In the 1980s, DCCT randomly assigned 1,441 people with Type 1 Diabetes to 6.5 years of intensive therapy with tight glycemic controls sustained at near-normal levels or to conventional symptom-based therapy. After the 6.5 years the EDIC group followed the participants with annual creatinine (Cr) and Glomerular Filtration Rates (GFR) measurements and impairment was set at less than 60. The two groups were followed for an amazing 22 years. The intensive group had a risk reduction rate of GFR impairment of 50% and developed less ESRD over the follow-up period. It was noted that during the DCCT trial, GFR initially decreased in the intensive group by 1.7 ml/min/1.73M2 but this effect was attenuated in the EDIC study. The rate of loss of GFR was decreased in the intensive group and on long term follow-up the mean GFR was higher for the intensive group by 2.5 ml/min/1.73M2. An overall NNT of 29 was needed in order to save one person from impaired GFR over 20 years after receiving 6.5 years of tight glycemic control. The study emphasizes the importance of tight glycemic control on the long-term effects of diabetes [14]. There are many implications from this trial, the largest of which is “Can this effect be replicated in Type 2 diabetics?”
Dr. Joshua Palmer is a 1st year resident at NYU Langone Medical Center
Peer reviewed by Robert Gianotti, MD Associate editor, Clinical Correlations
References:
1.Marchione M, Tanner L. Doctors: Test All Kids for Cholesterol by Age 11. Associated Press: Chicago, 11/11/11. http://hosted.ap.org/dynamic/stories/U/US_MED_KIDS_CHOLESTEROL_TESTS?SITE=KMOV&SECTION=HOME&TEMPLATE=DEFAULT
2. Kavey RE et al. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics 128:5. December 2011. http://pediatrics.aappublications.org/site/misc/2009-2107.pdf.
3. U.S. HHS. Health People 2020: Leading Health Indicators. http://www.healthypeople.gov/2020/topicsobjectives2020/default.aspx.
4. Lancet Editorial Staff. This Week in Medicine. The Lancet. 378:9804. p. i, 11/12/11.
5. Roe T et al. A New Era in Secondary Prevention after Acute Coronary Syndrome. N Engl J Med 10.1056. 11/13/2011. http://www.nejm.org/doi/full/10.1056/NEJMe1112770.
6. Barnhart KF et al. A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys. Sci. Transl. Med. 3, 108ra112 (2011).
7. Mega JL et al. Rivaroxaban in Patients with Acute Coronary Syndrome. N Engl J Med 10.1056. 11/13/2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1112277.
8. Goldhaber SZ et al. Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients. . N Engl J Med 10.1056. 11/13/2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1110899.
9. Tricoci P et al. Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndrome (TRACER). N Engl J Med 10.1056. 11/13/2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1109719.
9. Kastrati A et al. Abciximab and Heparin versus Bivalirudin for Non-ST-Segment Elevation Myocardial Infarction. N Engl J Med 10.1056. 11/13/2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1109596.
10. Campisi, J et al. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).
11. Baker DJ et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011. doi:10.1038/nature10600. http://www.natap.org/2011/HIV/nature10600.pdf.
12. Winslow R. Drug Offers Hope in Obesity Fight: Treatment Targeting Fat Cells Caused Significant Weight Loss in Monkeys; Human Trials to Begin Soon. Wall Street Journal; Online. 11/10/11. http://online.wsj.com/article/SB10001424052970203537304577028142340709990.html.
13. Wang S. Cell Study Finds a Way to Slow Ravages of Age. Wall Street Journal; Online. 11/3/11. http://online.wsj.com/article/SB10001424052970204621904577014011448483058.html.
14. De Boer IH et al. Intensive Diabetes Therapy and Glomerular Filtration Rate in Type 1 Diabetes. N Engl J Med 10.1056. 11/12/2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1111732.