The paper attached in PDF showed results from an observational study that used a technique referred to as propensity score matching to create matches for Group 1 and Group 2 participants.
Looking at the data in Tables 1 and 2 - discuss
1) Did matching based on the propensity score "work" in creating balance between the Groups and the Insulin Only groups? Why or why not?
2) The results of the paper were "negative" meaning that the expected effects were not observed. Discuss whether you believe the results provided in the paper advanced our understanding concerning the hypotheses for the paper. If you agree that they advanced our understanding - explain how. If you do not think they advanced our understanding explain why not - and what would you propose could be done to help advance our knowledge further.
3) Discuss what you believe may be the larger weakness/challenge with this particular study - choose one of these options and explain why it is the larger challenge.
a) Small sample size in the "exposed" groups (n-42/39)
b) Participants not randomized to receive the drugs being study.
c) Both are equally important - small sample size and lack of randomization
d) Neither is more important - there is a 3rd option that is really the most significant challenge/weakness in this paper.
Original article Purpose: Youth with type 1 diabetes mellitus (T1DM) are at risk of cardiovascular disease (CVD). We evaluated if metformin or statin use was associated with surrogate measures of improved CVD. Methods: We included participants from the SEARCH observational study. Participants treated with insulin plus metformin (n=42) or insulin plus statin (n=39) were matched with 84 and 78 participants, respectively, treated with insulin alone. Measures of arterial stiffness obtained were pulse wave velocity (PWV), augmentation index (AI75), and heart rate variability as standard deviation of the normal-to-normal interval (SDNN) and root mean square differences of successive NN intervals (RMSSD). Results: CVD measures were not significantly different among participants on insulin plus metformin versus those on insulin alone: PWV (5.9±1.0 m/sec vs. 5.8±1.5 m/ sec, P=0.730), AI75 (1.8 [-6.0 to 8.0] vs. -2.4 [-10.7 to 3.8], P=0.157), SDNN (52.4 [36.8– 71.1] m/sec vs. 51.8 [40.1–74.9] m/sec, P=0.592), and RMSSD (43.2 [29.4–67.6] vs. 47.4 [28.0–76.3], P=0.952). CVD measures were not different for statin users versus nonusers: PWV (5.7±0.8 m/sec vs. 5.9 ±1.1 m/sec, P=0.184), AI75 ( -4.0 [-9.5 to 1.7] vs. -6.7 [-11.3 to 5.7], P=0.998), SDNN (54.6 [43.5–77.2] m/sec vs. 63.1 [44.2–86.6] m/sec, P=0.369), and RMSSD (49.5 [31.2–74.8] vs. 59.2 [38.3–86.3], P=0.430). Conclusion: We found no associations of statin or metformin use with surrogate measures of CVD. Future prospective pediatric clinical trials could address this issue. Keywords: Metformin, Type 1 diabetes, Adolescents, Statin, Cardiovascular disease ©2019 Annals of Pediatric Endocrinology & Metabolism This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ISSN: 2287-1012(Print) ISSN: 2287-1292(Online) Introduction Youth with type 1 diabetes mellitus (T1DM) have an increased lifetime risk for cardiovascular disease (CVD).1) Low insulin sensitivity (IS) and dyslipidemia, among others, have been implicated in this increased risk.1) Low IS contributes to higher CVD risk in both youth and adults with T1DM.2-4) Our group previously found that youth with T1DM and low IS also have higher arterial stiffness as assessed by pulse wave velocity (PWV), a surrogate measure of CVD.5) Data from the Pittsburgh Epidemiology of Diabetes prospective study of 602 adults with T1DM showed that those with low versus normal IS had a higher 10-year incidence of nonfatal myocardial infarct and mortality.2) Furthermore, women with T1DM and low IS lose the known cardioprotection of female sex.3) Similar to adult studies, nonobese adolescents with T1DM and lower IS have a more atherogenic lipoprotein profile, i.e., lower low-density lipoprotein cholesterol (LDL-C) than healthy controls, and this atherogenic distribution correlates with low IS.6) In addition, lean adolescents with T1DM and low IS have impaired functional exercise capacity Association of metformin and statin medications with surrogate measures of cardiovascular disease in youth with type 1 diabetes: the SEARCH for diabetes in youth study Evgenia Gourgari, MD1,2, Jeanette M. Stafford, MS/MA 3, Ralph D'Agostino Jr, PhD3, Lawrence M. Dolan, MD4, Jean M. Lawrence, ScD, MPH, MSSA5, Amy Mottl, MD6, Catherine Pihoker, MD7, Elaine M. Urbina, MD8, R. Paul Wadwa, MD9, Dana Dabelea, MD, PhD10 1Division of Pediatr ic Endocrinology, Department of Pediatrics, Georgetown University, Washington, DC, 2Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health, Bethesda, MD, 3Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 4Department of Pediatrics, Cincinnati Children's Hospital and the University of Cincinnati, Cincinnati, OH, 5Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, 6UNC Division of Nephrology and Hypertension, University of North Carolina School of Medicine, Chapel Hill, NC, 7Department of Pediatrics, University of Washington, Seattle, WA, 8Cincinnati Children's Hospital Medical Center & University of Cincinnati, Cincinnati, OH, 9Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, 10Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA Received: 2 March, 2019 Revised: 21 May, 2019 Accepted: 4 June, 2019 Address for correspondence: Evgenia Gourgari, MD Division of Pediatric Endocrinology, MedStar Georgetown University Hospital, 4200 Wisconsin Avenue, N.W, 4th Floor, Washington, D.C. 20016, USA Tel: +1-202-243-3560 Fax: +1-877-680-5507 E-mail:
[email protected] https://orcid.org/0000-0002-5788- 7955 https://doi.org/10.6065/apem.2019.24.3.187 Ann Pediatr Endocrinol Metab 2019;24:187-194 http://creativecommons.org/licenses/by-nc/4.0 http://creativecommons.org/licenses/by-nc/4.0 https://orcid.org/0000-0002-5788-7955 https://orcid.org/0000-0002-5788-7955 https://doi.org/10.6065/apem.2019.24.3.187 https://crossmark.crossref.org/dialog/?doi=10.6065/apem.2019.24.3.187&domain=pdf&date_stamp=2019-9-25 Gourgari E, et al. • Metformin and statins in youth with T1DM 188 www.e-apem.org and evidence of diastolic dysfunction and left ventricular hypertrophy.4) Dyslipidemia is an established risk factor for CVD in individuals with and without diabetes.1) Previous studies, including those from our group, found that dyslipidemia in youth with T1DM is associated with increased carotid intima media thickness (CIMT) and higher arterial stiffness, measured as increased PWV.7,8) Arterial stiffness is widely used as a surrogate marker of CVD, and studies in adults show a association of increased arterial stiffness with future CVD events.9) For 1,746 youth with T1DM in the SEARCH cohort study, we reported an 11.6% age- adjusted prevalence of increased arterial stiffness.10) Our group and others found higher arterial stiffness in youth with T1DM compared to healthy controls.11-14) Furthermore, our group previously found an association of increased arterial stiffness with low IS in youth with T1DM.11) Another surrogate marker for subclinical CVD is heart rate variability (HRV). Decreased HRV is a sign of diabetic neuropathy and indicates the presence of cardiac autonomic dysfunction. Decreased HRV is associated with a 32%–45% increased risk of CVD events in individuals without previously established CVD.15-18) In the SEARCH cohort study, we reported a 14.4% age-adjusted prevalence of cardiovascular autonomic neuropathy.10) We also showed that youth with T1DM had decreased HRV, which is associated with increased arterial stiffness and poor glycemic control.15,19,20) Medications that improve IS and dyslipidemia improve CVD in adults with type 2 diabetes mellitus (T2DM), but use of these medications to manage youth with T1DM is still controversial.1,21) Metformin is a first-line agent for T2DM but is often used "off label" by pediatric endocrinologists, especially in youth with obesity and T1DM. Most studies found that metformin had no benefit for improving glycemic control in T1DM but reduced total daily insulin dose requirements and body mass index (BMI) in youth with obesity and T1DM.22) Statins, which are medications to improve total and LDL-C, reduce cardiovascular events in adults with diabetes, but few studies have investigated the effect of statins on surrogate measures of CVD in youth with T1DM.23,24) Our objective was to evaluate if treatment with metformin or statins was associated with decreased CVD risk as assessed by arterial stiffness, using data from the SEARCH for Diabetes in Youth study. Materials and methods 1. Participants The SEARCH for Diabetes in Youth study was initiated in 2000 in five sites across the United States to improve under- standing about youth-onset diabetes and its complications. Individuals diagnosed with diabetes before age 20 were identified from a population-based incidence registry network at five U.S. sites (South Carolina; Cincinnati, Ohio and surroun- ding counties; Colorado with southwestern Native American sites; Seattle, Washington, and surrounding counties; and Kaiser Permanente Southern California members from 7 counties) by the SEARCH for Diabetes in Youth Registry Study.10) Patients newly diagnosed with T1DM in 2002-2006 or 2008 were identified from ongoing surveillance of networks of hospitals and health care providers. Patients who could be contacted were recruited for a baseline visit at a mean and standard deviation (SD) of 9.3±6.4 months from diagnosis. A subset of participants with at least 5 years diabetes duration (to increase the likelihood of detecting complications) who were aged 10 years or older were recruited for a follow-up visit between 2012–2015, a mean (SD) of 7.9±1.9 years from diagnosis.10) A flowchart of the SEARCH cohort study has been published.10) 2. Data collection At both baseline and follow-up visits, trained personnel administered questionnaires to participants obtained fasting blood samples, and performed anthropometric measurements as previously described.10) Race/ethnicity was self-reported and categorized into non-Hispanic white and minority racial/ethnic groups, including Hispanic (regardless of race), non-Hispanic black, American Indian, Asian/Pacific Islander, and other or multiple races/ethnicities. BMI was calculated as weight in kilograms divided by height in meters squared and converted to a z-score. Three systolic and diastolic blood pressure levels were obtained after at least 5 minutes of rest and averaged for inclusion in the analysis. At both visits, a fasting blood draw occurred after an 8-hour overnight fast, and medications such as short-acting insulin were withheld the morning of the research visit. Samples were processed locally and shipped to a central laboratory (Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA), where high-density lipoprotein cholesterol (HDL-C), LDL-C, triglycerides (TG), and glycosylated hemoglobin (HbA1c) were measured. HbA1c was measured with high-performance liquid chromatography (TOSOH Bioscience, Inc., San Francisco, CA, USA). TG and HDL-C were measured using Roche Modular P (Roche Molecular Biochemical Diagnostics, Indianapolis, IN, USA). LDL-C was calculated by the Friedewald equation for participants with triglyceride concentration <400 mg/dl and by the beta quantification procedure for those with tg≥400 mg/dl, as previously described.11) is score was calculated based on a previously described equation developed and validated among search participants using data from a euglycemic– hyperinsulinemic clamp25): log is=4.64725−0.02032 mg/dl="" and="" by="" the="" beta="" quantification="" procedure="" for="" those="" with="" tg≥400="" mg/dl,="" as="" previously="" described.11)="" is="" score="" was="" calculated="" based="" on="" a="" previously="" described="" equation="" developed="" and="" validated="" among="" search="" participants="" using="" data="" from="" a="" euglycemic–="" hyperinsulinemic="" clamp25):="" log="" is="">