e6 Diabetes Care Volume 44, January 2021

Adolescent Hypertension and Risk for Boris Fishman,1,2,3,4 Ehud Grossman,3,4 Inbar Zucker,4,5 Omri Orr,1,2 Early-Onset Type 2 Diabetes: A Miri Lutski,4,5 Aya Bardugo,1,2 Nationwide Study of 1.9 Million Israeli Cole D. Bendor,1,2 Yoav Leiba,1,2 Tali Cukierman-Yaffe,4,6 Adolescents Estela Derazne,4 Ofri Mosenzon,7 1,2 1,2 Diabetes Care 2021;44:e6–e8 | https://doi.org/10.2337/dc20-1752 Dorit Tzur, Zivan Beer, Orit Pinhas-Hamiel,4,8 Tamar Fishman,9 Arnon Afek,4,10 Amir Tirosh,4,6 Itamar Raz,7 Hertzel C. Gerstein,11 and Gilad Twig1,2,4,6

The incidence of adolescent hyperten- who were examined between 1 January Cox models were applied. Follow-up sion is growing worldwide, mostly in 1993 and 31 December 2016. Excluded started at the day of the first medical conjunction with the growing obesity were those with prior diagnosis of dys- examination and ended at the date of prevalence (1,2). Adolescent hyperten- glycemia and those with missing baseline diabetes diagnosis, 31 December 2016, sion was shown to be a risk factor for height or weight data (3.8% in total). or deathdwhichever came first. Due to cardiovascular and renal outcomes later Essential hypertension diagnosis was the previously described significant in- in life, thus promoting current guidelines confirmed by a board-specified nephrol- teraction among BMI, hypertension, and to screen all pediatric and adolescent pop- ogist based on a preexisting diagnosis or type 2 diabetes, which was also evident in ulation for hypertension (1,3). Here, we screening for hypertension as described our cohort (Pinteraction , 0.01 for BMI elucidate the association of adolescent hy- previously (1). Briefly, adolescents with used as either a categorical or a con- pertension and early-onset type 2 diabetes blood pressure measurement during the tinuous variable), we analyzed sepa- in a nationwide cohort of adolescents. screening assessment of.140/90mmHg rately adolescents with lean and high In this population-based, retrospec- were referred for further investigation. BMI by overweight cutoff (85th BMI tive cohort study we linked the Israeli The final diagnosis was made when the percentile of the Centers for Disease Defense Forces conscription center da- average of 10 additional outpatient Control and Prevention, age and sex tabase with the Israeli National Diabetes blood pressure measurements was matched). We prespecified the multi- Registry (INDR). One year prior to man- .140/90 mmHg, when at least 50% of variable model to include the following datory military service at age 17 years, the measurements were above this level, variables that were assessed or received Israeli adolescents undergo comprehen- and after exclusion of secondary hyper- from other governmental ministries at sive medical evaluation based on their tension. The primary outcome was in- study entry: birth year, age, sex, BMI medical history, an interview and phys- cident type 2 diabetes as documented by (continuous), country of birth, residen- ical examination that includes mea- the INDR, which captures all cases of tial socioeconomic status, education surements of height, weight, and blood diabetes in Israel with a sensitivity of level, and cognitive performance, as pressure. Included were adolescents 95.1% (2). used previously (2). OBSERVATIONS –

1Department of Military Medicine, Hebrew University, Jerusalem, Israel e-LETTERS 2The Israel Defense Forces Medical Corps, Ramat Gan, Israel 3Internal Medicine D Department and Hypertension Unit, Sheba Medical Center, Ramat Gan, Israel 4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 5Israel Center for Disease Control, Ministry of Health, Ramat Gan, Israel 6Institute of Endocrinology, Sheba Medical Center, Ramat Gan, Israel 7Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel 8Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel 9Pharmacy Services, Meir Medical Center, Kfar-Saba, Israel 10Central Management, Sheba Medical Center, Ramat Gan, Israel 11Department of Medicine, McMaster University Hamilton, Ontario, Canada Corresponding author: Gilad Twig, [email protected] Received 13 July 2020 and accepted 2 October 2020 © 2020 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license. care.diabetesjournals.org Fishman and Associates e7

Figure 1—A: Cumulative incidence of type 2 diabetes according to BMI group and hypertension status (N 5 1,659,197). The table presents (for lean- and high-BMI groups separately) the number of persons at risk, cumulative person-years, and cumulative type 2 diabetes cases by the following follow-up time intervals since study entry: 5, 10, 15, and 20 years. PY, person-years; T2D, type 2 diabetes. B and C: The association of adolescent hypertension and incident type 2 diabetes in young adults according to adolescent BMI.^Adjustment for age at study entry, sex (except in the analysis limited for men), birth year, country of birth, BMI (continuous), residential socioeconomic status, years of formal education, and cognitive performance. Description of these covariates and their classification was previously published (2). §Unimpaired health was defined as absence of any chronic comorbidities (apart from hypertension) that require medical treatment or follow-up, history of a major surgery, or cancer. e8 Adolescent Hypertension and Type 2 Diabetes Diabetes Care Volume 44, January 2021

Of 1,659,197 adolescents in total, Previous longitudinal studies on asso- Adolescent hypertension was associated 4,143 (0.3%) were diagnosed with essen- ciations of hypertension or increased blood with future early-onset adulthood type 2 tial hypertension at study entry. Of the pressure with incident type 2 diabetes diabetes, both among individuals with 1,386,310 (83.6%) adolescents in the reported HRs that ranged between 1.4 lean and high BMI at adolescence. These lean group, 1,645 (0.1%) had hyperten- and 2.4. Most of those studies included individuals should be viewed as a pop- sion. Of the 272,887 adolescents in the middle-aged adults who developed di- ulation at risk and warrant awareness high-BMI group, 2,498 (0.9%) had hyper- abetes usually in the 6th decade of life or regarding the need for a tight medical tension. Men comprised 57% of the co- later. We are unaware of similar longi- follow-up and preventive and early ther- hort but .90% of those with hypertension. tudinal studies among adolescents or apeutic interventions. The mean BMI at study entry was higher studies that specifically examined the among those with than without hyper- incidence of early-onset type 2 diabetes, tension, both for the lean-BMI group, which was shown to have even more The authors thank Cindy 21.6 vs. 20.3 kg/m2, and for the high-BMI deleterious effects than older age of Acknowledgments. 2 Cohen for assistance in language editing. group, 30.9 vs. 28.3 kg/m . diabetes onset (4). Funding. This study was partially supported by a During a cumulative follow-up of In our study, 60% of those with hy- grant from the Israel Defense Forces Medical 21,171,855 person-years (median follow- pertension had high BMI at study entry. Corps (award number 4440917164). up 12.8 years [interquartile range 6.7– Hypertension among overweight and Duality of Interest. No potential conflicts of interest relevant to this article were reported. 18.7]), 6,263 persons were diagnosed obese adolescents remained a risk factor Author Contributions. B.F. designed the study, with type 2 diabetes (3,179 [0.2%] in for incident type 2 diabetes in both BMI statistically analyzed and interpreted the data, the lean-BMI group and 3,084 [1.1%] in groups. Importantly, the substantial ab- and drafted and revised the manuscript. E.G., the high-BMI group). Among those with solute attributable risk of hypertension O.O., A.B., and C.D.B. interpreted the data, hypertension at study entry, 13 (0.8%) for incident type 2 diabetes was higher in contributed to the discussion, and critically re- vised the manuscript. I.Z., M.L., and Y.L. acquired and 59 (2.3%) developed type 2 diabetes the high-BMI group. This corroborates the data, contributed to the discussion, and in the lean- and high-BMI groups, respec- the evidence in adults that hypertension critically revised the manuscript. T.C.-Y., O.M., tively. The mean 6 SD age of diagnosis of significantly augments the obesity-driven Z.B., O.P.-H., T.F., A.A., A.T., I.R., and H.C.G. type 2 diabetes was 32.0 6 4.8 years. risk for type 2 diabetes. Therefore, our contributed to the discussion and critically re- Figure 1A presents Kaplan-Meier survival study adds that adolescent hypertension, vised the manuscript. E.D. and D.T. acquired data and statistically analyzed the data. G.T. curves of cumulative incidence of type 2 in the presence and even in the absence designed and supervised the study, statisti- diabetes by BMI group and hypertension of high BMI, and without other comor- cally analyzed and interpreted the data, and status. Crude rates of incidence of type 2 bidities, is a potential risk factor or risk drafted and revised the manuscript. G.T. is the diabetes (per 105 person-years) were 17.5 marker for early-onset type 2 diabetes. guarantor of this work and, as such, had full for those without hypertension in the Several mechanisms may underlie this access to all the data in the study and takes responsibility for the integrity of the data and lean-BMI group, 59.7 for those with hy- association such as insulin resistance as a the accuracy of the data analysis. pertension in the lean-BMI group, 98.9 common pathway for both hypertension Prior Presentation. Parts of this study were for those without hypertension in the and type 2 diabetes and vascular damage presented in abstract form at the Israeli Di- high-BMI group, and 198.5 for those with induced by hypertension leading to en- abetes, Hypertension, Obesity & Stroke Confer- ence 2020, Tel Aviv, Israel, 26 February 2020. hypertension in the high-BMI group. dothelial dysfunction (5). In unadjusted models, the hazard ratio Our study is limited by absence of (HR) for incident type 2 diabetes among longitudinal data regarding weight, References adolescents with compared with adoles- blood pressure, lifestyle, and pharmaco- 1. Leiba A, Fishman B, Twig G, et al. Association cents without hypertension was 3.6 (95% logical treatment for hypertension. Also, of adolescent hypertension with future end- – stage renal disease. JAMA Intern Med 2019; CI 2.1 6.2) for those who were lean at detailed assessment of body composi- 179:517–523 study entry and 2.1 (1.7–2.7) for those tion, with particular relevance to the 2. Twig G, Zucker I, Afek A, et al. Adolescent with high BMI (Fig. 1B and C). The ad- high-BMI group, was not available. Fi- obesityand early-onset type 2 diabetes.Diabetes justed models yielded HRs of 2.3 (1.4– nally, our study poorly represents some Care 2020;43:1487–1495 4.1) in the lean-BMI and 1.3 (1.02–1.7) in ethnicities, such as East Asians and sub- 3. Flynn JT, Kaelber DC, Baker-Smith CM, et al.; Subcommittee on Screening and Man- the high-BMI groups (Fig. 1B and C). Saharan Africans. The strengths of our agement of High Blood Pressure in Children. Results persisted when the study sample study include systematic screening of a Clinical practice guideline for screening and was limited to men or to individuals with young population for hypertension, sys- management of high blood pressure in chil- unimpaired health at study entry (Fig. 1B tematic collection of medical and socio- dren and adolescents. Pediatrics 2017;140: e20171904 and C). Logistic regression models that demographic data, and linkage between 4. Lascar N, Brown J, Pattison H, Barnett AH, included an additional 383 persons (6% two national databases that provided Bailey CJ, Bellary S. Type 2 diabetes in adoles- of the overall incident cases) with missing sufficient statistical power to detect an cents and young adults. Lancet Diabetes Endo- date of diabetes diagnosis resulted in association with onset of diabetes that crinol 2018;6:69–80 adjusted odds ratios that were similar to occurred before the age of 40 years. 5. Climie RE, van Sloten TT, Bruno RM, et al. Macrovasculatureand microvasculatureat the those of the Cox modeling: 2.6 (95% CI In conclusion, our results emphasize crossroads between type 2 diabetes mellitus 1.6–4.4) in the lean-BMI group and 1.4 the association between two growing and hypertension. Hypertension 2019;73: (1.04–1.8) in the high-BMI group. public health issues among young adults. 1138–1149