Acta Diabetol DOI 10.1007/s00592-015-0785-1

ORIGINAL ARTICLE

Prevalence of cardiovascular risk factors in youth with type 1 diabetes and elevated body mass index Maria J. Redondo1 • Nicole C. Foster2 • Ingrid M. Libman3 • Sanjeev N. Mehta4 • Joanne M. Hathway4 • Kathleen E. Bethin5 • Brandon M. Nathan6 • Michelle A. Ecker5 • Avni C. Shah7 • Stephanie N. DuBose2 • William V. Tamborlane8 Robert P. Hoffman9 • Jenise C. Wong10 • David M. Maahs11 • Roy W. Beck2 • Linda A. DiMeglio12

•

Received: 19 February 2015 / Accepted: 2 June 2015 Ó Springer-Verlag Italia 2015

Abstract Aim The prevalence of cardiovascular risk factors in children with type 1 diabetes and elevated BMI in the USA is poorly defined. We aimed to test the hypothesis that children with type 1 diabetes who are overweight or obese have increased frequencies of hypertension, dyslipidemia, and micro-/macroalbuminuria compared to their healthy weight peers. Methods We studied 11,348 children 2 to\18 years of age enrolled in T1D Exchange between September 2010 and August 2012 with type 1 diabetes for C1 year and BMI C 5th age-/sex-adjusted percentile (mean age 12 years, 49 % female, 78 % non-Hispanic White). Overweight and obesity were defined based on Centers for Disease Control and

Managed by Massimo Federici.

Electronic supplementary material The online version of this article (doi:10.1007/s00592-015-0785-1) contains supplementary material, which is available to authorized users.

Prevention criteria. Diagnoses of hypertension, dyslipidemia, and micro-/macroalbuminuria were obtained from medical records. Logistic and linear regression models were used to assess factors associated with weight status. Results Of the 11,348 participants, 22 % were overweight and 14 % obese. Hypertension and dyslipidemia were diagnosed in 1.0 % and 3.8 % of participants, respectively; micro-/macroalbuminuria was diagnosed in 3.8 % of participants with available data (n = 7,401). The odds of either hypertension or dyslipidemia were higher in obese than healthy weight participants [OR 3.5, 99 % confidence interval (CI) 2.0–6.1 and 2.2, 99 % CI 1.6–3.1, respectively]. Obese participants tended to be diagnosed with micro-/macroalbuminuria less often than healthy weight participants (OR 0.6, 99 % CI 0.4–1.0). Conclusions Obese children with type 1 diabetes have a higher prevalence of hypertension and dyslipidemia than healthy weight children with type 1 diabetes. The possible association of obesity with lower micro-/macroalbuminuria rates warrants further investigation.

For the T1D Exchange Clinic Network. & Nicole C. Foster [email protected]

6

University of Minnesota, 516 Delaware St. SE, Minneapolis, MN, USA

7

Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305, USA

1

Baylor College of Medicine, 6621 Fannin St, Houston, TX 77030, USA

2

8

Jaeb Center for Health Research, 15310 Amberly Drive, Suite 350, Tampa, FL 33647, USA

Yale University, 333 Cedar St, New Haven, CT 06520, USA

9

Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA

Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205, USA

10

Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA

University of California at San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA

11

School of Medicine and Biomedical Sciences at the University at Buffalo, State University of New York, 402 Crofts Hall, Buffalo, NY 14260, USA

Barbara Davis Center for Childhood Diabetes, 1775 N. Ursula St, Aurora, CO 80045, USA

12

Indiana University School of Medicine, 702 Barnhill Dr, Indianapolis, IN 46202, USA

3

4

5

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Keywords Obesity
Overweight
BMI
Epidemiology
Hypertension
Dyslipidemia
Micro-albuminuria Abbreviations T1D Type 1 diabetes BMI Body mass index CVD Cardiovascular disease SMBG Self-monitoring of blood glucose HbA1c Hemoglobin A1c

Introduction The leading cause of death in the USA is cardiovascular disease (CVD), with coronary artery disease being the most common type [1, 2]. In adults with type 1 diabetes (T1D), CVD is more prevalent, presents at an earlier age, and carries greater mortality than in individuals without diabetes [3–9]. Children with type 1 diabetes have an increased prevalence of cardiovascular risk factors compared with their unaffected peers [10–13], and subclinical atherosclerosis has been documented in adolescents with T1D [4, 9, 14]. Overweight and obesity have emerged as common comorbidities in youth that may further increase the risk of future CVD. In otherwise healthy children, obesity predicts CVD, likely acting both directly through insulin resistance and indirectly through the actions of other components of the metabolic syndrome [15–20]. As many as 22 % of children with new onset [15, 21, 22] and 30 % with established [16, 23] T1D are overweight or obese. However, the prevalence of other cardiovascular risk factors in overweight or obese children with T1D in the USA is not known. We aimed to test the hypothesis that children with T1D who are overweight or obese have increased frequencies of CVD risk factors compared with healthy weight children with T1D, even after controlling for other metabolic, demographic, and socioeconomic risk factors. We studied the prevalence of hypertension, dyslipidemia, and micro-/macroalbuminuria in a large cohort of pediatric patients enrolled in the T1D Exchange clinic registry [24].

Methods The T1D Exchange clinic network includes 70 US-based pediatric and adult endocrinology practices. A registry of individuals with T1D commenced enrollment in September 2010 after each clinic received approval from their local institutional review board (IRB) [24]. Informed consent was obtained according to IRB requirements from adult

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participants and parents/guardians of minors; assent from minors was obtained as required. Data were collected for the registry’s central database from the participant’s medical record and by having the consented participant or parent complete a comprehensive questionnaire, as previously described [24]. The current analysis included participants 2 to \18 years of age at the time of enrollment with established T1D of C1 year duration. BMI percentiles for age and sex were calculated using the Centers for Disease Control and Prevention (CDC) growth charts from 2000 and were used to define weight status [25]. Underweight children (\5th percentile; n = 85) were excluded as the study aim was to evaluate cardiovascular risk factors in obese, overweight, and normal (healthy) weight children. Participants with T1D for \1 year were not included due to the weight fluctuation that often accompanies the clinical onset and initial therapy of T1D. This report includes data on 11,348 participants enrolled at 59 sites who care for pediatric patients through August 1, 2012. Information pertaining to sex, race/ethnicity, household income, insurance status, self-monitoring of blood glucose (SMBG), and parental education was obtained from the participant or parent/guardian of the participant. Age, date of diabetes diagnosis, height, weight, insulin delivery method (pump/injection), and hemoglobin A1c (HbA1c) were collected from medical chart review. Total daily insulin doses were collected from medical chart review if an insulin pump download was available; otherwise, total daily insulin was estimated by the participant or parent/guardian of the participant. The HbA1c level closest to registry enrollment, obtained between 6 months prior to and 1 month after enrollment, defined current glycemic control. Diagnoses of hypertension, dyslipidemia, and/or micro-/macroalbuminuria (based on current albuminuria status) were based on medical diagnoses documented in the patient’s medical record. Statistical methods BMI categories were defined according to pediatric standards for ages 2–19 years: healthy weight (C5th to \85th), overweight (C85th to\95th), and obese (C95th percentile) [26]. Associations between weight status (healthy, overweight, and obese) and each demographic and clinical characteristic were evaluated using ordinal logistic regression models. Due to nonlinearity, age, diabetes duration, and total daily dose of insulin were treated as categorical variables in the regression model. Linear regression models within age groups (\6 years old, 6 to \13 years old, and 13 to \18 years old) were used to examine the association between HbA1c and weight status, adjusting for sex, race/ethnicity, diabetes duration,

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household income, insulin delivery method, and parental education. HbA1c was tested for normality prior to implementing linear regression models. Residuals were reviewed and plotted against predicted values to determine that the assumption of normality was satisfied. Separate logistic regression models evaluated the association between weight status and hypertension, dyslipidemia, or micro-/macroalbuminuria adjusting for age, sex, race/ethnicity, HbA1c, and diabetes duration. All p values are two-sided. Given the large sample size and multiple comparisons, only p values \0.01 were considered significant. For data analyses, SAS software, version 9.3 (2011 SAS Institute Inc., Cary, NC) was used.

more likely to have been diagnosed with dyslipidemia than healthy weight participants (4.5 versus 2.9 %, adjusted OR 1.4, 99 % CI 1.0–1.9), but not hypertension (0.8 versus 0.7 %, adjusted OR 1.0, 99 % CI 0.5–1.9) (Fig. 1). Among 7,401 participants with micro-/macroalbuminuria data available in the medical chart, 3.8 % (n = 278) had a clinical diagnosis of micro-/macroalbuminuria. Obese participants tended to be less likely to be diagnosed with micro-/macroalbuminuria than healthy weight participants (adjusted OR 0.6, 99 % CI 0.4–1.0). There was also a trend toward a decrease in diagnosis of micro-/macroalbuminuria in overweight participants (adjusted OR 0.8, 99 % CI 0.5–1.2).

Results

Conclusions

The 11,348 participants ranged in age from 2.0 to 17.9 years (median 12.8 years); 49 % were female and 78 % were non-Hispanic White; and 56 % were using an insulin pump at the time of assessment. Median diabetes duration was 4 years (interquartile range 2 to 7 years). Mean HbA1c [±standard deviation (SD)] was 8.5 ± 1.5 % (69 ± 7 mmol/mol), and mean total daily insulin dose was 0.86 ± 0.43 U/kg. Additional cohort characteristics are shown in Table 1. Among the participants, 64 % (n = 7221) were healthy weight, 22 % (n = 2531) overweight, and 14 % (n = 1596) obese. Univariate analyses showed that compared with healthy weight participants, overweight/obese participants were more likely to be Hispanic or non-Hispanic Black and from households with lower incomes, public or no health insurance, and lower parental education level; checking their blood glucose less frequently; using injections rather than pumps; and using higher doses of insulin per kg of body weight (p \ 0.001 for all characteristics) (Table 1). Females and older participants with T1D had higher BMI than the 2000 CDC population, more so than males and younger participants with T1D (p \ 0.001 for both characteristics) (Table 1). HbA1c did not vary significantly by weight status in any age group (Table 2). Hypertension and dyslipidemia data were available for the entire cohort. One percent (n = 111) carried a clinical diagnosis of hypertension and 3.8 % (n = 430) had a clinical diagnosis of dyslipidemia (only 18 participants had a clinical diagnosis of both dyslipidemia and hypertension). Compared with healthy weight individuals, obese participants were more likely to have been diagnosed with hypertension [2.6 versus 0.7 %, adjusted odds ratio (OR) 3.5, 99 % confidence interval (CI) 2.0–6.1] and dyslipidemia [6.5 versus 2.9 %, adjusted OR 2.2, 99 % CI 1.6–3.1 (Fig. 1)] after adjusting for age, sex, race/ethnicity, HbA1c, and duration of diabetes. Overweight participants also were

In our study of 11,348 children with T1D, 22 % were overweight and 14 % were obese, which is consistent with previously reported rates in US pediatric T1D populations [22, 23] and underscores the importance of understanding the impact of obesity on the course of T1D. In the general pediatric population, the prevalence of overweight and obesity is, respectively, 15 and 17 % [27], which raises the concern that children with T1D may be particularly at risk of comorbidities from being overweight and perhaps progressing to an obese category. Children with T1D and overweight or obesity have increased prevalence of CVD risk factors. We found that overweight and obese children were more likely to be diagnosed with CVD risk factors for hypertension and dyslipidemia than healthy weight children with T1D. Diagnoses of hypertension and dyslipidemia were, respectively, 3.5 and 2.2 times more likely in obese children compared with healthy weight participants after adjusting for age, sex, race/ethnicity, HbA1c, and diabetes duration. Compared with healthy weight peers, overweight children with T1D were 1.4 times more likely to have dyslipidemia despite similar rates of hypertension. Our findings highlight the importance of obesity prevention for all youth and the need for more aggressive measures to prevent CVD in adulthood. Ongoing clinical trials with metformin on obese youth with T1D may improve CVD risk factors that are related to insulin resistance [28, 29]. Micro-/macroalbuminuria was observed less frequently in obese than healthy weight children. Our results are consistent with those from the SEARCH for Diabetes in Youth Study that also found a negative association between obesity and micro-/macroalbuminuria in youth with T1D [30]. A potential explanation for this observation is that fewer overweight/obese children had benign orthostatic proteinuria, which is seen more often in athletic youth and is not thought to lead to renal or cardiovascular disease [31,

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Acta Diabetol Table 1 Participant/clinical characteristics by weight status All N (%)

Weight status* Healthy weight N (%)

Overweight N (%)

Obese N (%)

11348

7221 (64)

2531 (22)

1596 (14)

2–5 years old

658 (6)

419 (6)

132 (5)

107 (7)

6–12 years old

5254 (46)

3523 (49)

1053 (42)

678 (42)

13–17 years old

5436 (48)

3279 (45)

1346 (53)

811 (51)

Female

5536 (49)

3414 (47)

1360 (54)

762 (48)

Male

5807 (51)

3805 (53)

1169 (46)

833 (52)

8800 (78)

5752 (80)

1907 (76)

1141 (72)

All

p value*

Age (years)a

\0.001

Sexa

\0.001

Race/ethnicitya White non-Hispanic

\0.001

Black non-Hispanic

699 (6)

391 (5)

165 (7)

143 (9)

Hispanic or Latino

1167 (10)

661 (9)

307 (12)

199 (13)

Other race/ethnicity

641 (6)

402 (6)

136 (5)

103 (6)

Less than $35,000

1582 (19)

874 (17)

375 (21)

333 (28)

$35,000 to \$75,000

2294 (28)

1416 (27)

513 (28)

365 (31)

C$75,000

4334 (53)

2919 (56)

920 (51)

495 (41)

Private insurance

7372 (73)

4895 (75)

1559 (70)

918 (66)

Other or no insurance

2749 (27)

1600 (25)

667 (30)

482 (34)

3504 (33)

2048 (31)

848 (37)

608 (41)

Household incomea

\0.001

Insurance statusb

\0.001

Education level (parent)a BHigh school diploma/GED

\0.001

Associate or bachelor degree

4308 (41)

2793 (42)

931 (40)

584 (40)

Masters, professional, or doctoral degree

2672 (25)

1853 (28)

541 (23)

278 (19)

1 to \5 years

5739 (51)

3718 (51)

1213 (48)

808 (51)

5 to \10 years

4071 (36)

2537 (35)

930 (37)

604 (38)

C10 years

1538 (14)

966 (13)

388 (15)

184 (12)

0–2

324 (3)

201 (3)

64 (3)

59 (4)

3–4

2817 (26)

1675 (24)

698 (29)

444 (29)

5–6

4037 (37)

2557 (37)

894 (37)

586 (39)

7–9

2634 (24)

1787 (26)

552 (23)

295 (19)

C10

1068 (10)

732 (11)

199 (8)

137 (9)

Median (25th, 75th percentile)

6 (4, 7)

Diabetes duration (years)a

0.06

\0.001

No. of blood glucose meter checks per day

6 (4, 8)

5 (4, 7)

5 (4, 7)

Insulin delivery methoda

\0.001

Pump

6312 (56)

4123 (57)

1389 (55)

800 (50)

Injection

4991 (44)

3065 (43)

1134 (45)

792 (50)

\0.50

1454 (14)

881 (13)

336 (14)

237 (16)

0.50 to \0.75

2760 (26)

1876 (27)

556 (23)

328 (22)

0.75 to \1.00

3523 (33)

2276 (33)

788 (33)

459 (30)

C1.00

2991 (28)

1798 (26)

708 (30)

485 (32)

Median (25th, 75th percentile)

0.82 (0.64, 1.03)

0.81 (0.64, 1.02)

0.84 (0.64, 1.04)

0.84 (0.63, 1.06)

Total daily dose of insulin (units/kg)a

\0.001

* p value from a univariate ordinal logistic regression model of weight status category (healthy, overweight, and obese) versus characteristic a

Age, diabetes duration, and total daily dose of insulin were treated as categorical variables in the regression model

b

Unclassified or missing data: sex (n = 5), race/ethnicity (n = 41), annual household income (n = 3138), insurance status (n = 1227), parental education (n = 864), checking of blood glucose data (n = 468), and insulin delivery method (n = 45)

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Acta Diabetol Table 2 Association between weight status and A1c By child age Weight status

p value*

Healthy weight

Overweight

Obese

N

N

Mean HbA1c (SD*)

N

Mean HbA1c (SD*)

Mean HbA1c (SD)

Age (years) 2–5 years old 6–12 years old 13–17 years old

417

8.2 (1.1)

131

8.1 (0.9)

106

8.2 (1.0)

0.75

3498 3261

8.3 (1.2) 8.8 (1.8)

1046 1342

8.4 (1.2) 8.8 (1.6)

675 809

8.4 (1.2) 8.8 (1.5)

0.43 0.03

SD standard deviation * p value from a linear regression model of HbA1c versus three-level weight status category (healthy, overweight, and obese), adjusted for sex, race/ethnicity, diabetes duration, household income, insulin delivery method, and parental education

Fig. 1 Presence of clinically diagnosed cardiovascular risk factors by weight status. Solid white bar normal healthy weight, black and white striped bar overweight, solid black bar obese. *OR odds ratio (99 % confidence interval); ORs computed from logistic regression models adjusting for age, sex, race/ethnicity, HbA1c, and diabetes duration

32]. However, the possibility of a protective effect from micro-/macroalbuminuria by obesity in T1D cannot be excluded. In support of the latter hypothesis, in children with type 2 diabetes in the TODAY study, higher BMI percentiles were associated with a decreased risk of having early diabetic retinopathy [33], and intriguingly, a recent study found that, in men with chronic kidney disease, higher fat mass decreased mortality risk [34]. On the other hand, the TODAY study did not find an association between micro-albuminuria and BMI [35]. Thus, the relationship between microvascular disease and obesity in T1D warrants further validation and evaluation. A previous Dutch study of 300 children with T1D from a single center also observed a higher prevalence of hypertension among children with elevated BMI compared with other children [36]. In contrast to our study, no differences in dyslipidemia and micro-albuminuria were found in healthy and overweight children in the Dutch study [36]. Race/ethnicity and other differences in genetic background may have contributed to the differences between the two studies. On the other hand, the much

smaller number of overweight and obese children in the Dutch study may not have provided sufficient power to detect relationships between overweight and dyslipidemia or micro-albuminuria. Among the major strengths of our study are its large sample size and multicenter nature of the registry, which improves representativeness of the sociodemographic and clinical characteristics of the population of children with T1D in the USA. Limitations of our study include that diagnosis of hypertension, dyslipidemia, and micro-albuminuria was obtained from clinical diagnosis in the medical chart. There were limited data on blood pressure measurements and lipid profiles available to us. This methodology may have led to underreporting of hypertension, dyslipidemia, and micro-/macroalbuminuria. Prospective studies with standardized measurements are warranted to validate our findings. Data on estimated glomerular filtration rate would be useful to clarify the significance of the relationship between obesity and microalbuminuria, particularly given the flaws of the latter as marker of progressive diabetic nephropathy [37].

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In conclusion, obese children with T1D have a higher frequency of hypertension and dyslipidemia than healthy weight children with T1D. The association with a lower frequency of micro-/macroalbuminuria warrants further investigation. Early identification and prompt treatment of these cardiovascular risks may lower the incidence of future cardiovascular disease-related morbidity and mortality as adult patients with T1D. Equally important, our findings highlight the need for new strategies and interventions aimed at preventing or reversing excessive weight gain in youth with T1D. Acknowledgments This work was supported through the Leona M. and Harry B. Helmsley Charitable Trust. Conflict of interest

The authors do not have any conflict of interest.

Ethical standard This human study has been reviewed by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Human and Animal Rights disclosure All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed Consent disclosure Informed consent was obtained from all patients for being included in the study.

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