Chief Investigator: Professor Jenny Couper

Funding Amount: $75,000

Recipient: University of Adelaide

Overview:

Heart and blood vessel disease is the most common serious adult complication of childhood diabetes. About 1/3 of children with type 1 diabetes in Australia are overweight . In children with out diabetes even small falls in body weight reduce the risk of heart disease. We will use the Australasian Diabetes Data Network to investigate whether overweight is an important driver of heart and blood vessel disease risk in 5000 children. The results will guide us how vigorously to treat childhood diabetes to minimise excess weight gain.

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Research Outcomes:

Researchers: Jenny Couper, Lynne Giles

Research Completed: 2020

Research Findings: In 7000 Australian children and young adults aged 2 – 25 years with type 1 diabetes, followed frequently over seven years on average, small increases in their body weight related to modest increases in blood fats and blood pressure, but without an adverse effect on their kidney health.  Weight gain increased blood pressure more in females, and females had all over higher weight, higher blood pressure, higher blood fats, and less favourable kidney health than males. Additional modifiable determinants of risk of heart and kidney disease were diabetes control and the use of insulin pumps.  Those participants who used insulin pump therapy had lower blood pressure, lower lipids, and better kidney health. Indigenous Australians had markedly higher levels of markers of risk of kidney complications. This is the first large study of risk factors for heart and kidney disease in young people with type 1 diabetes living in Australia. Practitioners must be cognisant of the increased vulnerability of all females and of indigenous youth.  We will next audit which young people are not getting prompt and adequate treatment of these risk factors. 

Key Outcomes: Determinants of cardiovascular risk in 7,000 youth with type 1 diabetes over seven years follow-up in the Australasian Diabetes Data Network (ADDN).

Results: 7061 youth with type 1 diabetes were followed for a median of 7.3 (IQR 4-11) years for 41 (IQR 29-56) visits, with no gender difference in duration of follow-up. Their baseline characteristics and co -variates measured over time are described in table 1. There were no gender differences except that more females used CSII (table 1). Of those participants who were resident in Australia 5666 /6490 (87.3%) were born In Australia. Median HbA1c for all participants over all visits during follow up was 8.0 (IQR 7.3-8.9)%, median BMI was 20.0 (IQR 17.5-23.3)kg/m2, median systolic/diastolic blood pressure was 110/65( IQR 100-120/60-71)mmHg, median non-HDL cholesterol was 2.9 (IQR 2.4-3.5) mmol/L, median LDL was 2.5 (IQR 2-3.1) mmol/L and median ACR was 0.7 (IQR 0.4-1.3)mg/mmol. There were no gender differences for these variables.

Relationships between BMI z-score and cardiovascular risk factors

BMI z related independently to standardised systolic (coefficient + 0.27 mmHg, 95%CI 0.25-0.29; p<0.001) and diastolic (+ 0.14mmHg, 95%CI 0.12-0.15; p<0.001) blood pressure score. The relationship was stronger in females (+0.31 mmHg, 95%CI 0.28-0.34 for systolic pressure; + 0.17, 95% CI: 0.15-0.19 for diastolic pressure) than in males (+0.24, 95% CI 0.21-0.26 for systolic pressure; +0.09, 95%CI 0.07-0.11 for diastolic pressure).

BMI z related independently to non –HDL cholesterol (coefficient + 0.16mmol/L, 95%CI 0.13-0.18; p<0.001) and LDL cholesterol (coefficient + 0.10mmol/L, 95%CI 0.07-0.13; p<0.001) without gender difference.

Other independent determinants of cardiovascular risk

Multivariate analyses for the determinants of systolic blood pressure, diastolic blood pressure, non-HDL cholesterol, LDL cholesterol, and urinary albumin /creatinine are shown in tables 2-6.

Independent determinants of both systolic and diastolic blood pressure in addition to BMI z-score, were gender, duration, age at diagnosis, insulin regimen, and HbA1c (Tables 2,3). Every 10-year increase in duration of type 1 diabetes was associated with a 0.3mmHg increase in systolic blood pressure and a 0.1mmHg increase in diastolic pressure (both p<0.001). 

Independent determinants of both non – HDL cholesterol and LDL cholesterol in addition to BMI z-score were gender, duration, age at diagnosis, insulin regimen, and HbA1c (Table 4,5).

Independent determinants of urinary albumin/creatinine were BMI z-score (an indirect relationship), gender, duration (an indirect relationship), insulin regimen, HbA1c and indigenous status (Table 6).

HbA1c level had small but significant independent relationships with standardised systolic and diastolic blood pressure, non-HDL cholesterol, LDL cholesterol, and urinary ACR (Tables 2-6).  

Females had higher BMI z-score, systolic and diastolic blood pressure, non-HDL cholesterol, LDL cholesterol and urinary albumin/creatinine than males correcting for other co –variates.

Indigenous youth (98% Aboriginal Australians) had markedly higher urinary ACR [median 1.02(0.6-2.18); 0.7(0.47-1.3)] and higher non-HDL cholesterol and LDL cholesterol than non-indigenous youth, correcting for other co –variates (tables 4-6).

47% of participants used continuous subcutaneous insulin infusion (CSII) for median XXX (IQR XXXX) years. Use of CSII was associated independently with a small but significant lowering of systolic and diastolic blood pressure, non-HDL cholesterol, LDL cholesterol and urinary ACR in comparison with participants using MDI or twice daily injections (tables 2,3 and 6). There was a stepwise increase in standardised systolic and diastolic blood pressure (table 2,3) and urinary ACR (table 6) from CSII to MDI to twice daily injections. In addition to controlling for HbA1c and other covariates in the analyses, a post hoc sensitivity analysis was performed removing all participants with a median HbA1c level that was greater than 9.0%. This did not alter the results of any of the above associations with CSII use (Supplement 1) .

Discussion

We report that in a large cohort of youth aged 2 – 25 years with type 1 diabetes, followed frequently over seven years on average, an increase in BMI relates to measurable but modest increases in non-HDL and LDL cholesterol and systolic and diastolic blood pressure, but without an adverse effect on urinary albumin excretion.  The relationship between BMI and blood pressure was stronger in females, and females had higher BMI, higher blood pressure, non-HDL and LDL cholesterol, and urinary albumin excretion than males. Additional modifiable determinants of cardiovascular risk factors were the same for blood pressure, lipids, and urinary albumin excretion –namely glycemic control and the use of insulin pumps.  Those participants who used insulin pump therapy had lower blood pressure, lower non-HDL and LDL cholesterol, and lower urinary albumin excretion. Higher HbA1c level had the anticipated adverse effect on cardiovascular risk factors, but the benefits of insulin pump therapy were independent of glycemic control. Indigenous Australians had markedly higher levels of urinary albumin excretion.

CSII use was associated recently with lower non–HDL and LDL cholesterol in a large cross- sectional study of children with type 1 diabetes from the SWEET register in which BMI, HbA1c and female gender were also associated with dyslipidemia (13). The effect size of CSII was similar to this study, indicating comparable effects across several continents. Our findings extend the benefit of CSII to a longitudinal effect on lipids, blood pressure and urinary albumin excretion. Just under half of our cohort (n= 3111) used CSII so giving us adequate power to demonstrate that the benefit rose stepwise from twice daily injections to multiple daily injections to CSII.  These benefits of CSII were independent on multivariate analysis and when in addition we performed a post hoc sensitivity analysis removing participants with HbA1c levels above 9.0%, the benefit of CSII persisted.

To our knowledge our investigation of the longitudinal impact of BMI on several cardiovascular risk factors measured at frequent intervals in routine clinics over seven years is unique in youth with type 1 diabetes. Two well executed studies from the SEARCH cohort have demonstrated the longitudinal relationship of BMI and lipids over 2 visits (14,15).  First, decreases in BMI related to only small improvements in lipids over 2 years in 1142 youth with type 1 diabetes (14) .  These improvements were greater when baseline BMI was higher. We detected modest but relatively larger changes in lipids in relation to BMI changes, showing an increase in non-HDL cholesterol of 0.16mmol/L (6.24mg/dl) with an increase of one BMI z. We detected no similar effect of initial BMI on the strength of the relationships with lipids or blood pressure.  A subsequent  analysis in the SEARCH study identified HbA1c, which was higher than in our cohort, and adiposity as modifiable risk factors for dyslipidemia (15) .  They also noted an adverse effect of female gender; insulin delivery method was not part of this analysis of 1478 youth with type 1 diabetes in whom the two visits were separated by 7 years.

The greater impact of higher BMI on blood pressure in females is to our knowledge original in this younger age group. Taken together with the higher BMI, blood pressure levels, cholesterol levels and urinary albumin excretion in females, and the higher BMI, blood pressure and lipids in females demonstrated in other cohorts, we provide further evidence for the early onset of the loss of the protective effect of female gender on cardiovascular risk in type 1 diabetes. However, the impact of female gender on cardiovascular risk in youth with type 1 diabetes must be qualified with the knowledge that male gender remains a risk factor for carotid intima  media thickness  in this age group (16). 

The high risk of renal and cardiovascular disease in the indigenous Aboriginal peoples of both Australia and Manitoba, Canada, is well established, but early changes  in youth have not  been identified (17,18). We extend this knowledge to the early onset of markedly higher urinary albumin excretion in indigenous Aboriginal youth, without a difference in blood pressure, compared with non-Indigenous youth. The numbers of indigenous Australians in our study were relatively small, but the differences were clear cut. The number of indigenous New Zealanders (virtually all Maori) were too small to examine ethnic differences. 

We and others have shown that urinary albumin  excretion, even within the normal range,  relates to structural  and functional  vascular changes  in youth with type 1 diabetes, namely intima media thickness (19) and arterial stiffness (20). Some of the urinary albumin excretion associations that we report were therefore unexpected.  Urinary albumin excretion decreased with increasing age and also with increasing BMI. These findings may possibly be explained by the recognised rise of urinary albumin excretion during early to mid-puberty in type 1 diabetes with a later fall in some individuals at the end of puberty and early adulthood, so that with increasing age during adolescence urinary albumin excretion may fall. It is possible that the increase in BMI at the later stages of puberty also in part explains the unexpected finding of lower urinary albumin excretion with increasing BMI, although this explanation appears less than complete.

Our study has limitations. The cohort, while large compared with previous reports, still only represents approximately 50% of youth in Australia and New Zealand with type 1 diabetes.  Other limitations are inherent to the measurements being collected in real world clinics – therefore blood pressure measurements were taken at rest but not over a set time interval as would occur under stricter standardised conditions. Likewise, measurement of lipids was in the non-fasting state and this precluded the inclusion of triglyceride measurements. As non-HDL cholesterol is not affected by high triglyceride levels it, rather than LDL cholesterol, was chosen as the co – primary outcome measure. However, data collection in routine clinics allowed for more frequent measurements than other similar aged cohorts describe. Another limitation was that other important factors that influence cardiovascular risk and interact with BMI, blood pressure and lipids, such as exercise, fitness, insulin resistance and sleep were not collected in the data registry. Neither were surrogate markers of structural and functional vascular changes in youth such as carotid intima media thickness, arterial resistance and endothelial function. In conclusion our large cohort, followed frequently over a substantial time period, reveals overall a small measurable impact of BMI on cardiovascular risk independent of glycemic control and a stepwise benefit in cardiovascular risk as insulin delivery intensifies from daily injections to insulin pump therapy. The striking impacts quantitatively were the adverse effects of higher BMI in females on blood pressure, female gender on lipids, and that of indigenous status on lipids and urinary albumin excretion. Our findings impress the need first to attend to all modifiable determinants of cardiovascular risk in youth with type 1 diabetes – from our and others’ findings these include glycemic control, BMI, and increasingly, insulin pump use. Practitioners must also be cognisant of the increased vulnerability of all females and of indigenous youth. 

Research Papers: The study was presented by JJC as an oral presentation at the International Society for Diabetes in Children and Adolescents (ISPAD) annual scientific meeting in Boston November 2019. Findings and conclusions are being prepared for submission to Diabetes Care, the top international clinical journal in Diabetes.

Related Publications: References:

1       Livingstone SJ, Levin D, Looker HC, Lindsay RS, Wild SH, Joss N, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010. JAMA. 2015 Jan 6;313(1):37-44. DOI: 10.1001/jama.2014.16425

2       Huo L, Harding JL, Peeters A, Shaw JE, Magliano DJ. Life expectancy of type 1 diabetic patients during 1997-2010: a national Australian registry-based cohort study. Diabetologia. 2016;59(6):1177-85. DOI: 10.1007/s00125-015-3857-4

3       Lind M, Svensson AM, Kosiborod M, Gudbjornsdottir S, Pivodic A, Wedel H, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014 Nov 20;371(21):1972-82. DOI: 10.1056/NEJMoa1408214

4       Writing Group for the DERG, Orchard TJ, Nathan DM, Zinman B, Cleary P, Brillon D, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA. 2015 Jan 6;313(1):45-53. DOI: 10.1001/jama.2014.16107

5       Maahs DM, Daniels SR, de Ferranti SD, Dichek HL, Flynn J, Goldstein BI, et al. Cardiovascular disease risk factors in youth with diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2014 Oct 21;130(17):1532-58. DOI: 10.1161/CIR.0000000000000094

6       Koivisto VA, Stevens LK, Mattock M, Ebeling P, Muggeo M, Stephenson J, et al. Cardiovascular disease and its risk factors in IDDM in Europe. EURODIAB IDDM Complications Study Group. Diabetes Care. 1996 Jul;19(7):689-97. DOI: 10.2337/diacare.19.7.689

7       Rawshani A, Sattar N, Franzén S, Rawshani A, Hattersley AT, Svensson A-M, et al. Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study. Lancet. 2018;392(10146):477-86. DOI: 10.1016/S0140-6736(18)31506-X

8       Minges KE, Whittemore R, Grey M. Overweight and obesity in youth with type 1 diabetes. Annu Rev Nurs Res. 2013; 31:47-69. DOI: 10.1891/0739-6686.31.47

9       Phelan H, Foster NC, Schwandt A, Couper JJ, Willi S, Kroschwald P, et al. Longitudinal trajectories of BMI z-score: an international comparison of 11,513 Australian, American and German/Austrian/Luxembourgian youth with type 1 diabetes. Pediatr Obes. 2020 Feb;15(2):e12582. DOI: 10.1111/ijpo.12582

10     Phelan H, Clapin H, Bruns L, Cameron FJ, Cotterill AM, Couper JJ, et al. The Australasian Diabetes Data Network: first national audit of children and adolescents with type 1 diabetes. Med J Aust. 2017;206(3):121-5. DOI: 10.5694/mja16.00737

11     Clapin H, Phelan H, Bruns L, Jr., Sinnott R, Colman P, Craig M, et al. Australasian Diabetes Data Network: Building a Collaborative Resource. J Diabetes Sci Technol. 2016;10(5):1015-26. DOI: 10.1177/1932296816648983

12     Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, et al. Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics. 2002;109(1):45-60. DOI: 10.1542/peds.109.1.45

13     Kosteria I, Schwandt A, Davis E, Jali S, Prieto M, Rottembourg D, et al. Lipid profile is associated with treatment regimen in a large cohort of children and adolescents with Type 1 diabetes mellitus: a study from the international SWEET database. Diabet Med. 2019:10.1111/dme.13963. DOI: 10.1111/dme.13963

14     Shah AS, Dolan LM, Dabelea D, Stafford JM, D’Agostino RB, Jr., Mayer-Davis EJ, et al. Change in adiposity minimally affects the lipid profile in youth with recent onset type 1 diabetes. Pediatr Diabetes. 2015;16(4):280-6. DOI: 10.1111/pedi.12162

15     Shah AS, Maahs DM, Stafford JM, Dolan LM, Lang W, Imperatore G, et al. Predictors of Dyslipidemia Over Time in Youth With Type 1 Diabetes: For the SEARCH for Diabetes in Youth Study. Diabetes care. 2017;40(4):607-13. DOI: 10.2337/dc16-2193

16     Shah AS, Dabelea D, Fino NF, Dolan LM, Wadwa RP, D’Agostino R, Jr., et al. Predictors of Increased Carotid Intima-Media Thickness in Youth With Type 1 Diabetes: The SEARCH CVD Study. Diabetes Care. 2016 Mar;39(3):418-25. DOI: 10.2337/dc15-1963

17     Haysom L, Williams R, Hodson E, Roy LP, Lyle D, Craig JC. Early chronic kidney disease in Aboriginal and non-Aboriginal Australian children: remoteness, socioeconomic disadvantage or race? Kidney Int. 2007;71(8):787-94. DOI: 10.1038/sj.ki.5002099

18     Yeates K, Tonelli M. Chronic kidney disease among Aboriginal people living in Canada. Clin Nephrol. 2010;74 Suppl 1: S57-S60. DOI: 10.5414/cnp74s057

19     Maftei O, Pena AS, Sullivan T, Jones TW, Donaghue KC, Cameron FJ, et al. Early atherosclerosis relates to urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes: Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT). Diabetes Care. 2014 Nov;37(11):3069-75. DOI: 10.2337/dc14-0700

20     Marcovecchio ML, Woodside J, Jones T, Daneman D, Neil A, Prevost T, et al. Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): urinary screening and baseline biochemical and cardiovascular assessments. Diabetes Care. 2014;37(3):805-13. DOI: 10.2337/dc13-1634

Future Outcomes: