The LONGTIME Study:

LONGevity in Type I diabetes and Macrovascular disease Epidemiology

Endocrinology Rounds – Nov 21, 2012

Selina Liu MD MSc FRCPC Endocrinology & MetabolismResident Research Career Development Program

Schulich School of Medicine & Dentistry

The LONGTIME Study - Background

Longstanding T1DM - associated with significant morbidity and mortality

Surprisingly, some individuals with T1DM of extreme duration (≥ 50 years) have survived relatively protected from the usual complications associated with T1DM Joslin Medalist Cohort UK Golden Years Cohort

These studies have primarily focused on microvascular complications no objective measure of macrovascular disease prevalence

The Joslin Medalist Cohort

Keenan HA et al. Diabetes Care 2007

Cross-sectional survey of 500 Joslin medalists, asked re: presence/absence of retinopathy, nephropathy, neuropathy self-reported retinopathy validated by clinical exam and fundus

photography 326 respondents

The Joslin Medalist Cohort

Lower Prevalence of Microvascular Complications

Any complication: 174/326 (53.4%)

Retinopathy:139/290 (47.9%)

Nephropathy:22/326 (6.7%)

Neuropathy:164/309 (53.1%)

Any Retinopathy Nephropathy Neuropathy0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Microvascular Complication

Pre

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ce (

%)

Keenan HA et al. Diabetes Care 2007

The Joslin Medalist Cohort

higher TGs, higher insulin dose, higher insulin dose/kg and lower HDL in those with any microvascular complication vs. those without

HbA1c, age, duration of DM, age at onset, BMI, total chol, LDL not significantly different between those with and without complications or for each microvascular complication

Keenan HA et al. Diabetes Care 2007

50-59 60-69 >690

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100

Decade of Duration

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The Joslin Medalist Cohort

Declining Prevalence of Retinopathy With Longer T1DM Duration

Keenan HA et al. Diabetes Care 2007

107/213

3/11

29/66

The Joslin Medalist Cohort

Keenan HA et al. Diabetes 2010

Cross-sectional study of 411 Medalists, and post-mortem pancreas morphology of 9 Medalists

More than 67% had detectable random c-peptide levels either minimal (0.03-0.2 nmol/L) or sustained (≥ 0.2 nmol/L)

Higher random c-peptide associated with: lower HbA1c, older age of onset, higher frequency of HLA DR3,

higher MMT responsiveness

all 9 pancreata – insulin+ b cells evidence of cellular apoptosis & proliferation, even in those from

2 Medalists with undetectable random C-peptide

The Joslin Medalist Cohort

Sun JK et al. Diabetes Care 2011

Cross-sectional study of 351 Medalists, documented prevalence of complications

Microvascular complications documented objectively: Retinopathy – fundus photography Nephropathy – avg of urine ACRs from 2 spot urine samples Neuropathy – Michigan Neuropathy Screening Instrument

Macrovascular complications - self-reported: CAD, angina, MI, cardiac/leg angioplasty or bypass graft

The Joslin Medalist Cohort

Sun JK et al Diabetes Care 2011

(49.4%)

(70.3%)

(39.4%)

(51.5%)

The UK Golden Years Cohort

Bain SC et al. Diabetic Medicine 2003

Cross-sectional study of 400 subjects with T1DM for ≥ 50 yrs

other than documenting serum creatinine/urine ACR for prevalence of albuminuria, prevalence of other complications (retinopathy, angina/MI) were by self-report and/or medical record review

The UK Golden Years Cohort

43% required laser therapy for diabetic retinopathy Blindness in only 2%

31% (men), 22% (women) – microalbuminuria 9% - macroalbuminuria

angina/prior MI in 34%

High mean HDL 1.84 ± 0.57 mmol/L

Bain SC et al Diabetic Medicine 2003

The UK Golden Years Cohort

Daousi C et al. Diabetic Medicine 2008

Cross-sectional study of 400 subjects with T1DM for ≥ 50 yrs

36% had albuminuria (micro- or macro-)

hypertriglyceridemia was associated with presence of albuminuria after adjusting for age, gender, HbA1c, disease duration, presence of

macrovascular disease

The UK Golden Years Cohort

Gill GV et al. Curr Med Res Opin 2009

Cross-sectional study of 411 subjects with T1DM for ≥ 50 yrs

27% had microalbuminuria, 9% had macroalbuminuria renal function (NKF/KDOQI):

Normal Stage 1 Stage 2 Stage 3 Stage 4 Stage 50%

10%

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50%

60%

70%

80%

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100%

NKF/KDOQI Defined Renal Function

Pre

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Stage 3 CKDModerately decreased GFR

(eGFR 30-59 mL/min/1.73m2)

very few had Stage 4 CKD, none had Stage 5 CKD

The LONGTIME Study - Rationale

The cohort of patients with T1DM followed by SJHC, represent a unique population that have survived with T1DM for an extreme duration along with the Joslin Medalist and UK Golden Years cohorts

The LONGTIME study cohort will be the first Canadian cohort of people with T1DM for an extreme duration characterized

The LONGTIME Study - Objectives

To objectively document the prevalence of macrovascular disease of the cohort of individuals with T1DM for ≥ 50 years carotid intima-media thickness (CIMT) – generalized atherosclerotic

burden speckle doppler ultrasound – myocardial strain EndoPAT – endothelial dysfunction

To fully characterize the clinical and biochemical features of this cohort microvascular and macrovascular complications glycemic control, routine biochemistry, advanced lipid profile, hair

cortisol, inflammatory biomarkers, HLA typing screen for MODY polymorphisms (to ensure T1DM)

The LONGTIME Study – Research Questions

1) Do individuals with extreme duration of T1DM have higher CIMT than predicted by healthy age-, gender-, and race-matched reference values?

2) Is there a difference in the clinical or biochemical characteristics between individuals with extreme duration of T1DM with macrovascular disease as compared to those without macrovascular disease?

The LONGTIME Study - Design

pilot, single-centre cross-sectional observational study

Inclusion criteria: T1DM for at least 50 years’ duration Informed consent to participate Willingness to perform required study procedures

Exclusion criteria: T1DM for < 50 years’ duration Lack of decision-making capacity to provide informed consent

The LONGTIME Study - Eligibility Eligible individuals identified by:

A) DEC list of Novo-Nordisk Half-Century Awardees B) WebDR query – as of Aug 1, 2012

Consultant Number of Potentially Eligible Patients

Dr. Hramiak 49

Dr. Edmonds 28

Dr. McManus 15

Dr. Paul 9

Dr. Mahon 8

Dr. McDonald 4

Dr. Morrison 1

Dr. Spaic 0

Dr. Joy 0

TOTAL 114

22

87

The LONGTIME Study - Procedures

Chart review

Study Visit #1 – SJHC Clinical Trials Unit Lab investigations (blood work, urine sample, hair sample) EndoPAT Detailed history and physical exam Questionnaires

Study Visit # 2 - Dr. Michael Weingert CIMT speckle-doppler ultrasound and strain rate imaging 12-lead ECG

The LONGTIME Study - Procedures

Participant recruitment & consent(~50 participants)

Study Visit #2(CIMT, speckle doppler ultrasound/strain rate imaging, ECG)

Eligible subjects identified – T1DM for ≥ 50 yrs(via WebDR, Half Century Award Lists)

Chart Review

Study Visit #1(lab investigations, EndoPAT, Hx & Px, questionnaires) May possibly

be coordinated on same day, for participant’s convenience

? At routine clinic visit

The LONGTIME Study – Lab Investigations CBC, lytes/urea/creatinine, HbA1c, urine ACR fasting lipid profile (LDL, HDL, triglycerides), hsCRP Serum 08:00 am cortisol TSH, free T3, free T4, anti-TPO, anti-TG ApoB, ApoA1, Lp(a)

MODY2 and 3 gene sequencing (HNF1A, GCK) Serum insulin, c-peptide adipokines

adiponectin, leptin, resistin, ghrelin, IL-6, MCP-1, adipsin, NGAL, PAI-1 hair cortisol HLA type, anti-islet cell antibodies (GADA, IA2A, ZnT8A)

Dr. R. Hegele

Dr. K. Summers

Dr. S. Van UumDr. Å. Lernmark

The LONGTIME Study – EndoPAT

Non-invasive assessment of endothelial function Uses finger plethysmography to measure peripheral arterial

tone Validated measure of CV risk assessment in general population Never studied in people with T1DM of extreme duration

http://www.itamar-medical.com/

The LONGTIME Study

Detailed History & Physical Exam full clinical assessment, including ankle brachial index (ABI)

Questionnaires Complication status Michigan Neuropathy Screening Instrument (MNSI) Hypoglycemia severity (HYPO score)

Ryan EA et al. Diabetes 2004;53(4):955-962

The LONGTIME Study

CIMT established index of generalized atherosclerosis in T1DM, CIMT is increased vs. age- and gender- matched

controls no CIMT studies in T1DM for ≥ 50 years

Speckle doppler ultrasound and strain rate imaging strain rate imaging – measures myocardial strain (percent

change in length of cardiac muscle) used in conjunction with 2D- and 3D-ultrasound to assess

segmental and global myocardial function no studies in T1DM for ≥ 50 years

The LONGTIME Study - Outcomes

Primary Outcome CIMT – vascular age calculated

Secondary Outcomes Anthropometric measurements (ht, wt, WC, BMI) Biochemical/laboratory measurements EndoPAT Non-invasive cardiac imaging:

Speckle Doppler ultrasound and myocardial strain rate imaging ECG

Questionnaires complication status (macrovascular and microvascular) HYPO Score MNSI

The LONGTIME Study – Power Calculations

In the Atherosclerosis Risk in Communities (ARIC) study: mean CIMT of the left common carotid artery (CCA) of Caucasian males aged 55 years

= 0.71 mm standard deviation of CIMT = 0.183 mm

Given our proposed sample size, n, of ~50 participants, and SD in CIMT, σ , of 0.183 mm and assuming 80% power and 2–tailed a error 5%, the smallest difference in CIMT detectable, Δ, is given by:

 

Δ2 = [(Za +Zb)22σ2]/n

 where Za = 1.96 (two-tailed), Zb = 0.84, σ = 0.183 mm, n = 50

  Thus, a difference in CIMT as small as 0.1 mm is detectable with 50

participants with T1DM of extreme duration expected in our study

Howard et al. Stroke 1993, Chambless et al. Ultrasound Med Biol 1996

The LONGTIME Study - Implications

The proposed pilot study will be the first study: to objectively document the prevalence of macrovascular disease, as measured

by CIMT to measure endothelial dysfunction, via EndoPAT to measure myocardial strain rate, via speckle doppler ultrasound

in individuals with T1DM of extreme duration (≥ 50 years) It will also be the first characterization of a Canadian cohort of

individuals with T1DM of extreme duration

The results of this study will provide support for future studies examining a larger cohort of individuals with extreme duration of T1DM, including those from other Canadian centres, to elucidate factors associated with longevity and survival in T1DM

The LONGTIME Study - Recruitment

Recruitment strategies:

Mention LONGTIME study at usual Endocrinologist clinic visit If a patient is interested, please notify Ronen or Selina to review letter

of information, obtain consent(If you know in advance that a potentially eligible patient is scheduled for a clinic visit, consider notifying Ronen or Selina prior to visit)

Letters mailed to eligible patients from usual Endocrinologist Provide contact info for study team

If you have any questions, please ask Selina or Ronen!!

The LONGTIME Study Team

Co-Principal Investigators: Irene Hramiak Selina Liu

Co-Investigators : Ronen Gurfinkel Jeffrey Mahon Kelly Summers Michael Weingert Stewart Harris

Collaborators: Stan Van Uum Åke Lernmark (Sweden)

References

Keenan HA, Costacou T, Sun JK et al. Clinical factors associated with resistance to microvascular complications in diabetic patients of extreme disease duration: The 50-year medalist study. Diabetes Care. 2007 Aug;30(8):1995-7.

Keenan HA, Sun JK, Levine J et al. Residual insulin production and pancreatic b-cell turnover after 50 years of diabetes: Joslin medalist study. Diabetes. 2010 Nov;59(11):2846-53.

Sun JK, Keenan HA, Cavallerano JD et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: The Joslin 50-year medalist study. Diabetes Care. 2011 Apr;34(4):968-74.

Bain SC, Gill GV, Dyer PH et al. Characteristics of type 1 diabetes of over 50 years duration (the Golden Years cohort). Diabet Med. 2003 Oct;20(10):808-11.

Daousi C, Bain SC, Barnett AH, Gill GV. Hypertriglyceridaemia is associated with an increased likelihood of albuminuria in extreme duration (> 50 years) type 1 diabetes. Diabet Med. 2008 Oct;25(10):1234-6.

Gill GV, Daousi C, Barnett AH, Bain SC. Chronic kidney disease in long duration type 1 diabetes lasting more than 50 years. Curr Med Res Opin. 2009 Feb;25(2):395-400.

References

http://www.itamar-medical.com/ Ryan EA, Shandro T, Green K et al. Assessment of the severity of hypoglycemia and

glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 2004;53(4):955-962

Howard G, Sharrett AR, Heiss G, et al. Carotid artery intimal-media thickness distribution in general populations as evaluated by B-mode ultrasound. Stroke. 1993;24(9):1297-1304.

Chambless LE, Zhong MM, Arnett D, Folsom AR, Riley WA, Heiss G. Variability in B-mode ultrasound measurements in the Atherosclerosis Risk in Communities (ARIC) study. Ultrasound Med Biol. 1996;22(5):545-54.