Transcript Document
The LONGTIME Study:
LONGevity in Type I diabetes and
Macrovascular disease Epidemiology
Selina Liu MD MSc FRCPC Endocrinology & Metabolism
Resident Research Career Development Program
Schulich School of Medicine & Dentistry
Endocrinology Rounds – Nov 21, 2012
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
100%
90%
Any complication:
174/326 (53.4%)
Nephropathy:
22/326 (6.7%)
70%
Prevalence (%)
Retinopathy:
139/290 (47.9%)
80%
60%
50%
40%
30%
20%
Neuropathy:
164/309 (53.1%)
10%
0%
Any
Retinopathy
Nephropathy
Microvascular Complication
Keenan HA et al. Diabetes Care 2007
Neuropathy
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
The Joslin Medalist Cohort
Declining Prevalence of Retinopathy With Longer T1DM Duration
Prevalence of Retinopathy (%)
100
90
80
70
60
107/213
29/66
50
40
3/11
30
20
10
0
50-59
60-69
Decade of Duration
Keenan HA et al. Diabetes Care 2007
>69
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
Higher random c-peptide associated with:
either minimal (0.03-0.2 nmol/L) or sustained (≥ 0.2 nmol/L)
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
(49.4%)
(70.3%)
(39.4%)
(51.5%)
Sun JK et al Diabetes Care 2011
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):
100%
90%
Stage 3 CKD
Moderately decreased GFR
(eGFR 30-59 mL/min/1.73m2)
80%
Prevalence (%)
70%
60%
50%
40%
very few had Stage 4 CKD,
none had Stage 5 CKD
30%
20%
10%
0%
Normal
Stage 1
Stage 2
Stage 3
Stage 4
NKF/KDOQI Defined Renal Function
Stage 5
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 racematched 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
Eligible subjects identified – T1DM for ≥ 50 yrs
(via WebDR, Half Century Award Lists)
Participant recruitment & consent
(~50 participants)
? At routine clinic visit
Chart Review
Study Visit #1
(lab investigations, EndoPAT, Hx & Px, questionnaires)
Study Visit #2
(CIMT, speckle doppler ultrasound/strain rate imaging, ECG)
May possibly
be coordinated
on same day,
for participant’s
convenience
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
Dr. R. Hegele
Dr. K. Summers
adiponectin, leptin, resistin, ghrelin, IL-6, MCP-1, adipsin, NGAL, PAI-1
hair cortisol
HLA type, anti-islet cell antibodies (GADA, IA2A, ZnT8A)
Dr. S. Van Uum
Dr. 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:
Co-Investigators :
Irene Hramiak
Selina Liu
Ronen Gurfinkel
Kelly Summers
Stewart Harris
Jeffrey Mahon
Michael Weingert
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 50year 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):12971304.
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.