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How to age healthy in type 1 diabetes
Bruce H.R. Wolffenbuttel, internist-endocrinologist Dept. of Endocrinology, UMC Groningen
Websites: www.umcg.net & www.gmed.nl Twitter: @bhrw
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Disclosure / duality of interest
Voor bijeenkomst mogelijk relevante relaties
(laatste 5 jaar) Bedrijfsnamen
• Bv. Sponsoring of onderzoeksgeld
• Bv. Honorarium of andere (financiële) vergoeding.
• Bv. Aandeelhouder
• Eur. Committee: KP7 EU grant (meerdere)
• DiabetesFonds NL
• JDRF
• NWO
• Min VWS, AZ, EcZaken
• Provincies Groningen, Friesland, Drenthe
• Nierstichting
• ZonMW
• MENZIS
• EASD / EFSD
• Becton Dickinson
• Eli Lilly
• Thermo-Fisher
• Pfizer
• Novo Nordisk
• Roche
• Sanofi
• Boehringer Ingelheim
• Ascensia
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Diabetes-related complications vs. diabetes duration
UMCG 2015
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Intensive insulin therapy postpones CV complications in type 1 diabetes - the DCCT experience
DCCT/EDIC Study Research group. NEJM 2005; 353:2643-53
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Distribution of CAC scores (Agatston units) by cohort and treatment group 8 years after DCCT
Cleary et al. Diabetes 2006; 55: 3556-65
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Advanced glycation endproducts cause complications
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Advanced glycation endproducts cause complications
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Mind your body weight !!
How to age healthy in type 1 diabetes
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Increasing prevalence of obesity in T1D (data from T1D Exchange Clinic Registry)
Miller KM, et al, Diabetes Care 2015;38:971-8
Children mean BMI
at P70-80! Adults >26yrs
almost 70%
overweight or obese
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Are we doing the right things ?
DCCT/EDIC, DiabCare 2016; 39: 1621-30
15 kg mean weight increase Blunted BP change by 60%
antihypertensive use
Vascular stiffening occurring
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Treatment of hyperlipidaemia more easy ?
DCCT/EDIC, DiabCare 2016; 39: 1621-30
HbA1c 8.0% over time
60% statin use after 28 yrs, mean LDL of 2.6 mmol/l
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Weight gain predicts worse atherosclerosis
Excessive weight gain results in:
• Higher waist circumference
• Need for more insulin (=pro-atherosclerotic)
• Higher blood pressure
• Greater intima-media thickness
• Higher coronary artery calcium scores
Purnell JQ, et al, Circulation 2012; 127: 180-7
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Consider glycation !!
How to age healthy in type 1 diabetes
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Advanced glycation endproducts cause complications
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Glycation and complications:
Correlation between blood glucose and HbA1c in T1DM
Hempe JM, et al. J Diab Compl 2002
0 5.5 11 16.5 22 mmol/l
low high
glycators
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High glycators more rapidly develop eye and kidney complications
McCarter RJ, et al. Diabetes Care 2004; 27: 1259-64
high degree of glycation of Hb also occurs in other tissues, leads to increased protein glycation and thereby faster development and
progression of complications
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Mean BG (mmol/l)
4 6 8 10 12 14 16
HbA1c (%)
6 7 8 9 10 11
Caucasian Asian Hispanic African
Ethnicity & relationship between blood glucose and HbA1c:
influence on HbA1c goal setting
Wolffenbuttel BHR, et al. Diabetes Care 2013
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Prevent hypoglycaemia !!
How to age healthy in type 1 diabetes
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Hypoglycaemia prolongs QT-interval (ECG)
QTc
prolongation hypo
normal
And can lead to
cardiac rhythm disturbances and sudden death
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Hypoglycaemia is related to diabetes type & duration
UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140-7
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Amiel SA, et al. Diabetes 1988;
McNeilly and McCrimmon. Diabetologia 2018 online
Counterregulatory failure in long-term type 1 diabetes
No diabetes
Conventionally treated type 1 diabetes
Intensive insulin therapy
Suppressed counterregulatory hormonal
and symptomatic responses to hypoglycaemia
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Possible causes / factors contributing to reduced hypoglycaemia 'awareness'
• Longer diabetes duration
• Strict glycaemic control
• Earlier or repeated hypoglycaemia
• Higher age
• Sleep
• Exercise
• Medication , i.e. non-selective beta-blockers, benzodiazepines
• Alcohol
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T1D with high glycation index will develop complications
KK
Higher BG Intensify
insulin therapy High HbA1c
Higher hypo incidence
More carbs &
prev. snacking
Weight gain
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T1D with high glycation index will develop complications
KK
Impaired awareness hypoglycaemia
Higher BG Intensify
insulin therapy High HbA1c
Cardiovascular complications Higher hypo incidence
More carbs &
prev. snacking
Weight gain High HbA1c but
normal glucose
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Use technology !!
How to age healthy in type 1 diabetes
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(RT-CGM) sensors anno 2018
Most critical: measurement in low BG area
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To prevent hypoglycaemia, technology to the rescue
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The technology to reduce hypoglycaemia is here
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RT-CGM technology
• RT-CGM sensor use started approx. 2010
• Currently in Groningen >120 people using RT-CGM continous, >40 previous users during pregnancy
• The most important indicator for RT-CGM use, i.e. hypoglycaemia unawareness, was only approved in 2017
• Of all RT-CGM started before 2017 in Groningen, >50% was exactly because of hypoglycaemia unawareness
• Benefit of RT-CGM use was IMMEDIATE, patient appreciation ultrahigh
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When brainless snails are ruling the world….
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Take your pills !!
How to age healthy in type 1 diabetes
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Proven therapies in type 1 diabetes
• Intensified insulin therapy, micro- and macrovascular
• ACE inhibitor treatment, micro- and macrovascular
• Antihypertensive therapy in general (very few studies)
• Photo / lasercoagulation in retinopathy
KK
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Type 1 diabetes:
Diabetes Control & Complications Trial
Intensive therapy = better glycaemic control =
fewer complications = higher risk of (severe) hypoglycaemia
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Type 1 diabetes:
Diabetes Control & Complications Trial
Intensive therapy = better glycaemic control =
fewer complications = higher risk of (severe) hypoglycaemia
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Genetic background + environmental factors =
course of health
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Complications and genetic predisposition
Candidate gene approach
• Retinopathy: VEGF gene
• Nefropathy: ELMO1 gene and ACE I/D gene
• PRKCB1 (in Chinese people with type 2 diabetes)
• Neuropathy: aldose reductase
• CVD: ADIPOQ
Genome-wide association studies
• Important predisposiotion area for CVD on chromosome 9
• Three possible genese for nefropathy on chromosomes 7, 11 en 13
• MCF2L2, ADIPOQ and SOX2 genes on chromosome 3 and nefropathy
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Genes for renal failure (analyses of a European consortium)
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Large numbers needed & small effect size
Ahlqvist E, et al. Nat Rev Nephrol 2015; 11:277–287
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Proven therapies in type 1 diabetes
• Intensified insulin therapy, micro- and macrovascular
• ACE inhibitor treatment, micro- and macrovascular
• Antihypertensive therapy in general (very few studies)
• Photo / lasercoagulation in retinopathy
• Genetics approaches to better predict development of complications have had remarkably LITTLE results
KK
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The statin discussion: are they ‘the best there is’ ?
• Cholesterol-lowering statin drugs:
postpone c.v. complications in people with hyperlipidaemia and/or T2D
• Since these drugs are ‘off patent’, they have become ridiculously INexpensive
(30 tabl simvastatin 40 mg = € 0.75)
• Side-effects may occur (muscle aches, rhabdomyolysis, G.I. problems)
• Statins increase BG and 'cause diabetes‘ 1
1Simsek S, et al. Diabet Med 2012;29:628-31
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The statin discussion: are they ‘the best there is’ ?
• Cholesterol-lowering statin drugs:
postpone c.v. complications in people with hyperlipidaemia and/or T2D
• Since these drugs are ‘off patent’, they have become ridiculously INexpensive
(30 tabl simvastatin 40 mg = € 0.75)
• Side-effects may occur (muscle aches, rhabdomyolysis, G.I. problems)
• Statins increase BG and 'cause diabetes‘ 1
1Simsek S, et al. Diabet Med 2012;29:628-31
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Serum LDL-cholesterol and age in people with type 1 diabetes – the Groningen database
Undertreated
Well controlled
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List of prospective randomized trials of statins in T1D
• Uhhh?
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Does poorly controlled T1DM warrant a statin ?
Consequences:
• proliferative retinopathy
• peripheral & autonomic neuropathy
• kidney failure
• severe vascular stiffening, hypertension, stroke
• cheiro-arthropathy
• atherosclerosis
When using a statin:
• low LDL exsudates, but still blind
• de novo cholesterol synthesis needed for nerve repair, risk of worsening !
• no effect on its development
• vessels still stiff, fewer endothelial lesions ??
• no effect on its development
• no evidence (yet) for a beneficial effect
Maybe statin only reduce to negative effects of weight gain in T1D ?
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Statins may not be that innocent !
• Statin use (adjusted odds ratio 1.3; 95% confidence interval 1.1-1.6; Wald P
= 0.04) significantly associated with peripheral neuropathy
Tierney JL, et al. J Diabetes 2013;5:207-15.
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Recruitment of adolescents and young adults with type 1 diabetes for a statin study
Bishop FK, et al. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Int J Pediatr Endocrinology 2012:24
1528 children &
adolescents under care
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Population–based evaluation of statins in Taiwanese people with T2D – 7-yr FU in National Health Insurance Research Database
• Statins associated with a significantly lower rate of:
• nonproliferative diabetic retinopathy -8%
• proliferative diabetic retinopathy -36%
• vitreous hemorrhage -38%
• macular edema -40%
• interventions such as retinal laser treatment (-29%) and vitrectomy (-42%)
• as well as:
• major adverse cardiovascular events -19%
• new-onset diabetic neuropathy -15%
• new-onset diabetic foot ulcers -27%
Kang EYC, et al. JAMA Ophthalmol 2019
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Choose your parents wisely !!
(or educate them)
How to age healthy in type 1 diabetes
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Skin autofluorescence in type 1 diabetes
• Skin autofluorescence (SAF) measures subcutaneous accumulation of AGE's
• SAF data of 88 children and young adults (aged 5–26 yrs) with T1D treated at
Diabeter
• Personal and anthropometric data, including age, height, weight, blood pressure, and information about exposure to tobacco smoking in the household, obtained from routine electronic patient charts
Vollenbrock CE, et al. J Diabetes. 2017;9:308-31
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Skin autofluorescence is increased in young people with type 1 diabetes exposed to secondhand smoking
People w. T1D exposed (black dots) and not exposed (open dots) to secondhand smoke
Vollenbrock CE, et al. J Diabetes. 2017;9:308-31
Parents smoking Parents not smoking
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Emigrate (or immigrate) !!
How to age healthy in type 1 diabetes
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Costs of insulin are skyrocketing in some countries
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Costs of insulin are skyrocketing in some countries
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Lower prices of FSL in France (extensively reimbursed) vs NL
Netherlands
Only reimbursed for:
Type 1 diabetes w. HbA1c > 8.0%
Children
Pregnancy (or intending to become pregnant)
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