Type 1 Diabetes, treatment, prediction and prevention Going to school - - PDF document
3/20/2014 Type 1 Diabetes, treatment, prediction and prevention Going to school Carla Greenbaum MD Director, Diabetes Program Math History English Philosophy Civics MATH 1 3/20/2014 MATH: Absolute and Relative Risk Type 1
Carla Greenbaum MD Director, Diabetes Program
Families with diabetes
300 people without a family member with diabetes X 0.3% = 1 with diabetes 300 people with a family member with diabetes X 5 % = 15 with diabetes and (300‐15) = 285 without diabetes
Normal islet Islet missing insulin producing beta cells Lots of immune cells
Islet Cell Antibodies (ICA) Insulin autoantibodies (IAA)
Jerry Palmer, University of Washington
Risk Group Type 1 diabetes Population 1:300 Family members 1:20
Association with class II HLA type and HLA involves the immune system Jerry Nepom, MD, PhD Benaroya Research Institute
Genetic Predisposition Beta cell mass (?Precipitating Event) Overt Immunologic abnormalities Normal insulin release Progressive loss insulin release Glucose normal Overt diabetes C-peptide present No C-peptide Age (years+
variable amount of beta cell mass/function
Beta cell function Time
a variable amount of beta cell mass/function
get diabetes at different times
Beta cell function Time
determines when you get diabetes
Beta cell function Time
secretion to keep up with demand
Genetic Predisposition Beta cell mass (?Precipitating Event) Overt Immunologic abnormalities Normal insulin release Progressive loss insulin release Glucose normal Overt diabetes C-peptide present No C-peptide Age (years+
Sensitivity: Proportion of people with disease who test positive: Number of people who have genetic risk who will get diabetes Number of people with diabetes Specificity: Proportion of people without diabetes who test negative: Number of people without genetic risk and who do not get diabetes Number of people without diabetes
Antibody: Protein made by the immune system to identify and destroy foreign* objects (like infections) *in autoimmune disease the immune system makes a mistake and destroys “self” not foreign objects
5 year risk Longer term risk No antibodies Less than 1% Likely less than 3% One antibody ~3% Likely less than 5% Two antibodies 35% Likely more than 90% Two antibodies and abnormal glucose 85% Likely almost everyone
Risk of diabetes among those with genetic risk (family members)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Survival Distribution Function
1 2 3 4 5 6 7
Years Followed
8
n = 26799
ICA, IAA, GAD, IA-2 ICA, IAA, GAD, IA-2
Ziegler, et al, JAMA 2013
100 %
Beta cell function Time Clinical onset
Pre-islet autoimmunity Islet autoimmunity Abnormal Glucose Tolerance
Honeymoon Longstanding DM with or without insulin secretion
Parikka et al; Diabetologia (2012) 1936
Age (yrs)
0 2 4 6 8 10 12 14
64% of children who got T1D before puberty had antibodies by age 2 95% of children who got T1D before puberty had antibodies by age 5
5 year risk Longer term risk No antibodies Less than 1% Likely less than 3% One antibody ~3% Likely less than 5% Two antibodies 35% Likely more than 90% Two antibodies and abnormal glucose 85% Likely almost everyone
Having islet autoimmunity has no symptoms, but it puts you at risk for getting diabetes
Having mild high blood pressure has no symptoms, but it puts you at risk for getting heart disease and stroke
Disease Hypertension Islet autoimmunity Consequence within 4-5 years ~5/100 get coronary heart disease or stroke 35/100 get T1D Relative risk reduction (effect size) of treatment Treating hypertension reduces heart disease by 16% and stroke by 40% Prevention studies designed with effect size
Absolute benefit of treatment Treating 100 patients with high blood pressure prevents 2 people from getting heart disease or stroke Treating 100 people would keep 14 from getting T1D Severity of event Heart disease or stroke – severe disability or death T1D is a manageable disease Risk of therapy Blood pressure treatment is costly, but adverse effects tolerated and alternatives available Cost, risk of adverse events, psychological effects, treating children
Daily capsule “oral tolerance”
autoantibody Monthly IV infusion for 1 year
insulin autoantibody
14 days IV infusion just once
abnormal glucose
Years
Proportion Free of Diabetes
1 2 3 4 5
6
0.0 0.2 0.4 0.6 0.8 1.0
Oral Insulin Placebo
Log-rank P=0.01
Proportion without T1D
Alopecia areata Ankylosing spondylitis Addisons disease Hemolytic anemia Autoimmune Hepatitis Thrombocytopenic purpura Behcets disease Pemphigus Crohns disease Dermatomyositis Lupus Graves disease Hashimotos Thyroiditis Multiple sclerosis Myasthenia gravis Pernicious anemia Polyarteritis Polychondritis Polymyositis Psoriasis Rheumatoid arthritis Scleroderma Sjogren’s syndroms Stiff man syndrome Giant cell Arteritis Ulcerative colitis Vasculitis Uveitis Vitiligo
0.8
Overall p < 0.001
0.4 0.5 0.6 0.7
3 6 12
Placebo Rituximab
Treatment period Pescovitz, NEJM 2006
Orban, Lancet 2012 Treatment period
Change in C‐peptide over time (primary endpoint)*
P=0.002
*Solid lines connect mean values; stars denote medians. Bars represent 25th and 75th percentile.
Herold, Lancet Endocrinology 2013
6 12 18 24
Months Treatment periods
47% 26% 7% 7% 8% 85% 68% 38% 23% 12%
10 20 30 40 50 60 70 80 90 100
3‐5 years (n=113 n=58) 6‐9 years (n=104 n=57) 10‐19 years (n=100 n=100) 20‐40 years (n=107 n=102) >40 years (n=104 n=50) % of people still making some of their own insulin
T1D Duration Diagnosed ≤18 years of age Diagnosed >18 years of age
Civics is the study of the great theoretical and practical aspects of citizenship, its rights and duties; the duties of citizens to each other as members of a political body and to the government
People with type 1 diabetes and their families are those that will need to participate in research
– make sure that everyone you know with type 1 diabetes knows that it “runs in families” – Make sure that family members know they can be tested for risk (testing is “free”) – Let them know that they may be eligible for research trials to see if we can keep islet autoimmunity from becoming type 1 diabetes
– Jointly at BRI and Seattle Children’s
– Check with the BRI team
BenaroyaResearch.org