•9/28/2017 •1 Innovations in the Treatment of Diabetes Dennis G. Karounos, M.D. Associate Professor of Internal Medicine, Immunology, Physiology, Graduate Center of Nutrition UKMC & VAMC Grants/research supported by: NIH, Department of Veterans Affairs, Novo Nordisk A/S, Eli Lilly, Amylin Pharmaceuticals, Astra/Zenaca, Bristol-Myer Squib, Peptor Ltd, Diamyd, Osiris, Spherix Consultant: Viacyte Disclosures Objectives 1. Discuss new therapies of diabetes 2. Report on the development of an artificial pancreas 3. Review strategies to prevent diabetes THE HORROR OF DIABETES • Pre-Insulin Era: – 50% Children die within 1yr of diagnosis • Case Presentation: – J.L. age 3, Weight 15# dehydration, emaciation (Dec. 15, 1922) – Treatment options • Starvation therapy • Insulin DISCOVERY OF INSULIN Dr. Frederick Banting & Charles Best (medical student) Bantings Plan: “ligate pancreatic duct... isolate internal secretion (of islet) ... to relieve glycosuria” •Notebook with experimental idea Oct. 31, 1920 SUCCESFUL INSULIN THERAPY •30 days after insulin therapy, Jan. 1923 •Wt. Increased to 29 # JAMA Feb. 15, 1923
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•9/28/2017
•1
Innovations in the Treatment of Diabetes
Dennis G. Karounos, M.D.Associate Professor of Internal Medicine, Immunology,
Physiology, Graduate Center of NutritionUKMC
& VAMC
Grants/research supported by: NIH, Department of Veterans Affairs, Novo Nordisk A/S, Eli Lilly, Amylin Pharmaceuticals, Astra/Zenaca, Bristol-Myer Squib, Peptor Ltd, Diamyd, Osiris, SpherixConsultant:Viacyte
Disclosures
Objectives
1. Discuss new therapies of diabetes
2. Report on the development of an artificial pancreas
3. Review strategies to prevent diabetes
THE HORROR OF DIABETES
• Pre-Insulin Era: – 50% Children die within 1yr
of diagnosis
• Case Presentation:– J.L. age 3, Weight 15#
dehydration, emaciation(Dec. 15, 1922)
– Treatment options• Starvation therapy• Insulin
DISCOVERY OF INSULIN
Dr. Frederick Banting & Charles Best (medical student) Bantings Plan:
Insulitis: arrow marks the “ENEMY” locationNormal Islet
Insulitis: Lymphocytic Infiltration &Destruction of Islets in Type 1 Diabetes
resulting in severe insulin deficiency
Pre-diabetes in Type 1 Diabetes
• Plasma glucose level and oral glucose tolerance test are normal• Decrease insulin secretion when measured with
an intravenous glucose tolerance test• Islet cell antibodies are detected: GAD antibodies, ICA512, &
Insulin autoantibodies (mIAA)• Candidates for Diabetes Prevention Trials
2010 Criteria for Diagnosis of Diabetes
1. A1C 6.5%.The test should be performed in a laboratory using a methodthat is NGSP certified and standardized to the DCCT assay.*
OR
2. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*
OR
3. Two-hour plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT.The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*
OR
4. In a patient with classic symptoms of hyperglycemia or hyperglycemiccrisis, a random plasma glucose 200 mg/dl (11.1 mmol/l).
*In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing
Source: American Diabetes Assoc. www.diabetes.org
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Innovations in the Treatment of Diabetes Dennis G. Karounos, MD
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Objective 1:
•Discuss new therapies of diabetes
New Therapies of Type 1 Diabetes
• Late-stage Investigational:
- Basal Insulins
- Rapid Acting Insulins
• Islet Implants
• Artificial Pancreas
SUBSTITUTION
•1 •5 •10 •15 •20•Asn
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•Arg•Arg
EXTENSION
•GlyA-CHAIN
B-CHAIN
New Therapies of Type 1 Diabetes
• Newly approved:
-Basal Insulins-Degludec
-U-300 glargine insulin
SUBSTITUTION
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•1 •5 •10 •15 •20 •25 •30
•Arg•Arg
EXTENSION
•GlyA-CHAIN
B-CHAIN
New Therapies of Type 1 Diabetes
Basal Insulin: Mechanism for Prolongation of Action:
- Decrease solubility: protamine (NPH) or zinc: (UL) –variable absorption
- pH dependent precipitation (glargine)
- Local albumin binding (detemir)-<24h duration
- Multiple hexamer complexes but soluble (degludec)
•1 •5 •10 •15 •20•Asn
•1 •5 •10 •15 •20 •25 •30
•Arg•Arg
•Gly
New Therapies of Type 1 Diabetes
Basal Insulins:
•1 •5 •10 •15 •20•Asn
•1 •5 •10 •15 •20 •25 •30
•Arg•Arg
•Gly
New/ Investigational
Basal InsulinsAdministration Status Peak
Effective Duration
Insulin lispro protamine suspension (ILPS)
QD or BID Approved outside USA
3 h 24 h
Pegylated insulin lispro((LY2605541)*
< once daily Phase 3 Peakless 24-44 h
Degludec (NN1250) QD or 3x/wk FDA Approval 2015
Peakless >24 h
*Bergenstal et al: Diabetes Care (2012) 35:2140-47
Five ongoing Phase 3 IMAGINE trials T1DM/T2DM
New Therapies of Type 1 Diabetes:Basal Insulin Degludec
Multiple Highly Complexed Hexamers
•Jonassen et al: Pharm Res (2012) 29:2104-14
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Innovations in the Treatment of Diabetes Dennis G. Karounos, MD
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New Therapies of Type 1 Diabetes: Basal Insulin Degludec
•Result: no difference in Major CV between Intensive
and Conventional Therapy Groups
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Clinical Implications: T2DM CV Trials
• Control of non-glucose risk factors especially HDL reduce CV events in patients with Type 2 DM.
• Intensive glucose control is beneficial if begun soon after diagnosis, but may be detrimental in long established Type 2 DM.
• Severe hypoglycemia is associated with an increase in CV events.
• Appropriate management of hypertension, dyslipidemia and other CV risk factors appears to be most effective at reducing cardiovascular morbidity and mortality in individuals with long-standing type 2 diabetes
Clinical Implications: T2DM CV Trials
Treat To Target: Clinical Inertia
Esposito et al: New guidelines for metabolic targets in diabetes Endocrine (2014) doi: 10.1007/s12020-014-0205-2
Objective 3:
•Identify current research for the prevention of diabetes
Path to Type 1 Diabetes
Genetic Risk ImmuneActivation
Stage 1 Stage 2 Stage 3
NormalBlood Sugar> 2 Autoantibodies
AbnormalBlood Sugar> 2 Autoantibodies
Clinical diagnosis> 2 Autoantibodies
Post-Diagnosis
Battaglia et al: Understanding & Preventing T1DM through the unique working model of TrialNet. Diabetologia 2017
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TrialNet Sites Clinical Trials to Prevent Diabetes:Type 1 Diabetes TrialNet Study Group
Conducting studies to:
• Test family members of people with type 1 diabetes to determine their risk to develop type 1.
• Learn more about common risk factors among people who develop type 1 diabetes.
• Test treatments that could delay or prevent onset of type 1 diabetes.
• Test treatments that might help people who have recently been diagnosed keep producing their own insulin.
TrialNet Studies
1. Studies for people who do not have type 1 diabetes, but are at increased risk because they have a family member with the disease
2. Studies for those recently diagnosed with type 1 diabetes (within 100 days)
3. Studies for participants previously enrolled in TrialNet Studies
TrialNet Studies
1. Natural History Study (TN01):
Studies for people who do not have type 1 diabetes, but are at increased risk because they have a family member with the disease
Over 178,648 relatives screened (as of 12-31-2016)