13oct-2017 ladm...
TRANSCRIPT
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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:
“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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Growing Prevalence of Diabetes
•9-2000
•2016 National Diabetes Fact Sheet, CDC (current)
•29 million (7.8% population)
•25% undiagnosed
•86 million w/ prediabetes
•Age > 65 yrs: 21.5%
•Year 2050:
•1:3 Americans with diabetes
•33% with diabetes!!!!!2016 CDC Diabetes Fact Sheet
Source: www.cdc.gov/diabetes/statistics
DANGEROUS TOLL: Diabetes in Kentucky
Over 424,670 (12.5%) adult Kentuckians have diabetes (national rate 8.1%) – nearly doubled from 2000 to 2014
Kentucky ranked in the top 10 in US (unfortunately we are not talking about basketball)
An additional 138,000 are undiagnosedCDC estimates that 1.1 million adults in KY have
prediabetes (37%, 1 in 3)DM is seventh leading cause of death in Kentucky
•Source: Kentucky Cabinet for Health and Family Services •http://chfs.ky.gov/dph/info/dpqi/cd/diabetesfactsheets.htm
• Type 1 diabetes• Immune mediated• Idiopathic• Latent Autoimmune Diabetes of Adults
•Type 2 diabetes•Other specific types
• Genetic defects of beta cell• Genetic defects in insulin action• Endocrinopathies
•Gestational diabetes
Etiologic ClassificationT1DM Pathogenesis: chronic autoimmune disease
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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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
•1 •5 •10 •15 •20 •25 •30
•Arg•Arg
EXTENSION
•GlyA-CHAIN
B-CHAIN
New Therapies of Type 1 Diabetes
• Newly approved:
-Basal Insulins-Degludec
-U-300 glargine insulin
SUBSTITUTION
•1 •5 •10 •15 •20•Asn
•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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New Therapies of Type 1 Diabetes: Basal Insulin Degludec
-similar glycemic control-decreased nocturnal hypoglycemia
Basal Insulin Degludec
-similar glycemic control
-decreased nocturnal hypoglycemia
FDA Approval:
•Sep 2015:
- degludec (Tresiba) & degludec/aspart70/30 (Ryzodeg)
Heller et al: Lancet (2012) 379:1494
FDA.gov
New Therapies of Type 1 Diabetes
• Late-stage Investigational:
-Ultra-Rapid Acting Insulins
New Therapies of Type 1 Diabetes
Ultra-Rapid Acting Insulins:
Formulations to accelerate effect:
- EDTA Zn chelation(decrease hexamers
- Citrate masks charge (BIOD-238 & BIOD-250)
- Hyaluronidases increase dispersion & absortpion
- Nicotinamide+Arginine (FIAsp)
Are New Basal Insulins Better?
• Ultra-long-acting Basal Insulin
- Evidence of reduced nocturnal hypoglycemia and decreased weight gain at comparable A1c lowering
- Large phase 3 clinical trials underway to confirm hepatic and cardiovascular safety
- Concentrated formulations (U-200, U-300) so reduced volume of administration
Are New Meal-time Insulins Better?
• Ultra-rapid-acting Bolus Insulin
- Evidence for reduced postprandial hyperglycemia and potentially more convenient dosing
- Larger phase 2 and 3 clinical trials underway to confirm efficacy, site tolerability and cardiovascular safety
Ratner, RE: American Diabetes Association, Alexandria, VA
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New Therapies of Type 1 Diabetes
•Islet Implants
Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglcemia
• Pros
- Improved glycemic control > 2yrs
- Some with insulin indepencence (~40%)
- Less traumatic procedure than whole pancreas transplant
David M. Harlan Dia Care 2016;39:1072-1074
“Caveat Emptor”
• Cons- Procedure-related bleeds
- Immunosupression-related complications (e.g. renal)
- Malignancy risk
- Cost
- Most still require insulin
- No clear survival benefit
- Limited islet supply
Islet ImplantsChamber system for macroencapsulation of islets.
Ludwig B et al. PNAS 2013;110:19054-19058
• ©2013 by National Academy of Sciences
Islet Implants
•Bioartificial pancreas for transplantation without immunosuppression
•Islets isolated from donor pancreas
•Persistent graft function for ten months
•(stimulated C-peptide from 0.04 to 0.8 nmol/L)
•Improvement in A1c with reduction in insulin requirements (52 units to 43 units)
•Oxygen replenished by daily sc injection via oxygen port
Stem cell-derived Islet Implants
•Bio-artificial pancreas for transplantation without immunosuppression
•Islet derived from embryonic stem cells- culture conditions optimized
•www.ViaCyte.com
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Islet Implants: “Macroencapsulation”
•Bioartificial pancreas for transplantation without immunosuppression
•www.ViaCyte.com
Clinical trials underway 2017:
•Sentinel impants
• for safety & implant viability studies:
• sites: UCSD & U Alberta
Xenotransplantation: Encapsulated porcine islets in patient with T1DM
• Long-term viability & function of transplanted encapsulated neonatal porcine islets
Xenotransplantation: “Microencapsulation”Encapsulated porcine islets in patient with T1DM
• Long-term viability & function of transplanted encapsulated neonatal porcine islets
•Insulin stain •Glucagon stain
Omentum embedded islet nodules:
Xenotransplantation: Encapsulated porcine islets in patient with T1DM 2016
• Long-term viability & function of transplanted encapsulated neonatal porcine islets
Xenotransplantation: Encapsulated porcine islets in patient with T1DM 2016
• Long-term viability & function of transplanted encapsulated neonatal porcine islets
10,000 islets
20,000 islets
2 groups of 4 patients each
Can Insulin be delivered by a pump?
•First insulin pump- Dr. Arnold Kadish,
- Los Angelos, CA 1963
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New Therapies of Type 1 Diabetes
•Artificial Pancreas-Closed-loop prototypes
-Bihormonal therapy (glucagon/insulin)
Closed-loop Prototypes:
Inpatient & Outpatient Clinic Trials
New Therapies of Type 1 Diabetes
Artificial Pancreas
Atkinson et al: Type 1 Diabetes Lancet (2014) 383:69-82
New Therapies of Type 1 Diabetes
Artificial Pancreas
•Integrated-closed loop delivery vs conventional insulin pump therapy:
• closed loop delivery improved overnight control
•Reduced nocturnal hypoglycemia
•Tested in closely supervised clinical research facility setting including bihormonal closed-loop system (glucagon/insulin)
• Also tested ambulatory closed-loop protoype closely-monitored
at patient’s home in free-living conditions•Garg et al: Diabetes Technol. Ther (2012) 14:205-9
•Buckingham et al: Diabetes Care (2010) 33:1013-17
•Thabit et al: Curr Opin Endocr Diab Obes (2014) 21(2)95-101
Clinical Trials of Hybrid Closed-loop Insulin Delivery
• Method:
- 12 adolescents, two 7 dayperiods of sensor-augmentedinsulin pump therapy
- Gender (M/F): 8/4
- Age: 15.4 + 2.6
- HbA1c: 8.3 + 0.9
- Duration on pump (years):5.6 + 2.9
- Total daily insulin: 0.84 + 0.22
Tauschman et al Diabetes Care 2016
Clinical trial reg. no. NCT01873066: www.clinicaltrials.gov
Clinical Trials of Hybrid Closed-loop Insulin Delivery
• Results: Sensor glucose in targetrange:
- 72% of time Close-loop
- vs 53% control period
- Mean glucose: 9.4 vs 10.3mmol/L (169 vs 185 mg/dl)
• Conclusions:
- Unsupervised, day-and-night hybrid closed loopinsulin delivery at home isfeasible and safe
Clinical trial reg. no. NCT01873066: www.clinicaltrials.gov
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Hybrid Closed-loop Insulin Pump
• Medtronic MiniMed 670G/ Enlite 3 hybrid Closed Loop System- Clinical trial results: single-arm, multi-center home & hotel clinical
investigation June 2015-May 2016
ClinicalTrials.gov Identifier: NCT02463097
Gray: Run-InRed: Study closed loop
Hybrid Closed-loop Insulin Pump
• Medtronic MiniMed 670G/ Enlite 3 hybrid Closed Loop System
- Clinical trial results: single-arm, multi-center home & hotel clinical investigation June 2015-May 2016
• 44% reduction in hypoglycemia (<70 mg/dl)
• 40% decline in glucose < 50 mg/dl
• 0.5% improvement in HbA1c
• 11% decline in time glucose > 180mg/dl
ClinicalTrials.gov Identifier:
• NCT02463097
First Artificial Pancreas approved by FDA Artificial Pancreas Prototype: Bigfoot Biomedical
• Pre-filled insulin cartridge
• Mobile app on smartphone acts as controller & user interface
• Dexcom G5 CGM glucose sensor
Innovative “Smart Insulin" Patch
• PNAS 112:27 8260-65
New Technology
• “Blinded” Continuous Glucose SensorAbbott’s FreeStyleLibre Pro
- Approved by FDA
- Applied in healthcare providers office
- Worn for 2 weeks
- Real-time version under FDA review
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New Technology
• Sensor for carb content
- & smart scale for serving size:
Long-term Biosensor for continuous monitoring of body chemistry
Pathophysiology of Insulin Resistanceand Type 2 Diabetes
Causes of Hyperglycemia in Type 2 Diabetes
C
Smoking and Diabetes:
Why is there so much diabetes in Kentucky?
Physicians Health Study
>20 cigarettes/day RR Diabetes > 2 fold
10-20 cigarettes/d RR Diabetes 1.5 fold
Increased Gestational Diabetes in women who smoke
Nicotine causes insulin resistance American Journal of Medicine 109(7):538, 2000.
Am J Epidemiol. 2004 Dec 15;160(12):1205-13.
How Is Smoking Related to Diabetes?
• smoking causes type 2 diabetes
• the more cigarettes you smoke, the higher your risk for type 2 diabetes
• smoking makes your diabetes harder to control
• smokers with diabetes have higher risks for serious complications
Source: http://www.cdc.gov/tobacco/campaign/tips/diseases/diabetes.html
The VADT Trial
Study Randomization
Older individuals with T2DM
1792
Intensive Therapy
A1c goal: <6%
Conventional Therapy
A1c goal: 8-9%
Primary Outcomes:
Major CV events
Amputation
Interventions for CAD, PVD
•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)
Positive for one autoantibody: 3,273
Positive for 2 or > autoantibodies: 4,888
Progressed to T1DM: 835
Battaglia et al Diabetologia, 2017
TrialNet Interventions• New-Onset Diabetes
– Anti-CD3 (via ITN collaboration)– Mycophenolate Mofetil +/- Anti-CD25– Anti-CD20 – Anti-CD3 +/- Exenatide– Thymoglobulin (via ITN collaboration)– IL-2 plus Sirolimus – Phase 1 Safety Study
(together with ITN)
Current TrialNet Studies
• Pathway to Prevention Study: UK is a site –please refer any first degree relative of person with type 1 diabetes to be screened
- Call (859) 323-1787 D. Karounos, PI
• Anti-CD3 mAb (Teplizumab) for Prevention Of Diabetes In Relatives At Risk For Type 1 Diabetes Mellitus
• CTLA4-Ig (Abatacept) for Prevention of Type 1 Diabetes in Relatives At-Risk
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Summary
• Immune therapy of diabetes will likely involve treatment with multiple agents to try to prevent destruction of islets
• New ultra-fast and ultra-long acting insulins will improve the therapy of diabetes
• Glucose sensors and insulin delivery devices now provide us with closed-loop insulin-delivery systems
Diabetes Research Group
• Dennis G. Karounos, M.D.Collaborators:
- J. Scott Bryson, Ph.D.
- David Randall, Ph.D.
- L. Ray Reynolds, M.D.
- Nicole C. Dombroski, D.O.
- Derick Adams, D.O.
- Matt Hager, M.D.
- Robert Lodder, Ph.D.
Research Coordinators:
•Ruth Oremus
•Lyndsey Dye