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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