New treatments for an old disease Ahdy Wadie Helmy, MD, FACP Associate Professor of Medicine IU School of Medicine
Type 2 Diabetes Mellitus that is hitting back with
vengeance
Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults 2EHVLW\ %0,NJP2) 1994
USA .
2000
2014
A new Diabetic case Dx every 20 secs(1.7 million/yr ) No Data
<14.0%
14.0%±17.9%
18.0%±21.9%
Diabetes kills 1 A merican
Diabetes
every 3 minutes
1994
22.0%±25.9%
2000
> 26.0%
2014
180 diabetics loose a limb
every 24 hrs 55 Diabetics end on dialysis No Data
every hrs <4.5% 24 4.5%±5.9%
6.0%±7.4%
7.5%±8.9%
>9.0%
&'&¶V'LYLVLRQRI'LDEHWHV7UDQVODWLRQUnited States Surveillance System available at http://www.cdc.gov/diabetes/data
Globally, same mess, only Bigger! Estimated global prevalence of diabetes EU 17.8 25.1 41%
NA 19.7 33.9 72%
China 20.8 42.3 204%
MEC 20.1 52.8 263%
LAC 13.3 33.0 248%
151 million
2000
SSA 7.1 18.6 261%
366 million
2011
India 31.7 79.4 251%
A+NZ 1.2 2.0 65%
642 million
2040
International Diabetes Federation. IDF Diabetes Atlas. 7th ed.accessed April 2016.
'LDEHWHVGRHVQ¶WGHYHORSRYHUQLJKW it takes years of preparation
Feeding More Insulin to suppress lipolysis
Liver Visceral Adiposity
Pancreas
Cardiac Muscle
ǃ-Cell mass in Type 2 diabetes 3.5
E -Cell volume (%)
3.0 -50%
2.5 2.0
-63%
1.5 1.0 0.5 0.0 ND
IFG
Obese
T2DM
ND
T2DM
Lean
ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus Butler et al. Diabetes. 2003
Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT Getting Back up on WKH&XUYH¶
40 Lean
30
¨,¨* IR
20
10 Obese
TZDs,Metformin 0
IS
NGT
IGT
T2DM
2-Hour Plasma Glucose (mg/dL) G=glucose; I=insulin; IR=insulin resistance. Gastaldelli A, et al. Diabetologia. 2004;47:31-39.
IR
Pathogenesis of Type 2 Diabetes Islet E-cell Diabetes
Diabetes Normal glucose tolerance
Insulin Secretion
Normal glucose tolerance
Insulin Secretion
Impaired Insulin Secretion 1 0
5
1st Phase
0
5
i.v. Glucose
1 0
1 5
2nd Phase
2 0
2 5
3 0
3 5
4 4 5 5 0 5 0 5 Time (minutes)
6 0
6 5
7 0
7 5
8 0
8 5
9 0
9 5
1 0 0
1st Phase (AIR ) -10 -5 0 Increased HGP
5
2nd Phase
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
i.v. Glucose
Time (minutes)
Decreased Glucose Uptake
Adapted from glucose Weyer C,production. et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502. HGP=hepatic
Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGT Decrease in AIR Necessary to Convert From NGT to IGT
ǻ AIR (%)
0 -10
Pima Indian
Latino/Hispanic
White
-8
-20
-18
-30 -32
-40
Insulin resistance
ĹĹĹ
ĹĹ
AIR=acute insulin response to glucose. Abdul-Ghani MA, et al. Diabetes Care. 2006;29:1130-1139.
Ĺ
Hormones in Sequence insulin secretion 2nd wave
insulin secretion Meal AIR
80
Beta Cells
15
Amylin
10
Insulin (mU/L)
20
40
20
5
0 -30
60
0
30
60
GLP-1: Secreted upon the ingestion of food Without diabetes; n = 27 Late-stage type 2; n = 12 Type 10 1; n = 190 Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398
90
120
Meal (min)
150
180
* * * * * * *
0 0 30 60 90 120 150180
The Incretins ³Gut-derived factors that increase glucose-VWLPXODWHGLQVXOLQVHFUHWLRQ´ ( Intestine Secretion of Insulin )
GLP-1: Secreted upon the ingestion of food
Promotes satiety and reduces appetite
Alpha cells:
p Postprandial glucagon secretion
Liver: Beta cells: Enhances glucose-dependent insulin secretion
p Glucagon reduces hepatic glucose output
Stomach: Helps regulate gastric emptying
Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169
The Incretin Effect is Reduced in Subjects with Type 2 Diabetes The Incretin Effect accounts for ~ 60% of total Insulin release following a meal Subjects with type 2 diabetes
80
80
60
60
Insulin (mU/L)
Insulin (mU/L)
Control subjects
40 * * * * * * *
20
30
60
90 120 150 180
Time (min)
Oral Glucose Nauck MA, et al. Diabetologia 1986;29:46±52. *P FRPSDUHGZLWKUHVSHFWLYHYDOXHDIWHURUDOORDG
* * *
20
0 0
40
0 0
30
60 90 120 150 180 Time (min)
Intravenous Glucose
GLP-1 Is Cleaved and Inactivated by DPP-4
T1/2= 1 to 2 min
Development of more incretin mimetics 50% overlap with human GLP-11 ± Binds GLP-1 receptors on ȕ-cells (in vitro)2 ± Resistant to DPP-IV inactivation3
liraglutide OD T½ 13 h
Liraglutide GLP-1 Human
Q A AAKE H AE G T F T S D V S SSYL Y L E GGQ K E F I AA
A Site of DPP-IV Inactivation
exenatide
2.4 h
T½ Ŷ Following injection, exenathours4
1Eng
2,3
has
97 % AA sequence identity with human GLP-1
J, et al. J Biol Chem 1992;267:7402±7405; Adapted from 2Nielsen LL, et al. Regul Pept 2004;117:77±88; DJ. Diabetes Care 2003;26:2929±2940; 4Calara F, et al. Clin Ther 2005;27:210±215.
3Drucker
Chemical Structures of GLP-1 RAs BYETTA Drug (Exenatide)
53% Homology Gila monster Exenatide IR saliva ®
(Byetta )
Exenatide ER (Bydureon®) VICTOZA Liraglutide (Liraglutide) (Victoza®) 97% Homology C-16 Fatty Acid Chain Albiglutide
(Tanzeum®)
Dulaglutide (Trulicity®)
Initial
Titrate
5 mcg BID within 60 mins of a meal Ĺ to 10 mcg (> 6H between after 1 month doses)
2 mg once weekly
Weekly N/A TANZEUM (Albiglutide) 0.6 mg once 1.2 mg once 97% daily daily per week Homology Dimer fused Ĺ to 50 mg to Albumin 30 mg once weekly
0.75 mg once weekly
once weekly if inadequate response
Ĺ to 1.5 mg once weekly if inadequate response
Max
Dose Adjustments
Weekly BYDUREON
10 mcg Renal impairment: CrCl 30-50 mL/min: use (Exenatide ER) caution;; CrCl < 30 mL/min not 53% recommended Homology Hepatic impairment: not studied Microsphere technology 2 mg once weekly
1.8 mg once daily
50 mg once daily
1.5 mg once weekly
Renal & hepatic impairment: use caution ± limited experience Renal impairment: use caution when Weekly initiating or escalating doses TRULICITY Hepatic impairment: not studied, unlikely (Dulaglutide) 90% Homology required Linked to modified IgG Renal impairment: use caution when initiating or escalating doses Hepatic impairment: use with caution
Deciding about First Injectable Drug for Patients Not Controlled by Oral Agents
DURATION-3 trial of once-weekly exenatide vs insulin glargine as first injectable therapy Exenatide QW (n=233)
Insulin glargine (n=223)
P Value
Change in A1C
-1.01%
-0.81%
0.03
Change in body weight
-5.5 lbs
+4.4 lbs
<0.001
0.9 events per patient- year
NR
3-year endpoint
Hypoglycemia 0.3 events (exposure-adjusted per patient- events) year NR = not reported.
Diamant M et al. Lancet. 2014:2:464-473.
ITKA 650 osmotic pump for continuous Exenetide infusion implanted yearly
60 Mcg daily was found to be the most tolerable dose . Diab Care. Vol 36 : 2013, lancet 04/2016
Exenetide QMS once-monthly suspension dosing ( Phase II study data )
Microsphere technology provides a continuous level of exenatide1 Microspheres consist of a biodegradable polymer that dissipates into CO2 and water1 Using a non-aqueous suspending medium of Medium Chain Trigs Miglyol 812 that keeps the microspheres suspended & preserved eliminating the need for reconstitution immediately before injection. ( 5, 8, 11 MG dosing ) with efficacy & tolerability c/w Exenetide QW
Subcutaneous injection of microsphere suspension of exenatide1
Individual microspheres aggregate and initial release of exenatide1
Microsphere degradation and continued release of exenatide1
Further degradation and metabolism of microsphere polymer provide sustained level of exenatide1
Wysham et al.Efficacy & Safety of multiple doses of exenetide once-monthly suspension in patients with Type 2 DM: a phase II RCT. Diabetes Care 2016;39:1768-1776.
DPP-4 Inhibitors Prevent the Inactivation of GLP-1
GLP-1 Modulates Numerous Functions in Humans GLP-1 Receptor Agonism
DPP-4 Inhibition
Decreases food intake
Slows gastric Emptying
Improves firstphase insulin response
Suppresses glucagon secretion, decreasing glucose output Stimulates glucosedependent insulin secretion
1. Stonehouse A, et al. Curr Diabetes Rev 2008;4:101-109; 2. Nielsen LL, et al. Regul Pept 2004;117:77-88 3. Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089; 4. Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991-5997
Sitagliptin
Linagliptin
Saxagliptin
Alogliptin
Comparison of Dipeptidyl Peptidase±4 (DPP-4) (Nesina ) ( januvia) ( Tradjenta) (onglyza ) Inhibitors Dose frequency 100 mg QD 5 mg QD 5 mg QD
6.25mg, 12.5,25
QD Half-life (t1/2), h DPP-4 inhibition at 24 h Elimination
Renal dose adjustments required
12.4
12.5±21.1
2.2±3.8
~80%
~80% (25 mg)
~55% (5 mg)
Kidney (mostly unchanged)
Bile but not kidney (mostly unchanged)
Liver and kidney Active metabolite
Yes
No Bile
Yes
21 hrs
Yes
Selectivity for DPP- >2600-fold vs DPP-8 >10,000-fold vs DPP-8/9 >400-fold vs DPP-8 4 >10,000-fold vs DPP- >100-fold vs DPP-9 9 Potential for drug± drug interaction Food effect
Low
Low
Strong CYP3A4/5 inhibitors
No
No
No
The Kidneys Play an Important Role in the Handling of Glucose Total glucose stored in body ~450 g Glucose utilization ~250 g/day
Brain ~125 g/day Rest of body ~125 g/day Glucose in Western diet ~180 g/day Renal glucose production (gluconeogenesis + ~70 g/day glycogenolysis) Renal glucose filtration & reabsorption ~180 g/day SGLT2 receptors Urinary glucose High Capcity/Low 0 g
affinity @ Prox Renal Tubules Wright EM, et al. J Intern Med. 2007.
Renal glucose re-absorption in healthy individuals
Filtered glucose load 180 g/day
SGLT2
~ 90%
SGLT1
~ 10%
Gerich JE. Diabet Med. 2010;;27:136±142.
23
Renal glucose re-absorption in patients with hyperglycaemia Filtered glucose load > 180 g/day
SGLT2
~ 90%
SGLT1
~ 10%
Gerich JE. Diabet Med. 2010;;27:136±142.
When blood glucose increases above the renal threshold (~ 10 mmol/l or 180 mg/dL), the capacity of the transporters is exceeded, resulting in urinary glucose excretion
Urinary glucose excretion via SGLT2 inhibition Filtered glucose load > 180 g/day
SGLT2 SGLT2 inhibitor
SGLT1
*Loss of ~ 80 g of glucose/day (~ 240 cal/day). Gerich JE. Diabet Med. 2010;;27:136±142.
SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis
Renal(CANAGLIFLOZIN) Glucose Handling After (DAPAGLIFLOZIN) (EMPAGLIFLOZIN) SGLT-2 Inhibition Urinary Glucose Excretion (g/day)
150
Dosing Frequency
Dosage
Diabetes Threshold SGLT-2 Inhibition 100 & 300 mg
100
5 & 10 mg
10.6 ± 13.1 Normal Threshold
Half-life (hours) 50
Metabolism
Elimination 0 0
~ 12.9 UGT1A9
Fecal / Renal
Renal / Fecal 200
Luseogliflozin 10 & 25 mg
Tofogliflozin
~ 12.4 upSGLT2 receptors Ertugliflozin regulated in diabetes, increasing glucose UGT2B7, UGT1A3 reabsorption UGT1A8, UGT1A9
UGT1A9, UGT2BA
100
Ipragliflozin
300
Renal / Fecal 400
Renal Dosing < 45 mL/min < 60(mg/dL) mL/min < 45 mL/min Plasma Glucose (eGFR): Farber et al. J Clin Invest. 1951;30: 125-129. Mogensen CE. Scand J Clin Lab Invest. 1971;28:101-109. NotSJ, Recommended Silverman M, Turner RJ. Handbook of Physiology. In: Windhager EE, ed. Oxford University Press. 1992: 2017-2038. Cersosimo E, et al. Diabetes. 2000;49:1186-1193. DeFronzo RA, et al. Endocr Pract. 2008;14: 782-790.
Large CV Outcomes Trials in Diabetes Study
SAVOR
EXAMINE
DPP4-i
saxagliptin
alogliptin
Comparator
placebo
n
TECOS
CAROLINA
CARMELINA
sitagliptin
linagliptin
linagliptin
placebo
placebo
sulfonylurea
placebo
16,500
5,400
14,000
6,000
8,300
Results
2013
2013
2015
2017
2017
Study
LEADER
ELIXA
SUSTAIN 6
EXSCEL
REWIND
GLP1-RA
liraglutide
lixisenatide
semaglutide
exenatide LR
dulaglutide
Comparator
placebo
placebo
placebo
placebo
placebo
n
16,500
14,000
6,000
5,400
8,300
Results
6/2016
2015
10/2016
2018
2019
✓ ✓
NCT01986881
Study
EMPA-REG
CANVAS
DECLARE
SGLT-2-i
empagliflozin
canagliflozin
dapagliflozin
ertugliflozin
Comparator
placebo Reported 7300 EASD 2015 2015
placebo
placebo
placebo
4300
22,200
3900
2017
2019
2020
n Results
Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk
Simvastatin for 5.4 years
Pre-statin era 1994
Ramipril for 5 years
Empagliflozin for 3 years
Pre-ACEi/ARB era
>80% ACEi/ARB
<29% statin
>75% statin
2000
1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm; 2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm
2015 28
Insulin degludec from solution to subcutaneous depot
(Multi-hexamer formation key to protraction mechanism..Tresiba ®)
Phenol Zn2+ Insulin degludec injected As phenol from the vehicle diffuses degludec hexamers link up via single side-chain contacts
Long multi-hexamers assemble
Insulin degludec: slow release following injection
Subcutaneous depot
Zn2+
Insulin degludec multi-hexamers
Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers
Monomers are absorbed from the depot into the circulation
Insulin degludec: Mechanism of protraction
Multi-hexamers
Subcutaneous tissue
Half-life is ~24 hours, duration Monomers >42 hours, VWHDG\VWDWHídays Comes in 2 different degrees of green pens (Forest G/Garden G) U200& U100 Capillary membrane
Capillary blood
Cell Membrane
Insulin degludec in blood
Albumin binding
Insulin Receptors
Timing of flexible insulin degludec administration Mon
Tue
Wed
Thu
8h
morning
Fri
Sat
Sun
8h
morning
morning
8-12 AND 36-40 hours between insulin administration 40h
40h
evening
40h
evening
24h
evening
evening
Insulin detemir (Levemir®) Insulin glargine (Lantus®) Insulin glargine U300 (Toujeo®) Insulin glargine (BasaglarTM)
ONSET 90 min 90 min Up to 6 h 90 min
Similar reduction in A1c compared to U-100 glargine
Up to 24 h (detemir 16-24 h) Up to 24 h (glargine 24 h) Up to 30 h Up to 24 h (glargine 24 h)
For patients maintained on insulin Less glargine (U-100), expect a higher daily nocturnal dose requirement of (U-300) to maintain the same hypoglycemia level of glycemic control with U-300 glargine
Combination of Basal Insulin with a GLP-1 Agonist has a Scientific Logic
Complementary actions
Insulin Degludec/Liraglutide ( Xultophy ) P Basal insulin analogs
GLP-1 agonists
Simple to initiate Control nocturnal and FPG Lower hypoglycaemia risk vs NPH Modest weight increase (1±3 kg) Achieve A1C targets in ~50±60%
Simple to initiate Pronounced PPG control No increase in hypoglycaemia Weight lowering/neutral effects Achieve A1C targets in ~40±60%
Insulin Lantus/Lixisenitide ( iGlarlixi ) OK Additive effects
Once-daily prandial lixisenatide versus once-daily rapidacting insulin in patients with type 2 diabetes mellitus insufficiently controlled with basal insulin: analysis of data from five randomized, controlled trials.. GETGOAL DUO -2
Triple Composite Outcome
Journal of Diabetes and Its Complications 2014 28, 40-44DOI: (10.1016/j.jdiacomp.2013.10.003) Copyright © 2014 Terms and Conditions
Ultra rapid Acting Inhaled Insulin Pulling Zinc ions out will destabilize the hexamer structure allowing for quicker
absorption. Max Blood concentrations within 15 mins, rapid hypoglycemic effect with 2-3 hrs total duration of action.
Technosphere® ,QVXOLQ $)5(==$ Technosphere insulin particles made up of diketopiperazine derivatives and insulin, which self-organize into a lattice array, and form particles of 2±4 µm diameter.
Peak Effect: pH < 6 SQ( RAA): ~1 hrs
as
Inhaled: 53 min
$)5(==$ Cough ~30% Duration: Inhaled: 160-180 min 10 U SCchanges Ins No clinically meaningful in SQ(RAA): 2-4 hrs 3)7¶V VKRUW-term) pH > 6 in the lungs
More Changes to Insulin Formulations
BioD-090(VIAject) recombinant insulin + (EDTA);; loosely packed insulin multimers with rapid dissociation into monomers & dimers.
Ultra-fast-acting insulin aspart(FIAsp)
recombinant insulin + nicotinamide & arginine causing increased local blood flow & so accelerated pharmacokinetics.
Hyaluronidase + analogue insulin ( uPH20/Hylenex) accelerated insulin action, time to peak, PP glycemic excursions reduced by 82 %, and statistically significant reduction in hypoglycemic events. Injectable nano-network ( smart insulin );; where Dextran nanoparticles loaded with insulin & glucose-specific enzymes, causing glucose-dependent insulin release
Hyaluronidase Mechanism of Action
Hyaluronidases increase the dispersion of SC Insulin
Produces earlier and greater peak insulin concentrations, leading to improved postprandial glycemic control
39
Using Nanotechnology;; Oral Insulin Delivery by PH Sensitive Microspheres Gel/Microsphere system with polymethacrylic acid + PEG In stomach (pH 2) pores in the polymer shrink & block protein release In neutral pH ( small intestine) the pores swell & release protein
PH 2
PH 7
Buccal Insulin Delivery using RapidMist Technology
G2 The insulin canister hold 400 units and delivers 10 units per puff in a precisely metered dose. The formulated insulin is called Oral-lynLQLWLDOO\,had a 10% absorption. University of Toronto Researchers enhanced the Oral-lyn formulation, a 9-fold increase in serum insulin at 15 minutes and nearly 500 percent higher absorption of insulin over the 2-hour test period was verified in comparison to dogs that received the original formulation; a 33 percent decrease in serum glucose around minute 30 for the enhanced Generex Oral-lynIRUPXODWLRQZDV noted in comparison to a 12 percent increase in serum glucose in those that received the original formulation. It may be taken just before the first bite and just after the last. This flexibility offers both Type 1 and Type 2 patients a unique opportunity to aggressively treat diabetes with a minimal risk of hypoglycemia. The formulated insulin is stable at room temperature (North America) for 6 months or more. The micelles that are formed, containing the insulin, are > 7 microns and cannot enter the deep lungs regardless of effort. It is important to remember that only 20 ± 40% of subcutaneous injection is absorbed. As will be mentioned below, insulin appears in the blood within 5 min, peaks at 30 min and is back to baseline at 2 hr«7KLVnarrow window is unique to buccal insulin. It is possible because of the rich vascularity below the buccal epithelium. As with nitroglycerin, the insulin PK-PD is very fast, thus affording flexibility. The ODFNRIDµWDLO¶RILQVXOLQDFWLYLW\ZRXOGIDYRUOHVVK\SRJO\FHPLD
Older Therapies revisited ( teaching old dogs new tricks)
IR XR
DR
Published in: André J. Scheen; Expert Opinion on Pharmacotherapy 2016, 17, 627-630. DOI: 10.1517/14656566.2016.1149166 Copyright © 2016 Informa UK Limited, trading as Taylor & Francis Group
Effect of TZD ( Pioglitazone ) & on Fat Topography
Recent Data from IRIS trial
( Insulin Resistance Intervention after Stroke ) (Pio reduced DM risk by 52 % in Stroke Pts, Reduced MACE by 24 % over 5 yrs) Hi TG Hi FFA
Intramuscular Fat
TZD Subcutaneous Fat
Intrahepatic Fat Intraabdominal Fat
TG FFA
4% more
20 % less
DeFronzo RA, JCEM 89:463-478, 2004 Inzucchi et al. Pioglitazone prevents Diabetes in patients with IR & CVA. Diabetes Care 2016;39:1684-1692.
Any questions ?
