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 2000 2014

USA .
A new Diabetic case Dx
every 20 secs(1.7 million/yr )
No Data <14.0% 14.0%±17.9% 18.0%±21.9% 22.0%±25.9% > 26.0%
Diabetes kills 1 A merican
Diabetes
every 3 minutes
1994 2000 2014
180 diabetics loose a limb
every 24 hrs
55 Diabetics end on dialysis
No Data every
<4.5% 24 4.5%±5.9%
hrs 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
NA 17.8
19.7 25.1
33.9 41%   China
72%
20.8
42.3
MEC
204%  
20.1
52.8
263%
SSA
7.1 India
18.6 31.7
261%   79.4
LAC
251%
13.3
33.0
248%
A+NZ
151 million 366 million 642 million 1.2
2.0
65%  

2000 2011 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

3.0
-50%
E -Cell volume (%)

2.5

2.0 -63%
1.5

1.0

0.5

0.0
ND IFG T2DM ND T2DM

Obese 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  

40
Getting Back up on WKH&XUYH¶

Lean
30

¨,¨* 20
IR
10
Obese
TZDs,Metformin
0

IS NGT IGT T2DM IR

2-Hour Plasma Glucose (mg/dL)
G=glucose; I=insulin; IR=insulin resistance.
Gastaldelli A, et al. Diabetologia. 2004;47:31-39.
 Pathogenesis  of  Type  2  Diabetes  
Islet E-cell  
Diabetes

Normal glucose tolerance

Diabetes
Normal glucose tolerance
Insulin Secretion

Impaired
Insulin Secretion
Insulin Secretion

1st Phase 2nd Phase

- - 0 5 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 1
1 5 0 5 0 5 0 5 0 5 0 5 0 5 0 5 0 5 0 5 0
0 Time (minutes) 0
i.v. Glucose

1st Phase (AIR ) 2nd Phase

-10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Increased Decreased Glucose
HGP Time (minutes) Uptake
i.v. Glucose

HGP=hepatic
Adapted from glucose et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.
Weyer C,production.
 Insulin  Secretion  and  Insulin  Resistance    
in  Different  Ethnic  Populations  With  IGT  
Decrease in AIR Necessary to Convert From NGT to IGT

Pima Indian Latino/Hispanic White

0

-10
-8
ǻ AIR (%)

-20
-18
-30
-32
-40

Insulin
resistance ĹĹĹ ĹĹ Ĺ
AIR=acute insulin response to glucose.
Abdul-Ghani MA, et al. Diabetes Care. 2006;29:1130-1139.
 Hormones  in  Sequence  
insulin secretion insulin secretion
Meal 2nd wave
AIR 80
20

Beta Cells 60

Insulin (mU/L)
15

10 Amylin 40

* * *
5 20 * * *
*

0
0
-30 0 30 60 90 120 150 180 0 30 60 90 120 150180
GLP-1: Secreted Meal (min)
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
  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:
p Glucagon reduces
Beta cells: hepatic glucose output
Enhances glucose-dependent
insulin secretion
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

Control subjects Subjects with type 2 diabetes

80 80

60 60
Insulin (mU/L)

Insulin (mU/L)
40 40
*
20 * * * * * *
* * 20
*

0 0
0 30 60 90 120 150 180 0 30 60 90 120 150 180
Time (min) Time (min)
Oral Glucose Intravenous Glucose
Nauck MA, et al. Diabetologia 1986;29:46±52.
*P ”FRPSDUHGZLWKUHVSHFWLYHYDOXHDIWHURUDOORDG
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
H AE G T F T S D V S SSYL Q A AAKE
Y L E GGQ K E F I AA has
A Site of DPP-IV Inactivation
Human

2,3
97 % AA
exenatide  
sequence
T½  
Ŷ Following 2.4  h  
injection, exenathours4 identity with
human GLP-1
1Eng J, et al. J Biol Chem 1992;267:7402±7405; Adapted from 2Nielsen LL, et al. Regul Pept 2004;117:77±88;
3Drucker DJ. Diabetes Care 2003;26:2929±2940; 4Calara F, et al. Clin Ther 2005;27:210±215.
 Chemical  Structures  of  GLP-­1  RAs  
BYETTA
Drug   Initial   Titrate   Max   Dose  Adjustments  
(Exenatide)
53% Homology
5  mcg  BID  within   Weekly
Gila monster
Exenatide  IR  
saliva ®
60  mins  of  a  meal     Ĺ  to  10  mcg   BYDUREON
10  mcg   Renal  impairment:  CrCl  30-­50  mL/min:  use  
(Byetta )   (>  6H  between   after  1  month   (Exenatide ER)
doses)   53% caution;;  CrCl  <  30  mL/min  not  
recommended  
Homology
Hepatic  impairment:  not  studied  
Microsphere
Exenatide  ER   2  mg  once   technology
2  mg  once  
Weekly
N/A  
(Bydureon®)   weekly   weekly  
TANZEUM
(Albiglutide)
VICTOZA 0.6  mg  once  
Liraglutide  
(Liraglutide) daily   97%
1.2  mg  once   1.8  mg  once   Renal  &  hepatic  impairment:  use  caution  
(Victoza®)   daily  per  week  
Homology daily   ±  limited  experience  
 
97% Homology Dimer fused
C-­16 Fatty Acid to Albumin
Ĺ  to  50  mg   Renal  impairment:  use  caution  when  
Weekly
Chain
Albiglutide   30  mg  once   once  weekly  if   50  mg  once   initiating  or  escalating  doses  
TRULICITY
(Tanzeum®)   weekly   inadequate   daily   (Dulaglutide)
Hepatic  impairment:  not  studied,  unlikely  
response   90% Homology
required  
Linked to
modified IgG
Ĺ  to  1.5  mg   Renal  impairment:  use  caution  when  
Dulaglutide   0.75  mg  once   once  weekly  if   1.5  mg  once  
initiating  or  escalating  doses  
(Trulicity®)   weekly   inadequate   weekly  
response   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   Insulin  
3-­year  endpoint   QW     glargine   P  Value  
(n=233)   (n=223)  

Change  in  A1C   -­1.01%   -­0.81%   0.03  

Change  in  body  

-­5.5  lbs   +4.4  lbs   <0.001  
weight  
Hypoglycemia   0.3  events   0.9  events  
(exposure-­adjusted   per  patient-­ per  patient-­ NR  
events)   year   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   Individual   Microsphere   Further  degradation  

of  microsphere   microspheres   degradation  and   and  metabolism  of  
suspension  of   aggregate  and  initial   continued  release  of   microsphere  polymer  
exenatide1   release  of  exenatide1   exenatide1   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

Suppresses glucagon
secretion, decreasing
Improves first-
glucose output
phase insulin
response
Stimulates glucose-
dependent 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)  
(  januvia)   (  Tradjenta)   (onglyza  )   (Nesina  )  

Dose  frequency   100  mg  QD   Inhibitors  

5  mg  QD     5  mg  QD  
6.25mg,  12.5,25  
         QD  
 
Half-­life  (t1/2),  h   12.4   12.5±21.1     2.2±3.8  
         21  hrs  
DPP-­4  inhibition  at   ~80%    ~80%  (25  mg)   ~55%  (5  mg)      
24  h  

Elimination   Kidney   Bile  but  not  kidney   Liver  and  kidney  

(mostly  unchanged)   (mostly  unchanged)   Active  metabolite  

No  
Renal  dose   Yes   Yes  
adjustments  
 Yes  
required   Bile
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± Low   Low   Strong  CYP3A4/5  

drug  interaction   inhibitors  

Food  effect   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  
Filtered glucose
with  hyperglycaemia  
load > 180 g/day

SGLT2
When blood
glucose increases
~ 90% above the renal
threshold
(~ 10 mmol/l or 180
mg/dL), the
capacity of the
SGLT1
transporters is
exceeded,
~ 10% resulting in urinary
glucose excretion

Gerich  JE.  Diabet  Med.  2010;;27:136±142.  

 Urinary  glucose  excretion  via  SGLT2  
Filtered glucose
inhibition  
load > 180 g/day

SGLT2
SGLT2
inhibitor SGLT2 inhibitors
reduce glucose
re-absorption
in the proximal
tubule, leading to
SGLT1 urinary glucose
excretion* and
osmotic diuresis

*Loss  of  ~  80  g  of  glucose/day  (~  240  cal/day).  

Gerich  JE.  Diabet  Med.  2010;;27:136±142.    
 Renal(CANAGLIFLOZIN)
Glucose Handling After
(DAPAGLIFLOZIN) (EMPAGLIFLOZIN)
SGLT-2 Inhibition
150
Urinary Glucose Excretion

Dosing Frequency
Diabetes Threshold Ipragliflozin
SGLT-2 Inhibition
100
Luseogliflozin
Dosage 100 & 300 mg 5 & 10 mg 10 & 25 mg
(g/day)

Tofogliflozin
Half-life (hours) 10.6 ± 13.1 Normal ~ 12.9 ~ 12.4 up-
SGLT2 receptors
Threshold Ertugliflozin
50
regulated in diabetes,
Metabolism UGT1A9, UGT2BA UGT1A9 increasing glucose
UGT2B7, UGT1A3
reabsorption
UGT1A8, UGT1A9

Elimination 0 Fecal / Renal Renal / Fecal Renal / Fecal

0 100 200 300 400
Renal Dosing < 45 mL/min
Plasma Glucose < 60(mg/dL)
mL/min < 45 mL/min
(eGFR):
Farber
NotSJ, et al. J Clin Invest. 1951;30: 125-129. Mogensen CE. Scand J Clin Lab Invest. 1971;28:101-109.
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   TECOS   CAROLINA   CARMELINA  

DPP4-­i  

Comparator  
saxagliptin  

placebo  
✓ ✓
alogliptin  

placebo  
sitagliptin  

placebo  
linagliptin  

sulfonylurea  
linagliptin  

placebo  

n   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  

Study   EMPA-­REG   CANVAS   DECLARE   NCT01986881

SGLT-­2-­i   empagliflozin   canagliflozin   dapagliflozin   ertugliflozin  

Comparator   placebo   placebo   placebo   placebo  

n    Reported    
7300   4300   22,200   3900  
EASD  2015    
Results   2015   2017   2019   2020  
 Number needed to treat (NNT) to prevent one death across landmark trials in
patients with high CV risk

Simvastatin Ramipril Empagliflozin

for 5 years
for 5.4 years for 3 years

Pre-ACEi/ARB era >80% ACEi/ARB

Pre-statin era <29% statin >75% statin

1994 2000 2015

1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm;

28
2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm
 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  
Insulin  degludec  in  blood   Albumin  binding    
Capillary  blood  

Cell  Membrane   Insulin  Receptors  

 Timing  of  flexible  insulin  degludec  
administration  

Mon   Tue   Wed   Thu   Fri   Sat   Sun  

8h   8h  

morning   morning     morning    

8-­12  AND  36-­40  hours  between  insulin  administration  
40h   40h   40h   24h  

evening   evening   evening   evening  

 ONSET
90 min Similar reduction in
Up to 24 h (detemir 16-24 h)
‡ Insulin detemir (Levemir®)
90 min Up to 24 h (glargine 24 h)
‡ Insulin glargine (Lantus®)
Up to 6 h
A1c compared to
Up to 30 h
‡ Insulin glargine U300 (Toujeo®)
‡ Insulin glargine (BasaglarTM)
90 min U-100 glargine
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
hypoglycemia
the same
level of glycemic control
with U-300
glargine
 Combination  of  Basal  Insulin  with  a  GLP-­1  Agonist    
has  a  Scientific  Logic  

Complementary  
Insulin Degludec/Liraglutide ( Xultophy ) P
actions  

Basal  insulin  analogs   GLP-­1  agonists  

‡ Simple  to  initiate   ‡ Simple  to  initiate  
‡
‡
Insulin Lantus/Lixisenitide ( iGlarlixi ) OK
Control  nocturnal  and  FPG  
Lower  hypoglycaemia  risk  vs  NPH  
‡
‡
Pronounced  PPG  control  
No  increase  in  hypoglycaemia  
‡ Modest  weight  increase  (1±3  kg)   ‡ Weight  lowering/neutral  effects  
   
‡ Achieve  A1C  targets  in  ~50±60%   ‡ Achieve  A1C  targets  in  ~40±60%  

Additive    
effects  
 Once-daily prandial lixisenatide versus once-daily rapid-
acting 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$)5(==$Œ  
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  
‡$)5(==$Œ
Cough ~30%
Duration:    
‡ No‡ clinically
Inhaled:  160-­180  min  
meaningful 10 U SCchanges
Ins in
‡ SQ(RAA):  2-­4  hrs  
3)7¶VVKRUW-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-lynŒLQLWLDOO\,had a 10% absorption. University of Toronto Researchers enhanced the Oral-lynŒ
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-lynŒIRUPXODWLRQZDV
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 TG
Hi FFA TZD FFA

Intramuscular 4%
Fat Subcutaneous
Fat more

Intrahepatic
Fat
Intraabdominal 20 %
Fat
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
?