Microsoft PowerPoint - Hartman.pptPathophysiology of Type 2 Diabetes: The Ominous Octet
outlined in orange are the three core pathophysiologies of type 2 diabetes, known as the triumvirate. Dysfunctions
DeFronzo RA. Diabetes. 2009;58:773-795.
Multiple drugs in combination may be required to improve glucose homeostasis
Treatment should target underlying pathophysiology
Poor Glucose
Obesity Trends* Among U.S. Adults
BRFSS, 1995 (*BMI ≥≥≥≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19%
Obesity Trends* Among U.S. Adults
BRFSS, 2005 (*BMI ≥≥≥≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥≥≥≥30%
‘Perfect Storm’ of Diabetes
• Hispanic and Black populations
• Hispanic
• Older, as Boomers reach maturity…
Prevalence of the Insulin Resistance Syndrome (NCEP)* in the US Population
IFG=impaired fasting glucose; IGT=impaired glucose tolerance.
Representative depiction of time course and function.
Kendall DM et al. Am J Med. 2009;122(6A):S37-S50.
Pathophysiology and Progression of Type 2 Diabetes
Years
0
-15 -10 -5 0 5 10 15 20 25 30
200
150
100
50
250
50
In early stages, as insulin resistance rises, there is a compensatory increase in insulin secretion and glucose levels remain normal
As β-cell dysfunction worsens, insulin secretion falls, IGT and hyperglycemia become apparent, and overt type 2 diabetes develops
Glucose levels, both pre- and postprandially, increase steadily as the individual progresses from normoglycemia to IGT and, finally, type 2 diabetes
Treat to which target?
– A1C <6.5%
target”
• Frail “a less stringent target, such as 8%”
• Canadian Diabetes Assn • 7% or lower
• If it can be safely achieved <6.0% should be considered
Treat to which target?
• Natl Institute for Health and Clinical
Excellence • Between 6.5 – 7.5 % on the basis of vascular risk
• Scottish Intercollegiate Guidelines
Network • “around 7.0”
20
Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles
n = 58 n = 58 n = 58 n = 58n = 58
Monnier L et al. Diabetes Care. 2003;26:881–885. Permission requested.
A1C
ADA/EASD: Titration of Metformin
ADA/EASD: Titration of Metformin
Glucagon Secretion in a Glucose-Dependent Manner
Native GLP-1
Mean (SE); n=10; *P<0.05. Reproduced from Nauck MA et al. Diabetologia. 1993;36:741–744.
Placebo
300
200
100
0
*** * *
* * *
Time (min)
Time (min)
Native human GLP-1(7-37)1*
*GLP-1(7-37) represents <20% of total circulating endogenous GLP-1.3 GLP-1=glucagon-like peptide 1; t½=half-life.
1. Modified from Drucker DJ, Nauck MA. Lancet. 2006;368:1696-1705. 2. Victoza® [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2010. 3. Deacon CF. Horm Metab Res. 2004;36:761-765. 4. Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88:220-224. 5. Agersø H et al. Diabetologia. 2002;45:195-202.
Proteolytic inactivation by DPP-4
Val
Ser
Glu
Arg
Val
Ser
97% amino acid homology
Effect of Liraglutide Versus Standard Therapy on Weight
*P<0.0001 vs glimepiride; †P<0.05 vs placebo; ‡P<0.0001 vs placebo. Data are LOCF. llActive comparator dose was ½ of approved maximal US dose. Optimal titration of glargine dose was not achieved in most patients.
1. Garber A et al. Lancet. 2009. 2. Data on file. Princeton, NJ: Novo Nordisk Inc.; 2008. 3. Nauck M et al. Diabetes Care. 2009. 4. Marre M et al. Diabetic Med. 2009. 5. Zinman B et al. Diabetes Care. 2009. 6. Russell-Jones D et al. Diabetologia. 2009.
M e
a n
w e
ig h
t c
h a
n g
Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Rosiglitazone GlarginePlacebo
‡ †
‡
*†
*†
• Victoza® is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials
Increase dose to
1.8 mg QD,
Initiate dosing at
0.6 mg QD*
(1 week)
to reduce
GI symptoms
*0.6 mg dose is not effective for glycemic control. GI=gastrointestinal; QD=once daily.
Victoza® [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2010.
0.6mg1.2mg1.8mg
32
EXENATIDE Monotherapy Provided Consistent Improvement in A1C and Weight Loss
Least squares means are adjusted for screening A1C strata and baseline value of the dependent variable.
BYETTA is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials.
24-Week, Double-Blind, Placebo-Controlled Study
EXENITIDE 10 mcg Monotherapy
Mean A1C Reduction From Baseline Mean Weight Loss From Baseline
EXENATIDE 10 mcg BID
h a
1 C
aCompared with placebo. bLeast squares mean (LSM) adjusted for prior antihyperglycemic therapy status and baseline value. cDifference from placebo. dCombined number
of patients on sitagliptin or placebo. eP<0.001 overall and for treatment-by-subgroup interactions.
CI, confidence interval.
2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
Mean baseline A1C: 8.0%
Overall <8 ≥8–<9 ≥9Baseline A1C, %
–1.4
h a
1 C
–0.7
Study 021 and 023
Saxagliptin 5 mg + Metformin IR
n=186
Mean baseline=8.1%
* In these studies, saxagliptin 5 mg and metformin IR were administered as separate tablets. Bioequivalence was established between
Kombiglyze XR and saxagliptin plus metformin XR as separate tablets. † Intent-to-treat population using last observation on study, or last observation prior to pioglitazone rescue therapy for patients needing rescue. ‡ Least squares mean adjusted for baseline value. § P<0.0001 compared to metformin IR + placebo. || P<0.05 compared to metformin IR + placebo.
IR=immediate release.
1. Data on file SAXA 064, Bristol-Myers Squibb Company, Princeton, NJ.
Kombiglyze XR Provided Significant A1C Reductions at 6 Months*†
Significantly More Patients Reached A1C <7%
17% vs 44%||
In appropriate adult patients with type 2 diabetes in addition to diet and exercise
A 1
C F
ro m
B a
s e
li n
+0.1
0.2
SAXAGLIPTIN™ 5 mg Provided Complementary A1C Reductions
Significant A1C Reduction Across Clinical Trials at 6 Months When Partnered With MET, GLY, a TZD, or as Monotherapy
Significant A1C Reduction Across Clinical Trials at 6 Months When Partnered With MET, GLY, a TZD, or as Monotherapy
SAXAGLIPTIN Was Weight and Lipid Neutral
P<0.0001 (n=186)
P<0.0001 (n=306)
P<0.0001 (n=250)
P<0.0001 (n=183)
P<0.0001 (n=103)
Initial Combo With MET
Add-On to the SU Glyburide
Baseline A1C: 8.5%
Monotherapy Baseline A1C: 8.0%
GLY=glyburide.
Onglyza Added to Glyburide Provided Statistically Significant Reductions in A1C at 6 Months*
In addition to diet and exercise
* Intent-to-treat population using last observation on study, or last observation
prior to metformin rescue therapy for patients needing rescue. † Least squares mean adjusted for baseline value. ‡ P<0.0001 compared to placebo + up-titrated glyburide.
SU=sulfonylurea.
Onglyza 5 mg + Glyburide 7.5 mg
n=250
e (
% )† +0.1
-0.6‡
92% of patients in the placebo + SU group required up-titration to the maximum SU study dose of 15 mg
92% of patients in the placebo + SU group required up-titration to the maximum SU study dose of 15 mg
04FEB2011:12:57:36 - f_profile_mean.sas/f_pk_mean_log_ss_clamp_ideg_fas.cgm nn1250/nn1250-1993/freeze_ctr_03/stats
Treatment IDeg 0.4 U/kg IDeg 0.6 U/kg IDeg 0.8 U/kg
In su
li n
d eg
lu d
ec s
er u
m c
o n
Time since injection (hours)
0 10 20 30 40 50 60 70 80 90 100 110 120
04FEB2011:12:57:42 - f_profile_mean.sas/f_pk_mean_log_ss_clamp_iglar_fas.cgm nn1250/nn1250-1993/freeze_ctr_03/stats
Treatment IGlar 0.4 U/kg IGlar 0.6 U/kg IGlar 0.8 U/kg
S er
u m
Time since injection (hours)
0 10 20 30 40 50 60 70 80 90 100 110 120
Half-life
(hours)
Mean 25.4 hours 12.5 hours
NN1250-1993; PK/PD response of Degludec at steady-state in T1DM. Submitted for ADA 2011
Degludec Glargine