prof. khalifa m. abdallah professor of internal medicine unit of diabetes & metabolic diseases...
TRANSCRIPT
Prof. Khalifa M. AbdallahProf. Khalifa M. AbdallahProfessor of Internal MedicineProfessor of Internal Medicine
Unit of Diabetes & Metabolic DiseasesUnit of Diabetes & Metabolic Diseases
Alexandria Faculty of MedicineAlexandria Faculty of Medicine
Importance of early glycemic control in management of type 2
diabetes
OverviewOverview
The importance of early and The importance of early and sustained glycemic controlsustained glycemic control
The rationale for early insulinizationThe rationale for early insulinization Advantages of basal insulin therapyAdvantages of basal insulin therapy Take home messageTake home message
Diabetes MellitusDiabetes MellitusA Constellation of A Constellation of
ComplicationsComplications
GastropathGastropathyy
Autonomic Autonomic NeuropathyNeuropathy
Renal Renal DiseaseDisease
Peripheral Peripheral NeuropathyNeuropathy
Retinopathy/ Retinopathy/ Macular Macular
EdemaEdema
HypertensionHypertensionCardiovascular Cardiovascular
DiseaseDisease
DyslipidemiaDyslipidemia
Peripheral Peripheral
Vascular Vascular DiseaseDisease
Erectile Erectile DysfunctionDysfunction
DiabetesDiabetes
- A1c & - A1c & MMicrovascular icrovascular CComplicationsomplications60 – 70 % Reduction of Complications60 – 70 % Reduction of Complications
Rel
ativ
e R
isk
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
HbA1c (%)
15
13
11
9
7
5
3
16 7 8 9 10 11 12
Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.
Risk Reduction in DCCTR
isk R
ed
uct
ion
DCCT Research Group. N Engl J Med. 1993;329:977-986.
Neuropathy AlbuminuriaRetinopathy
76%
54%60%
54%
39%
Onset
Progression
20
0
40
60
80
albuminuria
Effects of reduction of A1c by 1.9% in intensively Effects of reduction of A1c by 1.9% in intensively treated grouptreated group
P=0.002 P=0.002 P=0.002 P=0.04 P=0.04
UKPDS 35. BMJ 2000; 321: 405-12.
A1c : Myocardial Infarction and A1c : Myocardial Infarction and Microvascular Complication Microvascular Complication
0
20
40
60
80
0 5 6 7 8 9 10 11
Myocardial infarction
Microvasculardisease
Mean HbA1c (%)
Inci
dence
per
100
0 p
ati
ent-
years
UKPDS: Glucose Control Study SummaryUKPDS: Glucose Control Study Summary
The intensive glucose control policy maintained a lower The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in years from diagnosis of type 2 diabetes with reduction in risk of:risk of:
12% for any diabetes related endpoints p=0.02912% for any diabetes related endpoints p=0.029
25% for microvascular endpoints p=0.009925% for microvascular endpoints p=0.0099
16% for myocardial infarction p=0.05216% for myocardial infarction p=0.052
UKPDS: Glucose Control Study SummaryUKPDS: Glucose Control Study Summary
The intensive glucose control policy maintained a lower The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in years from diagnosis of type 2 diabetes with reduction in risk of:risk of:
12% for any diabetes related endpoints p=0.02912% for any diabetes related endpoints p=0.029
25% for microvascular endpoints p=0.009925% for microvascular endpoints p=0.0099
16% for myocardial infarction p=0.05216% for myocardial infarction p=0.052
40
1513 13
10
4 5
0
10
20
30
40
50
Ische
mic
hear
t dise
ase
Other
hea
rt
Other
hea
rt
disea
se
disea
se
Diabet
es
Diabet
es
Mali
gnan
t
Mali
gnan
t
neop
lasm
s
neop
lasm
s
Cereb
rova
scula
r
Cereb
rova
scula
r
disea
se
disea
se
Pneum
onia/
Pneum
onia/
influe
nza
influe
nza
All oth
er
All oth
er
Dea
ths
(%)
Causes of Death in People With DiabetesCauses of Death in People With Diabetes
WHO Report 1997. World Health Organisation. Geneva 1997
of Diabetic Patients Deaths are from CV Causes65%
Can long-term glycemic control Can long-term glycemic control reduce the risk of cardiovascular reduce the risk of cardiovascular
disease? disease?
Summary of ACCORD, ADVANCE and Summary of ACCORD, ADVANCE and VADTVADTACCORDACCORDADVANCEADVANCEVADTVADT
No. of participants No. of participants 10,251 10,251 11,140 11,140 1791 1791
Participant Participant age ,years age ,years
62 62 66 66 60 60
HbA1C at Baseline, HbA1C at Baseline, % %
8.18.17.57.59.49.4
Significant Effect on Significant Effect on Macrovascular Macrovascular Outcomes?Outcomes?
NoNoNoNoNoNo
Significant Effect on Significant Effect on Microvascular Microvascular Outcomes?Outcomes?
NANASignificant for Significant for nephropathy, nephropathy,
not retinopathynot retinopathy
NoNo
Rosiglitazone use, Rosiglitazone use, (intensive vs. (intensive vs. standard)standard)
90% vs. 58%90% vs. 58%17% vs. 11%17% vs. 11%85% vs. 85% vs. 78%78%
Duration of follow-Duration of follow-up, years up, years
3.43.45.05.066
ACCORD ADVANCE and VADT- No Significant ACCORD ADVANCE and VADT- No Significant Effect on Macro or Micro Vascular OutcomesEffect on Macro or Micro Vascular Outcomes
ACCORDACCORDADVANCEADVANCEVADTVADT
No. of participants No. of participants 10,251 10,251 11,140 11,140 1791 1791
Participant age ,years Participant age ,years 62 62 66 66 60 60
Duration of diabetes at Duration of diabetes at study entry, years study entry, years
10108811.511.5
HbA1C at Baseline, % HbA1C at Baseline, % 8.18.17.57.59.49.4
Participants with prior Participants with prior cardiovascular event, cardiovascular event, % %
353532324040
Duration of follow-up, Duration of follow-up, years years
3.43.45.05.066
DCCT / EDIC: majority of patients receive DCCT / EDIC: majority of patients receive intensive therapy and HbAintensive therapy and HbA1C1C levels converge levels converge
DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653
HbA
1c
)%(
YearDCCT
11
10
9
8
7
6
09
ConventionalIntensive
1 2 3 4 5 6 7 8 DCCT end
1 2 3 4 5 6 7
EDIC
Conventional group encouraged to switch
to intensive treatment
HbA
1c
)%(
YearDCCT
11
10
9
8
7
6
09
ConventionalIntensiveConventionalIntensiveIntensive
1 2 3 4 5 6 7 8 DCCT end
1 2 3 4 5 6 7
EDIC
Conventional group encouraged to switch
to intensive treatment
1 2 3 4 5 6 7
EDIC
Conventional group encouraged to switch
to intensive treatment
DCCT / EDIC – incidence of all DCCT / EDIC – incidence of all predefined cardiovascular predefined cardiovascular
outcomeoutcome
Patients previously receiving intensive treatment Patients previously receiving intensive treatment in the DCCT study had a in the DCCT study had a 57%57% reduced incidence reduced incidence of nonfatal myocardial infarction, stroke or death of nonfatal myocardial infarction, stroke or death from cardiovascular diseasefrom cardiovascular disease
DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653
UKPDS: Post-Trial Changes in UKPDS: Post-Trial Changes in HbAHbA1c1c
UKPDS resultspresented
Mean (95%CI)
UKPDS 80. N Eng J Med 2008; 359
After median 8.5 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040
Microvascular disease RRR: 25% 24% P: 0.0099 0.001
Myocardial infarction RRR: 16% 15% P: 0.052 0.014
All-cause mortality RRR: 6% 13% P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
UKPDS: Legacy Effect of Earlier Glucose UKPDS: Legacy Effect of Earlier Glucose ControlControl
N Eng J Med 2008
Can long-term glycemic control Can long-term glycemic control reduce the risk of cardiovascular reduce the risk of cardiovascular
disease? disease?
Yes
If early and sustained glycemic control started before atherosclerosis is established
At present, The question is not At present, The question is not whetherwhether to intensively treat people with type 2 to intensively treat people with type 2 diabetes at onset of the disease to prevent diabetes at onset of the disease to prevent long-term complications. long-term complications.
The question rather is The question rather is howhow to intensively to intensively treat patients with type 2 diabetes to treat patients with type 2 diabetes to consistently keep A1c < 7% all through consistently keep A1c < 7% all through the course of the diseasethe course of the disease
Glycemic control & A1c TargetGlycemic control & A1c Target
ADAADAAACEAACE
A1c (%)A1c (%)<7<7<6.5<6.5
Preprandial Preprandial (mg/dl)(mg/dl)
80-12080-120<110<110
Postprandial Postprandial (mg/dl)(mg/dl)
140-180140-180<140<140
Bedtime (mg/dl)Bedtime (mg/dl)100-140100-140100-140100-140
ADA: American Diabetes AssociationAACE: American Association of Clinical Endocrinologists
Two-thirds of Type 2 Patients are not Achieving Two-thirds of Type 2 Patients are not Achieving Glycemic ControlGlycemic Control
NHANES = National Health and Nutrition Examination Survey.
1Koro et al. Diabetes Care. 2004;27:17-20; 2 “State of Diabetes in America,” American Association of Clinical Endocrinologists, 2003-2004. Available at: http://www.aace.com/public/awareness/stateofdiabetes/ DiabetesAmericaReport.pdf. Accessed January 6, 2006.
A1c 6.5%
AACE survey 2003-20042
N=157,000 type 2 patients
39 US states included
33%33%33%33%
A1c <7%NHANES1
1988-1994N=1215
1999-2000N=372
44.5%44.5%44.5%44.5% 35.8%35.8%35.8%35.8%
Traditional Type 2 Diabetes Traditional Type 2 Diabetes Management: Management:
A “Treat-to-Fail Approach”A “Treat-to-Fail Approach”H
bA
1c G
oal
Duration of Diabetes
OAD monotherapy
Diet andexercise
OAD combination
OAD up-titration
OAD + multiple daily
insulininjections
OAD + basal insulin
6
7
8
9
10
Published Conceptual ApproachMean HbA1c of patients
OAD=oral antihyperglycemic agent.Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
Conventional stepwise treatment approach
Delays often occur between stepping up Delays often occur between stepping up from monotherapy to combination from monotherapy to combination
therapytherapy
0
5
10
15
20
25
Month
s
Metformin onlyn = 513
14.5 months
Sulfonylurea onlyn = 3394
20.5 months
Length of time between first monotherapy HbA1c > 8.0% and switch/addition in therapy (months)
Brown, JB et al. Diabetes Care 2004; 27:1535–1540.
Brown JB et al. Diabetes Care 2004;27:1535-1540.
0
20
40
60
80
100
%o
f Su
bje
cts
Percentage of subjects advancing when A1C >7% < 8%
Clinical Inertia :Failure to Advance Therapy When Required
Diet
66.6%
Sulfonylurea Metformin
35.3%44.6%
Combination
18.6%
At insulin initiation, the average patient had:• 5 years with A1C > 8%• 10 years with A1C > 7%
Diagnosis
Lifestyle Intervention + Metformin
No Yes
Add Basal Insulin
Add Sulfonylurea
Add DPP-4 inhibitor
Add Glitazone
ADA-EASD-Consensus 2006
Sulphonylureas failed to maintain Sulphonylureas failed to maintain glycemic control glycemic control
0
-1
-2
1
Gliclazide
Tan (n=297)
Glyburide
Hanefeld (n=250)
Chicago (n=230)
GlimpirideGlyburide
Periscope (n=181)
Glibenclamide
ADOPT (n=1441)
1 2 3 4 5 10
Glyburide
UKPDS (n=1573)
HB
A1
c %
Red
ucti
on
Time (years)0
Is
let -
cell
funct
ion %
(of
norm
al by H
OM
A)
HOMA = homeostasis model assessment
Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;UKPDS. Diabetes. 1995;44:1249-1258
Years
0
20
40
60
80
100
10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6
Time of diagnosis
UKPDS: Islet UKPDS: Islet -cell function and the -cell function and the progressive nature of diabetesprogressive nature of diabetes
Pancreatic function =50% of normal
Advantages of insulinAdvantages of insulin
It lowers mean blood glucose in a It lowers mean blood glucose in a predictable dose-dependent mannerpredictable dose-dependent manner
Can be tailored to individual needs Can be tailored to individual needs on a unit-to-unit basison a unit-to-unit basis
It has the longest experience than It has the longest experience than any other drug (90 years)any other drug (90 years)
No contraindications to its useNo contraindications to its use
Insulin is the only drug that directly reduces Insulin is the only drug that directly reduces lipolysis and free fatty acid concentrations lipolysis and free fatty acid concentrations in blood, thus reducing lipotoxicityin blood, thus reducing lipotoxicity
Insulin improves lipoprotein metabolism, Insulin improves lipoprotein metabolism, decreases LDL cholesterol and triglycerides, decreases LDL cholesterol and triglycerides, and increases HDL cholesteroland increases HDL cholesterol
Insulin improves endothelial dysfunctionInsulin improves endothelial dysfunction
Advantages of insulinAdvantages of insulin
thoughts/concerns about thoughts/concerns about starting insulinstarting insulin
Common Fears:Common Fears: NeedlesNeedles HypoglycemiaHypoglycemia Weight gainWeight gain
Common Beliefs:Common Beliefs: Insulin is the last optionInsulin is the last option Insulin causes complicationsInsulin causes complications Insulin is a personal failureInsulin is a personal failure Adverse impact on relationships/lifestyleAdverse impact on relationships/lifestyle
What should I tell people What should I tell people with Type 2 diabetes about with Type 2 diabetes about
insulin?insulin?
‘‘Most people with Type 2 diabetes Most people with Type 2 diabetes eventually need insulin because their eventually need insulin because their
own production of insulin falls off own production of insulin falls off with time and they therefore with time and they therefore
inevitably become insulin deficient’inevitably become insulin deficient’
What should I tell peopleWhat should I tell peoplewith Type 2 diabetes about insulin?with Type 2 diabetes about insulin?
‘‘If you need insulin, it doesn’t mean If you need insulin, it doesn’t mean you failed. Tablets cannot control blood you failed. Tablets cannot control blood
glucose forever, because they don’t glucose forever, because they don’t stop the problem of your own declining stop the problem of your own declining
insulin production getting worse’insulin production getting worse’
Islet Islet -cell dysfunction worsens over -cell dysfunction worsens over time, regardless of therapytime, regardless of therapy
What should I tell the person with What should I tell the person with Type 2 diabetes who needsType 2 diabetes who needs
insulin, but doesn’t want to take it?insulin, but doesn’t want to take it?
‘‘Insulin will not make your diabetes Insulin will not make your diabetes worse. In fact, it will help control your worse. In fact, it will help control your
glucose, so you’ll have fewer glucose, so you’ll have fewer complications and you’ll feel better.’complications and you’ll feel better.’
Strict glycaemic control reduces the Strict glycaemic control reduces the risks of both microvascular and risks of both microvascular and macrovascular complicationsmacrovascular complications
Insulin RegimensInsulin Regimens
1. Basal insulin ( NPH or long-acting 1. Basal insulin ( NPH or long-acting insulin analogue) + OADinsulin analogue) + OAD
2. Total insulin replacement therapy2. Total insulin replacement therapy
- Premixed insulins- Premixed insulins
- Basal-bolus- Basal-bolus
24-hour Plasma Glucose Curve:24-hour Plasma Glucose Curve:Rationale for Adding Basal InsulinRationale for Adding Basal Insulin
Time of Day
400
300
200
100
00600 06001000 1400 1800 2200 0200
Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Glu
cose
(m
g/d
L) Diabetes
Normal
400
300
200
100
00600 06001000 1400 1800 2200 0200
24-hour Plasma Glucose Curve:24-hour Plasma Glucose Curve:Rationale for Adding Basal InsulinRationale for Adding Basal Insulin
Normal
Diabetic
Time of Day
Glu
cose
(m
g/d
L)
Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Starting With Basal Insulin in DM 2 Starting With Basal Insulin in DM 2 – Advantages– Advantages
1 injection with no mixing1 injection with no mixing Insulin pens for increased acceptanceInsulin pens for increased acceptance Slow, safe, simple titrationSlow, safe, simple titration Low dosageLow dosage Effective improvement in glycemic Effective improvement in glycemic
control control Limited weight gainLimited weight gain
Mean A1C Levels During Study
6
7
8
9
0 4 8 12 16 20 24
Mean A
1C
(%
)
Time (weeks)
Insulin glargine
NPH insulin
Target A1C (%)
Insulin Glargine vs. NPH Insulin Added to Oral Therapy
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Mullins P et al. Clin Ther 2007;29:1607−19.
Less Hypoglycemia with Insulin Glargine vs NPH
6 7 8 9 10HbA1c
3500
3000
2500
2000
1500
1000
Hyp
ogly
cem
ia
even
ts p
er 1
00
patie
nt-y
ears
NPH Insulin glargine
200
150
100
50
06 7 8 9 10
HbA1c
Hyp
ogly
cem
ia
even
ts p
er 1
00
patie
nt-y
ears
T1DM
T2DM
p=0.004 between treatments
p=0.021 between treatments
Insulin Glargine vs. NPH InsulinInsulin Glargine vs. NPH InsulinAdded to Oral TherapyAdded to Oral Therapy
Hypoglycemia defined as PG 72 mg/dL, by hour
Glargine
NPH insulin
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
20 22 24 2 4 6 8 10 12 14 16 18
Time of Day (hour)
Even
ts p
er
Pati
ent-
Year
**
**
*
*
Basal insulin
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
*
Symptomatic Hypoglycemia by Time of Day
*P < 0.05 vs. glargine.
Insulin Glargine Trials Showing Effective Reduction in HbA1c
Hb
A1
c (%
)
APOLLO LAPTOP Triple Therapy
LANMET
10
9
8
7
6
5Treat-To-
TargetINITIATE
7.147.156.96
7.146.80
8.71 8.85 8.809.5
8.808.61
6.96
Baseline Study endpoint
Target: FPG 100 mg/dLSubjects )n=364( were randomly assigned to:
Insulin glargine once daily + continued OADs
Premixed human insulin 70/30 BID
Baseline End PointTime (wk)0 24
Treatment Regimen
*Sulfonylurea + metformin*Sulfonylurea + metforminOAD=oral antidiabetic drugOAD=oral antidiabetic drugJanka HU, et al. Janka HU, et al. Diabetes Care.Diabetes Care. 2005;28:254-259. 2005;28:254-259.
Insulin Glargine Plus OADs vs Insulin Glargine Plus OADs vs Twice-daily Premixed 70/30 Human Twice-daily Premixed 70/30 Human
InsulinInsulin
OADs*
Change in A1C from Baseline to Study End Point*
*Intent-to-treat analysis*Intent-to-treat analysis OAD=oral antidiabetic drugOAD=oral antidiabetic drug
Janka HU, et al. Janka HU, et al. Diabetes Care.Diabetes Care. 2005;28:254-259. 2005;28:254-259.
8.85 8.83
7.157.49
5
6
7
8
9
Insulin glargine + OAD Premixed
P=0.0003
A1C
Insulin Glargine Plus OADs vs Insulin Glargine Plus OADs vs Twice-daily Premixed Human Twice-daily Premixed Human
InsulinInsulin
BaselineBaseline
24 week24 week
LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA
Failures
Janka H et al. Diabetes Care 2005;28:254−259.
*Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l])
N=371 insulin-naïve patientsInsulin glargine + OADs vs twice-daily human NPH insulin (70/30)
Follow-up: 24 weeks
Hypogly
caem
ia*
(even
ts/p
ati
ent
year)
0
1
2
3
4
5
p=0.0009
5
6
7
8
9
HbA
1c
(%)
7.5%7.2%
1.3% 1.7%
p=0.0003
Twice-daily premixed insulin
Insulin glargine + OADs
2.6
5.7
ConclusionsConclusions
Due to declining Due to declining -cell function, insulin -cell function, insulin therapy will be necessary for most therapy will be necessary for most patients with Type 2 diabetespatients with Type 2 diabetes
Insulin therapy should be initiated early Insulin therapy should be initiated early when glycemic control exceeds the when glycemic control exceeds the recommended targetsrecommended targets
Insulin effectively lowers HbAInsulin effectively lowers HbA1c1c, thereby , thereby reducing the risks of both micro- and reducing the risks of both micro- and macrovascular complicationsmacrovascular complications
Insulin glargine when used as a basal Insulin glargine when used as a basal insulin has the following advantages:insulin has the following advantages:It effectively lowers fasting and mean It effectively lowers fasting and mean blood glucoseblood glucoseEasily initiated and titratedEasily initiated and titratedLow risk of hypoglycemiaLow risk of hypoglycemia
Conclusions-cont.Conclusions-cont.
Thank YouThank You
Insulin glargine offers long-term efficacy without the need for intensification
Gordon J, et al. Int J Clin Pract. 2010;64(12):1609-18.
Insulin glargine provides superior long term efficacy vs. NPH.
52