Importance of early glycemic control
in management of type 2 diabetes
Prof. Khalifa M. Abdallah
Professor of Internal Medicine
Unit of Diabetes & Metabolic Diseases
Alexandria Faculty of Medicine
Overview




The importance of early and sustained
glycemic control
The rationale for early insulinization
Advantages of basal insulin therapy
Take home message
Diabetes Mellitus
A Constellation of Complications
Erectile
Dysfunction
Renal
Disease
Peripheral
Vascular
Disease
Diabetes
Gastropathy
Dyslipidemia
Cardiovascular
Disease
Peripheral
Neuropathy
Retinopathy/
Macular Edema
Autonomic
Neuropathy
Hypertension
- A1c & Microvascular Complications
60 – 70 % Reduction of Complications
Retinopathy
15
Nephropathy
Relative Risk
13
11
9
Neuropathy
7
5
Microalbuminuria
3
1
6
7
8
9
10
HbA1c (%)
Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.
11
12
Risk Reduction in DCCT
Effects of reduction of A1c by 1.9% in intensively treated
group
80
Onset
Risk Reduction
76%
Progression
60
54%
60%
54%
40
39%
20
P=0.002
P=0.002
P=0.002
P=0.04
P=0.04
Neuropathy
Albuminuria
albuminuria
0
Retinopathy
DCCT Research Group. N Engl J Med. 1993;329:977-986.
A1c : Myocardial Infarction and Microvascular
Complication
80
Microvascular
disease
Incidence per
1000 patient-years
60
Myocardial infarction
40
20
0
0 5
UKPDS 35. BMJ 2000; 321: 405-12.
6
7
8
9
10
11
Mean HbA1c (%)
UKPDS: Glucose Control Study Summary
The intensive glucose control policy maintained a lower HbA1c by
a mean of 0.9% over a median follow up of 10 years from
diagnosis of type 2 diabetes with reduction in risk of:
12% for any diabetes related endpoints
25% for microvascular endpoints
16% for myocardial infarction
p=0.029
p=0.0099
p=0.052
UKPDS: Glucose Control Study Summary
The intensive glucose control policy maintained a lower HbA1c by
a mean of 0.9% over a median follow up of 10 years from
diagnosis of type 2 diabetes with reduction in risk of:
12% for any diabetes related endpoints
25% for microvascular endpoints
16% for myocardial infarction
p=0.029
p=0.0099
p=0.052
Causes of Death in People With Diabetes
50
65%
40
40
of Diabetic Patients Deaths
are from CV Causes
30
20
10
0
15
13
13
10
4
5
Can long-term glycemic control reduce
the risk of cardiovascular disease?
Summary of ACCORD, ADVANCE and VADT
ACCORD
ADVANCE
VADT
10,251
11,140
1791
Participant age ,years
62
66
60
HbA1C at Baseline, %
8.1
7.5
9.4
Significant Effect on
Macrovascular
Outcomes?
No
No
No
Significant Effect on
Microvascular
Outcomes?
NA
Significant for
nephropathy, not
retinopathy
No
90% vs. 58%
17% vs. 11%
85% vs.
78%
3.4
5.0
6
No. of participants
Rosiglitazone use,
(intensive vs. standard)
Duration of follow-up,
years
ACCORD ADVANCE and VADT- No Significant Effect
on Macro or Micro Vascular Outcomes
ACCORD
ADVANCE
VADT
No. of participants
10,251
11,140
1791
Participant age ,years
62
66
60
Duration of diabetes at
study entry, years
10
8
11.5
HbA1C at Baseline, %
8.1
7.5
9.4
Participants with prior
cardiovascular event, %
35
32
40
Duration of follow-up,
years
3.4
5.0
6
DCCT / EDIC: majority of patients receive
intensive therapy and HbA1C levels converge
11
Intensive
Conventional
Conventional group
encouraged to switch
to intensive
treatment
HbA1 c (%)
10
9
8
7
6
0
1 2 3 4 5 6 7 8 9 DCCT 1
DCCT
end
Year
2
3
4
EDIC
DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653
5
6
7
DCCT / EDIC – incidence of all
predefined cardiovascular outcome

Patients previously receiving intensive treatment in the
DCCT study had a 57% reduced incidence of nonfatal
myocardial infarction, stroke or death from
cardiovascular disease
DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653
UKPDS: Post-Trial Changes in HbA1c
UKPDS results
presented
UKPDS 80. N Eng J Med 2008; 359
Mean (95%CI)
UKPDS: Legacy Effect of Earlier Glucose Control
After median 8.5 years post-trial follow-up
Aggregate Endpoint
1997
2007
Any diabetes related endpoint
RRR: 12%
P: 0.029
9%
0.040
Microvascular disease
RRR:
25%
P: 0.0099
24%
0.001
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
N Eng J Med 2008
RRR = Relative Risk Reduction, P = Log Rank
Can long-term glycemic control reduce
the risk of cardiovascular disease?
Yes
If early and sustained glycemic control started
before atherosclerosis is established
At present, The question is not whether
to intensively treat people with type 2
diabetes at onset of the disease to prevent
long-term complications.
The question rather is how to intensively
treat patients with type 2 diabetes to
consistently keep A1c < 7% all through
the course of the disease
Glycemic control & A1c Target
ADA
AACE
<7
<6.5
Preprandial (mg/dl)
80-120
<110
Postprandial (mg/dl)
140-180
<140
Bedtime (mg/dl)
100-140
100-140
A1c (%)
ADA: American Diabetes Association
AACE: American Association of Clinical Endocrinologists
Two-thirds of Type 2 Patients are not Achieving
Glycemic Control
NHANES1
44.5%
35.8%
1988-1994
N=1215
AACE survey
2003-20042
A1c <7%
1999-2000
N=372
33%
A1c 6.5%
N=157,000 type 2 patients
39 US states included
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.
Traditional Type 2 Diabetes Management:
A “Treat-to-Fail Approach”
Mean HbA1c
of patients
Published Conceptual Approach
OAD +
Diet and
exercise
OAD
monotherapy
OAD
up-titration
OAD
combination
OAD +
basal insulin
multiple daily
insulin
injections
HbA1c Goal
10
9
8
7
6
Duration of Diabetes
Conventional stepwise treatment approach
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.
Delays often occur between stepping up from
monotherapy to combination therapy
Months
Length of time between first monotherapy HbA1c > 8.0% and
switch/addition in therapy (months)
25
20.5 months
20
15
14.5 months
10
5
0
Metformin only
n = 513
Sulfonylurea only
n = 3394
Brown, JB et al. Diabetes Care 2004; 27:1535–1540.
Clinical Inertia:
Failure to Advance Therapy When Required
Percentage of subjects advancing when A1C >7% < 8%
100
% of Subjects
80
At insulin initiation, the average patient had:
5 years with A1C > 8%•
10 years with A1C > 7%•
66.6%
60
44.6%
35.3%
40
18.6%
20
0
Diet
Sulfonylurea
Brown JB et al. Diabetes Care 2004;27:1535-1540.
Metformin
Combination
Diagnosis
Lifestyle Intervention + Metformin
No
Add
Basal Insulin
HbA1c ≥7%
Add
Sulfonylurea
Yes
Add
Glitazone
ADA-EASD-Consensus 2006
Add
DPP-4 inhibitor
Sulphonylureas failed to maintain glycemic
control
Glyburide
HBA1c % Reduction
1
Glimpiride
Glyburide
0
Glibenclamide
Gliclazide
Glyburide
Hanefeld (n=250)
-1
Tan (n=297)
Chicago (n=230)
Periscope (n=181)
-2
ADOPT (n=1441)
UKPDS (n=1573)
0
1
2
3
4
Time (years)
5
10
UKPDS: Islet -cell function and the
progressive nature of diabetes
Time of diagnosis
Islet -cell function
(% of normal by HOMA)
100
80
60
40
Pancreatic function
= 50% of normal
20
0
10 9 8 7 6 5 4 3 2 1 0
1
2
3
4
5
6
Years
HOMA = homeostasis model assessment
Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;
UKPDS. Diabetes. 1995;44:1249-1258
Advantages of insulin




It lowers mean blood glucose in a
predictable dose-dependent manner
Can be tailored to individual needs on a
unit-to-unit basis
It has the longest experience than any
other drug (90 years)
No contraindications to its use
Advantages of insulin



Insulin is the only drug that directly reduces
lipolysis and free fatty acid concentrations in
blood, thus reducing lipotoxicity
Insulin improves lipoprotein metabolism,
decreases LDL cholesterol and triglycerides,
and increases HDL cholesterol
Insulin improves endothelial dysfunction
thoughts/concerns about
starting insulin

Common Fears:




Needles
Hypoglycemia
Weight gain
Common Beliefs:




Insulin is the last option
Insulin causes complications
Insulin is a personal failure
Adverse impact on relationships/lifestyle
What should I tell people with
Type 2 diabetes about insulin?
‘Most people with Type 2 diabetes
eventually need insulin because their own
production of insulin falls off with time and
they therefore inevitably become insulin
deficient’
What should I tell people
with Type 2 diabetes about insulin?
‘If you need insulin, it doesn’t mean you
failed. Tablets cannot control blood
glucose forever, because they don’t stop
the problem of your own declining insulin
production getting worse’

Islet -cell dysfunction worsens over time,
regardless of therapy
What should I tell the person with Type 2
diabetes who needs
insulin, but doesn’t want to take it?
‘Insulin will not make your diabetes worse.
In fact, it will help control your glucose, so
you’ll have fewer complications and you’ll
feel better.’

Strict glycaemic control reduces the risks
of both microvascular and macrovascular
complications
Insulin Regimens


1. Basal insulin ( NPH or long-acting
insulin analogue) + OAD
2. Total insulin replacement therapy
- Premixed insulins
- Basal-bolus
24-hour Plasma Glucose Curve:
Rationale for Adding Basal Insulin
Glucose (mg/dL)
400
Diabetes
300
200
Normal
100
0
0600
1000
1400
1800
2200
Time of Day
Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
0200
0600
24-hour Plasma Glucose Curve:
Rationale for Adding Basal Insulin
Glucose (mg/dL)
400
300
200
Diabetic
100
Normal
0
0600
1000
1400
1800
Time of Day
Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
2200
0200
0600
Starting With Basal Insulin in DM 2 –
Advantages

1 injection with no mixing

Insulin pens for increased acceptance

Slow, safe, simple titration

Low dosage

Effective improvement in glycemic control

Limited weight gain
Insulin Glargine vs. NPH Insulin Added
to Oral Therapy
Mean A1C Levels During Study
9
Mean A1C (%)
Insulin glargine
NPH insulin
8
7
Target A1C (%)
6
0
4
8
12
16
Time (weeks)
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
20
24
Less Hypoglycemia with Insulin
Glargine vs NPH
Hypoglycemia
events per 100
patient-years
3500
NPH
Insulin glargine
3000
T1DM
2500
p=0.004 between
treatments
2000
1500
1000
6
7
9
10
HbA1c
200
Hypoglycemia
events per 100
patient-years
8
150
T2DM
p=0.021 between
treatments
100
50
0
6
7
Mullins P et al. Clin Ther 2007;29:1607−19.
8
HbA1c
9
10
Insulin Glargine vs. NPH Insulin
Added to Oral Therapy
Events per Patient-Year
Symptomatic Hypoglycemia by Time of Day
Glargine
Basal
insulin
1.4
1.2
**
*
1.0
*
0.8
NPH insulin
*
*
*
0.6
0.4
0.2
0
20
22
24
2
4
6
8
10
12
14
16
18
Time of Day (hour)
Hypoglycemia defined as PG  72 mg/dL, by hour
*P < 0.05 vs. glargine.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Insulin Glargine Trials Showing Effective
Reduction in HbA1c
10
9.5
HbA1c (%)
9
8.85
8.71
8.61
8.80
8.80
8
7
6.96
7.14
6.96
7.15
7.14
6.80
6
5
Treat-ToTarget
LANMET
APOLLO
LAPTOP
Baseline Study endpoint
Triple
Therapy
INITIATE
Insulin Glargine Plus OADs vs
Twice-daily Premixed 70/30 Human Insulin
Treatment Regimen
Target: FPG 100 mg/dL
Subjects (n=364) were randomly assigned to:
Insulin glargine once daily + continued OADs
OADs*
Premixed human insulin 70/30 BID
0
Baseline
Time (wk)
*Sulfonylurea + metformin
OAD=oral antidiabetic drug
Janka HU, et al. Diabetes Care. 2005;28:254-259.
24
End Point
Insulin Glargine Plus OADs vs
Twice-daily Premixed Human Insulin
Change in A1C from Baseline to Study End Point*
Baseline
P=0.0003
9
24 week
8.85
8.83
8
A1C
7.49
7
7.15
6
5
Insulin glargine + OAD
*Intent-to-treat analysis
OAD=oral antidiabetic drug
Janka HU, et al. Diabetes Care. 2005;28:254-259.
Premixed
LAPTOP: Insulin Glargine Versus
70/30 Premixed Insulin in OHA
Failures
Twice-daily premixed
insulin
Insulin glargine + OADs
p=0.0003
9
1.3%
1.7%
HbA1c (%)
8
7
6
5
7.5%
7.2%
Hypoglycaemia* (events/patient year)
N=371 insulin-naïve patients
Insulin glargine + OADs vs twice-daily
human NPH insulin (70/30)
Follow-up: 24 weeks
5
5.7
4
3
2
p=0.0009
2.6
1
0
*Confirmed symptomatic hypoglycaemia
(blood glucose <60 mg/dl [<3.3 mmol/l])
Janka H et al. Diabetes Care 2005;28:254−259.
Conclusions



Due to declining -cell function, insulin therapy
will be necessary for most patients with Type 2
diabetes
Insulin therapy should be initiated early when
glycemic control exceeds the recommended
targets
Insulin effectively lowers HbA1c, thereby
reducing the risks of both micro- and
macrovascular complications
Conclusions-cont.
Insulin glargine when used as a basal insulin
has the following advantages:
 It effectively lowers fasting and mean
blood glucose
 Easily initiated and titrated
 Low risk of hypoglycemia
Thank You
Insulin glargine offers long-term efficacy without the
need for intensification
Insulin glargine provides superior long term efficacy vs. NPH.
Gordon J, et al. Int J Clin Pract. 2010;64(12):1609-18.
52