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Diabetes mellitus:
An update
D. Hunt
March 2010
Significance of diabetes mellitus
• 5% of the population has diagnosed diabetes
• prevalence increases with age:
20 - 44:
1%
45 - 65:
5%
> 65:
10%
• the true prevalence of diabetes is estimated
to be twice the prevalence of diagnosed
diabetes
Significance of diabetes mellitus
Frequency of diagnosed and undiagnosed diabetes and
IGT, by age (U.S. data - Harris)
40
35
30
% of
population
IGT
Undiagnosed diabetes
Diagnosed diabetes
25
20
15
10
5
0
20-34
35-44
Harris. Diabetes Care 1993;16:642-52.
45-54
55-64
65-74
Eye Disease
Type 1:
Type 2:
25% after 15 years
4% - 12% after 15 years
Diabetes is the leading cause of adult-onset blindness
Kidney Disease
Type 1:
Type 2:
30% after 15 years
20% after 15 years
Diabetes is the leading cause of end-stage renal disease
Foot complications
Loss of foot sensation > foot ulcers and
infections > foot amputations
Amputation rate: 2 - 30/1000 patient-years
Diabetes is the leading cause of non-traumatic amputation
Cardiovascular Disease Risk is
Increased 2 to 4 Times
Framingham study: diabetes and CAD mortality at 20-year follow-up
20
18
16
Annual CAD 14
Deaths per 1,000 12
10
Persons
8
6
4
2
0
Diabetics
Nondiabetics
17.4
17.0
8.5
3.6
Men
Haffner Am J Cardiol 1999;84:11J-4J.
Women
UK Prospective Diabetes Study
Blood glucose control reduces the
risk of diabetic complications,
especially microvascular
complications
UK Prospective Diabetes Study
20-year Interventional Trial from 1977 to 1997:
 5,102 patients with newly-diagnosed DM2
 Median follow-up 10.0 years, range 6 to 20 years
 Results presented in 1998
Microvascular Endpoints
% of patients with an event
30%
renal failure or death, vitreous haemorrhage or photocoagulation
346 of 3867 patients (9%)
Conventional
Intensive
p=0.0099
20%
10%
Risk reduction 25%
(95% CI: 7 % to 40%)
0%
0
3
6
9
12
Years from randomisation
15
Myocardial Infarction
fatal or non fatal myocardial infarction, sudden death
573 of 3867 patients (15%)
% of patients with an event
30%
Conventional
Intensive
p=0.052
20%
10%
Risk reduction 16%
(95% CI: 0 % to 29%)
0%
0
3
6
9
12
Years from randomisation
15
UK Prospective Diabetes Study
20-year Interventional Trial from 1977 to 1997
 5,102 patients with newly-diagnosed DM2
 Median follow-up 10.0 years, range 6 to 20 years
 Results presented in 1998
10-year Post-Trial Monitoring from 1997 to 2007
 Annual follow-up of the survivor cohort
 Clinic-based for first five years
 Questionnaire-based for last five years
Median overall follow-up 17.0 years, range 16 to 30 years
Post-Trial Changes in HbA1c
UKPDS results
presented
Microvascular Disease
(photocoagulation, vitreous haemorrhage, renal failure)
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
Myocardial Infarction
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (SU/Ins) vs. Conventional glucose control
All-cause Mortality
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
Legacy Effect of Earlier Glucose Control
After median 8.5 years post-trial follow-up
Aggregate Endpoint
1997
2007
12%
0.029
9%
0.040
Any diabetes related endpoint
RRR:
P:
Microvascular disease
RRR:
25%
P: 0.0099
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
24%
0.001
RRR = Relative Risk Reduction, P = Log Rank
Legacy Effect of Earlier Metformin Therapy
After median 8.8 years post-trial follow-up
Aggregate Endpoint
1997
2007
Any diabetes related endpoint
RRR: 32%
P: 0.0023
21%
0.013
Microvascular disease
RRR:
P:
29%
0.19
16%
0.31
Myocardial infarction
RRR:
P:
39%
0.010
33%
0.005
All-cause mortality
RRR:
P:
36%
0.011
27%
0.002
RRR = Relative Risk Reduction, P = Log Rank
UKPDS Conclusions
• Despite an early loss of glycemic differences, a
continued reduction in microvascular risk and
emergent risk reductions for MI and death were
observed during 10 years of post-trial follow-up
Pharmacologic Management of
Type 2 Diabetes
• If glycemic targets are not achieved within 2 to 3
months of lifestyle management, pharmacotherapy
should be initiated.
• Timely adjustments should be made to attain target
A1C within 6 to 12 months.
• In patients with marked hyperglycemia (A1C ≥ 9.0%),
pharmacotherapy should be initiated concomitantly
with lifestyle management, and consideration be given
to either combination therapy or insulin.
Management of hyperglycemia in type 2
diabetes
Clinical Assessment
L
Lifestyle intervention (initiation of nutrition therapy and physical activity)
I
A1C <9.0%
A1C >9.0%
Symptomatic with metabolic
decompensation
F
E
S
Initiate metformin
Initiate pharmacotherapy immediately
without waiting for effect from lifestyle
interventions:
T
• Consider initiating metformin concurrently
with another agent from a different class or
Y
• Initiate insulin
L
E
If not at target
Initiate insulin
± metformin
Oral agents beyond metformin
↓
= < 1.0% decrease in A1C
↓ ↓ = 1.0–2.0% decrease in A1C
↓ ↓ ↓ = >2.0% decrease in A1C
Oral agents:
(agents listed in alphabetical order)
Class
Alpha-glucos.
inhibitor
Incretin: DPP-4
inhib.
Insulin
Meglitinides
Sulfonylureas
TZD
A1C
Hypoglyc.
Advantages
Disadvantages
↓
Rare
Improved postprandial
control weight neutral
GI side effects
↓↓↓
Rare
Improved postprandial
control; weight neutral
New agents (unknown long-term
safety)
↓↓↓↓
Yes
No dose ceiling
Weight gain
↓↓↓
Yes
Improved postprandial
control
Newer sulfonylureas
(gliclazide) are
associated with less
hypoglycemia than
glyburide
Requires TID to QID dosing
Durable monotherapy
6-12 weeks for maximal effect
Edema, rare CHF, fractures in females
↓↓
↓↓
Yes
Rare
Weight gain
*less hypoglycemia in the context of
missed meals
If not at target
• Add another drug from a different class; or
• Add bedtime basal insulin to other agent(s); or
• Intensify insulin regimen
Timely adjustment to and/or addition of
antihyperglycemic agents should be made to attain target
A1C within 6 to 12 months
Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada; Canadian Journal of Diabetes: 2008 Vol:32
Supplement
Natural History
of Type 2 Diabetes
Insulin
resistance
Glucose
level
b-cell
dysfunction
Normal
Impaired glucose
tolerance
Henry. Am J Med 1998;105(1A):20S-6S.
Insulin
production
Time
Type 2 diabetes
Natural deterioration of b-cell function
b-cell function
b cell function in type 2
diabetic patients
Years after diagnosis
Insulin
Type
Starts
Peaks
Duration
Lispro
Aspart
Glulisine
Regular
Toronto
5-10 min
0.5-1 hrs
3.5 hrs
30 min
2-4 hrs
6-8 hrs
N/NPH
1-2 hrs
6-10 hrs
16-24 hrs
Detemir
-
6 – 8 hrs
Up to 24 hrs
Glargine
1.5 hrs
None
Up to 24 hrs
Insulin regimens – Type 2 DM
Many different potential regimens!
– Oral + hs insulin (basal)
– Oral + AM insulin (basal)
– Pre-mixed insulin with breakfast and supper
– Short-acting with meals + bedtime basal
Holman RR. NEJM 2009;361:1736-47
Aims
First Phase

One-year head-to-head comparison of the efficacy
of three different types of analogue insulins, when given in
addition to dual oral antidiabetic therapy:

Biphasic insulin

Prandial insulin

Basal insulin
Patient Disposition
235
Assigned to
biphasic insulin
(biphasic aspart)
34
Discontinued
201 (86%)
Completed
three years



239
Assigned to
prandial insulin
(aspart)
234
Assigned to basal
insulin
(detemir)
51
Discontinued
188 (79%)
Completed
three years
45 Discontinued
189 (81%)
Completed
three years
Overall, 18.4% of patients did not complete three years
No difference in proportions between groups (p=0.15)
No difference in baseline characteristics between those who
completed or did not complete three years follow up
Transition to a Complex Insulin Regimen
From one year onwards, if HbA1c levels were >6.5%, sulfonylurea therapy
was stopped and a second type of insulin was added
First Phase
708 T2DM
on dual
oral agents
R
*
Second Phase
Add biphasic insulin*
twice a day
Add prandial insulin
at midday
Add prandial insulin*
three times a day
Add basal insulin
before bed
Add basal insulin*
once (or twice) daily
Add prandial insulin
three times a day
Intensify to a complex insulin regimen in
year one if unacceptable hyperglycaemia
Demographic Characteristics
Biphasic
N=235
68%
Prandial
N=239
64%
Basal
N=234
61%
94%
90%
93%
9 (6-12)
9 (6-14)
9 (6-12)
Taking sulfonylurea
98%
100%
99%
Taking metformin
96%
95%
97%
Age (years)
61.7±8.9
61.6 ±10.5
61.9±10.0
Body mass index (kg/m2)
30.2 ±4.8
29.6 ±4.5
29.7 ±4.6
HbA1c (%)
8.6 ±0.8
8.6 ±0.8
8.4 ±0.8
Male
White Caucasian
*Diabetes duration (yrs)
*interquartile range
No significant differences between groups
Glycaemic targets and Insulin Injections
Fasting and pre-meal: 4.0-5.5 mmol/l (72-99 mg/dl)
Two-hours post meal: 5.0-7.0 mmol/l (90-126 mg/dl)
12
6
Biphasic
Prandial
*
Basal
* Twice a day if required
12
18
24
6
Complex Insulin Regimens
Proportion eligible for a second type of
insulin per protocol
Proportion taking
two types of insulin
Insulin Doses Over 3 Years
Median±95% confidence interval
Biphasic
±prandial
Prandial
±basal
Basal
±prandial
Total Daily Insulin Doses at 3 Years
Median±95% confidence interval
HbA1c Values Over 3 Years
Median±95% confidence interval
Overall
6.9%
(6.8 to 7.1)
Biphasic
±prandial
Prandial
±basal
Basal
±prandial
Primary Outcome: HbA1c at 3 Years
Median±95% confidence interval
Body Weight over 3 Years
Median±95% confidence interval
Biphasic
±prandial
Prandial
±basal
Basal
±prandial
Increase in Body Weight Over 3 Years
Mean±1SD
Hypoglycaemia
Categorised as
 Grade 1
- Symptoms only
with glucose (if measured) ≥3.1 mmol/l (≥56 mg/dl)
 Grade 2
- Symptoms plus glucose <3.1 mmol/l (<56 mg/dl)
 Grade 3
- Third party assistance required
Grade 2 or 3 Hypoglycaemia Over 3 Years
Biphasic
±prandial
Prandial
±basal
Basal
±prandial
Grade 2 or 3 Hypoglycaemia Over 3 Years
All
patients
Patients with
HbA1c ≤6.5%
Overview of Main Results
Biphasic
Fewer hypoglycaemic episodes
Less weight gain
Less increase in waist
circumference
++
+
+
Prandial Basal
+
+
+
+++
++
++
4T trial
 Three quarters of patients added a second insulin
 Those commencing therapy with a basal or prandial
insulin more often achieved glycaemic targets than
patients commencing with a biphasic insulin
 Patients commencing therapy with basal insulin had
fewer hypoglycaemic episodes and less weight gain
These findings provide clear evidence in people with
type 2 diabetes to support starting insulin therapy
with a once a day basal insulin, and then adding
a mealtime insulin if glycaemic targets are not met
Beyond Glycemic Control
Blood pressure control
Lipid therapy
Microvascular complication screening and
management
UK Prospective Diabetes Study
Blood Pressure
Control Study
Randomisation
1148 hypertensive patients
on antihypertensive therapy
n = 421
not on antihypertensive therapy
n = 727
randomisation
less tight blood pressure control
aim : BP < 180/105 mmHg
avoid ACE inhibitor : Beta blocker
n = 390
34%
tight blood pressure control
aim : BP < 150 / 85 mmHg
ACE inhibitor
n = 400
35%
Beta blocker
n = 358
31%
Blood Pressure : Tight vs Less Tight Control
cohort, median values
180 Less tight control Tight control
mmHg
160
140
100
80
60
0
2
4
6
Years from randomisation
8
Any diabetes-related endpoints
% of patients with events
50%
Less tight blood pressure control (390)
Tight blood pressure control (758)
40%
30%
20%
10%
risk reduction
24% p=0.0046
0%
0
3
6
Years from randomisation
9
Diabetes-related deaths
20%
Less tight blood pressure control (390)
% of patients with events
Tight blood pressure control (758)
15%
10%
5%
risk reduction
32% p=0.019
0%
0
3
6
Years from randomisation
9
Blood Pressure Control Study
Any DM-related endpoint
Diabetes-related deaths
Stroke
Microvascular disease
24%
32%
44%
37%
p=0.0046
p=0.019
p=0.013
p=0.0092
Heart failure
Retinopathy progression
Deterioration of vision
56%
34%
47%
p=0.0043
p=0.0038
p=0.0036
ACCORD
Blood Pressure
Study
ACCORD Study Group. NEJM 2010
ACCORD BP Trial
 4,733 patients with DM2; high CVS risk
 SBP 130 – 180
 Randomized to target SBP <140 v. <120
 Primary outcome: nonfatal MI, nonfatal CVA; CVS death
 Follow-up: 4.7 years; 95% complete
ACCORD Study Group. NEJM 2010
Baseline Characteristics
<120
<140
2362
2371
62
62
% females
48%
48%
Hx CVS event
34%
33%
SBP
139.0
139.4
9
10
8.4
8.3
N
Age
Duration DM
GHb (%)
ACCORD BP Trial
 Achieved SBP: 119 v. 133
 Antihypertensive medications: 3.4 v. 2.3
ACCORD Study Group. NEJM 2010
ACCORD BP Trial
 Achieved SBP: 119 v. 133
 Antihypertensive medications: 3.4 v. 2.3
 Primary outcome:
Nonfatal MI, nonfatal CVA, CVS death (%/year):
1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)
ACCORD Study Group. NEJM 2010
ACCORD BP Trial: Outcomes
 Nonfatal MI, nonfatal CVA, CVS death (%/year):
1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)
 Total mortality: 1.3% v. 1.2%, p=0.55
 CVS death: 0.5% v. 0.5%
 Stroke: 0.3% v. 0.5%, p=0.01
ACCORD Study Group. NEJM 2010
ACCORD BP Trial: Conclusion
 Targeting a SBP < 120, as compared to a SBP <
140, does not improve CVS outcomes in patients
with DM2 at high risk of CVS events
ACCORD Study Group. NEJM 2010
ACCORD
Lipid Therapy
Study
ACCORD Study Group. NEJM 2010
ACCORD Lipid Trial
 5,518 patients with DM2; high CVS risk
 LDL 1.5 – 4.6; HDL < 1.4; TG < 8.5
 All patients received open label simvastatin
 Randomized to fenofibrate (160 mg) v. placebo
 Primary outcome: nonfatal MI, nonfatal CVA; CVS death
 Follow-up: 4.7 years
ACCORD Study Group. NEJM 2010
Baseline Characteristics
Fenofibrate
Placebo
2765
2753
62
62
% females
31%
31%
Hx CVS event
36%
37%
LDL
2.6
2.6
HDL
1.0
1.0
TG
2.1
2.1
N
Age
ACCORD Lipid Trial
 Achieved LDL: 2.1 v. 2.1
 Achieved HDL: 1.1 v. 1.0
 Achieved TG: 1.7 v. 1.9
ACCORD Study Group. NEJM 2010
ACCORD Lipid Trial
 Achieved LDL: 2.1 v. 2.1
 Achieved HDL: 1.1 v. 1.0
 Achieved TG: 1.7 v. 1.9
 Primary outcome:
Nonfatal MI, nonfatal CVA, CVS death (%/year):
2.2% v. 2.4%; HR 0.92 (0.79 – 1.08, p=0.32)
• Total mortality: 1.5% v. 1.6%, p=0.33
ACCORD Study Group. NEJM 2010
ACCORD Lipid Trial: Outcomes
Pre-specified subgroups:
 Sex:
Men: 11.2% v. 13.3%
Women: 9.1% v. 6.6%, p=.01
 Dyslipidemia (HDL<0.9, TG > 2.3):
Dyslipidemia patients: 12.4% v. 17.3%
Non-dyslipidemic patients: 10.1% v. 10.1%, p=.057
ACCORD Study Group. NEJM 2010
ACCORD Lipid Trial: Conclusions
 Routine fenofibrate therapy, in addition to
simvastatin, does not improve CVS outcomes in
patients with DM2 at high risk of CVS events
 Addition of fenofibrate to simvastatin may benefit
patients with significant dyslipidemia
ACCORD Study Group. NEJM 2010
Conclusions
• Glycemic control
• BP control
• Lipid management