Issues in Diabetes Care
Academic Half-day
February 2002
D. Hunt
Outline
1. Significance of diabetes mellitus
2. Glycemic control: - evidence
- oral agents
- insulin
3. Blood pressure control
4. Nephropathy and microalbuminuria
5. Cases
Significance of diabetes mellitus
• 5% of the population has diagnosed diabetes
• 10% Type 1; 90% Type 2
• prevalence increases with age:
20 - 44:
45 - 65:
> 65:
1%
5%
10%
• the true prevalence of diabetes is estimated to be
twice the prevalence of diagnosed diabetes
1.5 Million Canadians Have 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
Proliferative retinopathy
Type 1:
Type 2:
25% after 15 years
4% - 12% after 15 years
Blindness: 10% - 15% of patients with proliferative
retinopathy have severe visual loss within 2 years
Diabetes is the leading cause of adult-onset blindness
Nephropathy
Type 1:
Type 2:
30% after 15 years
20% after 15 years
Follow-up from the Multiple Risk Factor Intervention
Trial:
RR for end-stage renal disease: 9.0 (7.4 - 11.0)
Diabetes is the leading cause of end-stage renal disease
Neuropathy
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
14
Annual CAD
12
Deaths per 1,000
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
Macrovascular disease
Multiple Risk Factor Intervention Trial:
Follow-up of 350,000 screened patients
RR for cardiovascular death: 3.0
Swedish cohort study:
Baseline age: 51 - 59 Follow-up: 16 years
RR for cardiovascular death: 2.9 (2.3 - 5.6)
Glycemic control - Type 1 diabetes
The Diabetes Control and Complications Trial:
– 1441 patients with Type 1 diabetes
– intensive insulin therapy vs conventional therapy
– follow-up 6.5 years
Early retinopathy:
Microalbuminuria:
Neuropathy:
24% vs 7%
20% vs 13%
10% vs 3%
Glycemic control
Can these results be applied to people with Type 2
diabetes?
Potential benefits: Decreased microvascular disease
Potential adverse effects: Increased cardiovascular
mortality with oral hypoglycemic agents and insulin
UK Prospective Diabetes Study
Does an intensive glucose
control policy reduce the risk
of complications for people
with Type 2 diabetes?
Randomisation of Treatment Policies
Main Randomisation
n=4209 (82%)
342 allocated to
metformin
3867
Conventional Policy
30% (n=1138)
Intensive Policy
70% (n=2729)
Sulphonylurea
n=1573
Insulin
n=1156
Treatment Policies in 3867 patients
Conventional Policy
n = 1138
• initially with diet alone
• aim for
near normal weight
best fasting plasma glucose < 15 mmol/L
asymptomatic
• when marked hyperglycaemia develops
allocate to non-intensive pharmacological therapy
Treatment Policies in 3867 patients
Intensive Policy with sulphonylurea or insulin
n = 2729
• aim for
fasting plasma glucose < 6 mmol/L
asymptomatic
• when marked hyperglycaemia develops
on sulphonylurea
add metformin
move to insulin therapy
on insulin, transfer to complex regimens
Actual Therapy
Intensive Policy
aim for < 6 mmol/L
Conventional Policy
accept < 15 mmol/L
100
proportion of patients
diet alone
additional non-intensive
pharmacological therapy
80
60
intensive
pharmacological
therapy
40
diet alone
20
0
1
2
3
4
5
6
7
8
9
10 11 12
1
2
3
4
5
Years from randomisation
6
7
8
9
10 11 12
HbA1c
cross-sectional, median values
9
HbA1c (%)
Conventional
8
Intensive
7
6.2% upper limit of normal range
6
0
0
3
6
9
12
Years from randomisation
15
Any Diabetes Related Endpoint
1401 of 3867 patients (36%)
First occurrence of any one of:
• diabetes related death
• non fatal myocardial infarction, heart failure or angina
• non fatal stroke
• amputation
• renal failure
• retinal photocoagulation or vitreous haemorrhage
• cataract extraction or blind in one eye
Any Diabetes Related Endpoint (cumulative )
1401 of 3867 patients (36%)
% of patients with an event
60%
Conventional (1138)
Intensive (2729)
p=0.029
40%
20%
Risk reduction 12%
(95% CI: 1% to 21%)
0%
0
3
6
9
12
Years from randomisation
15
Diabetes Related Deaths
414 of 3867 patients (11%)
Any of:
• fatal myocardial infarction or sudden death
• fatal stroke
• death from peripheral vascular disease
• death from renal disease
• death from hyper/hypoglycaemia
Diabetes Related Deaths (cumulative)
414 of 3867 patients (11%)
% of patients with an event
30%
Conventional (1138)
Intensive (2729)
p=0.34
20%
10%
0%
0
3
6
9
12
Years from randomisation
15
Microvascular Endpoints (cumulative)
% 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 (cumulative)
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
Aggregate Clinical Endpoints
RR
p
0.5
Relative Risk
& 95% CI
1
2
Any diabetes related endpoint 0.88 0.029
Diabetes related deaths
0.90 0.34
All cause mortality
0.94 0.44
Myocardial infarction
0.84 0.052
Stroke
1.11 0.52
Microvascular
0.75 0.0099
Favours Favours
intensive conventional
Progression of Retinopathy
Two step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale
RR
p
0 - 3 years
1.03 0.78
0 - 6 years
0.83 0.017
0 - 9 years
0 - 12 years
0.83 0.012
0.79 0.015
0.5
Relative Risk
& 99% CI
1
2
Favours Favours
intensive conventional
Microalbuminuria
Urine albumin >50 mg/L
RR
p
Baseline
Three years
0.89
0.83
0.24
0.043
Six years
Nine years
Twelve years
Fifteen years
0.88
0.76
0.67
0.70
0.13
0.00062
0.000054
0.033
0.5
Relative Risk
& 99% CI
1
2
<
Favours Favours
intensive conventional
Glycemic control - UKPDS
Intensive blood glucose control reduces
the risk of diabetic complications, the
greatest effect being on microvascular
complications
UK Prospective Diabetes Study
Does metformin in overweight
diabetic patients have any
advantages or disadvantages?
Randomisation
Main Randomisation
4209
Overweight
1704
Conventional Policy
411
Non overweight
2505
Intensive Policy
1293
Insulin or Sulphonylurea
951
Metformin
342
overweight
patients
Proportion of patients with events
Any diabetes related endpoint
0.6
Conventional (411)
Intensive (951)
Metformin (342)
0.4 M v C
p=0.0023
0.2
MvI
p=0.0034
0.0
0
3
6
9
12
Years from randomisation
15
overweight
patients
Proportion of patients with events
Diabetes related deaths
0.4
Conventional (411)
Intensive (951)
Metformin (342)
0.3
Mv C
p=0.017
0.2
0.1
MvI
p=0.11
0.0
0
3
6
9
12
Years from randomisation
15
overweight
patients
Proportion of patients with events
Myocardial Infarction
0.4
Conventional (411)
Intensive (951)
Metformin (342)
0.3
MvC
p=0.010
0.2
0.1
MvI
p=0.12
0.0
0
3
6
9
12
Years from randomisation
15
overweight
patients
Proportion of patients with events
Microvascular endpoints
0.3
Conventional (411)
Intensive (951)
Metformin (342)
0.2 M v C
p=0.19
0.1
MvI
p=0.39
0.0
0
3
6
9
12
Years from randomisation
15
Metformin Comparisons
overweight patients
RR
Any diabetes related endpoint
Metformin
p
0.2
RR (95% CI)
1
0.68 0.0023
Diabetes Related deaths
Metformin
0.58
0.017
All cause mortality
Metformin
0.64
0.011
Myocardial infarction
Metformin
0.61
0.01
favours
metformin
favours
conventional
5
Metformin in Overweight Patients
• compared with conventional policy
32% risk reduction in diabetes-related endpoints
42% risk reduction in diabetes-related deaths
36% risk reduction in all cause mortality
39% risk reduction in myocardial infarction
p=0.0023
p=0.017
p=0.011
p=0.01
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
Oral Antihyperglycemic Agents:
Biguanides (metformin)
LIVER
• Decreases hepatic glucose production
• Enhances peripheral glucose uptake
• Increased insulin sensitivity in the periphery
• HbA1c: 7.1% vs. 8.6% (US Metformin Study)
7.4% vs. 8.0% (UKPDS)
• Not associated with hypoglycemia
• May promote weight loss
Meltzer et al CMAJ 1998;159(Suppl):S1-29.
MUSCLE
Oral Antihyperglycemic Agents:
Biguanides (metformin)
LIVER
MUSCLE
• May cause GI side effects
– Introduce slowly!
• Contraindicated in renal/hepatic insufficiency
• Lactic acidosis (0.03 cases/1000 patient years)
• Dose 250 – 500 mg BID/TID, to max of 2500 mg/d
Meltzer et al CMAJ 1998;159(Suppl):S1-29.
Oral Antihyperglycemic Agents:
Thiazolidinediones (TZDs)
LIVER
• New class of oral agents
• Designed to increase insulin sensitivity
• Pioglitazone, rosiglitazone
Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.
ADIPOSE
TISSUE
MUSCLE
Oral Antihyperglycemic Agents:
Thiazolidinediones (TZDs)
Mechanism:
• Activate the peroxisome proliferator-activated receptor gamma
(PPARγ) nuclear receptor
• Expressed in adipose tissue, large colon, hematopoietic cells
• Involved in efficient energy storage and adipogenesis
• Activation of the gene in adipose tissue leads to:
– Apoptosis of larger fully differentiated adipocytes (insulin resistant)
– Differentiation of pre-adipocytes into small metabolically active
adipose cells
Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.
Oral Antihyperglycemic Agents:
Thiazolidinediones (TZDs)
Net effect:
• Increased insulin sensitivity
• Increased insulin-dependent glucose uptake
• Improved glycemic profile
• Reduction in triglyceride levels
– Increased LPL activity
Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.
Oral Antihyperglycemic Agents:
Thiazolidinediones (TZDs)
Effect on glycemic control when combined with other
oral agents:
Pioglitazone:
HbA1c:
FBG:
Rosiglitazone: HbA1c:
FBG:
0.8% - 1.3%
2.1 – 3.2 mmol/L
1.0% – 1.2%
2.4 – 2.9 mmol/L
Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.
Oral Antihyperglycemic Agents:
Thiazolidinediones (TZDs)
Effect on lipid control when combined with other oral
agents:
Pioglitazone:
Triglycerides:
HDL:
decrease 20%
increase 10%
Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.
Thiazolidinediones
Side effects:
- Edema/fluid retention - 4%
- Congestive heart failure
- Weight gain – 4.5 kg
- Ovulation – polycystic ovarian syndrome
Contraindications:
- Elevated liver function tests (>2.5 x upper limit of normal)
- Class 2,3,4 heart failure
- Edema
Monitoring: Liver function tests every 2 months for 1 year
Thiazolidinediones:
Clinical aspects
• Dosing:
– Pioglitazone: 15-45 mg daily
– Rosiglitazone: 2-4 mg bid or 4-8 mg qd
• Half-life:
– Pioglitazone: 16-24 h
– Rosiglitazone: 3-4 h
• Initial effect: 2-4 weeks
• Full effect: 8-12 weeks
Sites of Action of Currently Available
Therapeutic Options
LIVER
ADIPOSE
TISSUE
GLUCOSE PRODUCTION
Biguanides
Thiazolidinediones
INTESTINE
MUSCLE
PANCREAS
INSULIN SECRETION
Sulfonylureas
Meglitinides
GLUCOSE
ABSORPTION
Alpha-glucosidase inhibitors
Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5.
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
(Biguanides)
Oral Antihyperglycemic Agents:
Sulfonylureas
• Stimulate pancreatic
insulin release
–
–
–
–
–
PANCREAS
First-generation: tolbutamide, chlorpropamide
Second-generation: Glyburide, gliclazide
HbA1c:
1 – 2%
Weight gain: 2 – 3 kg
Risk of severe hypoglycemia: 1 – 1.5%/year
Meltzer et al CMAJ 1998;159(Suppl):S1-29.
Oral Antihyperglycemic Agents:
Meglitinides
• Stimulate pancreatic
insulin release
–
–
–
–
–
PANCREAS
Repaglinide
Rapid onset and short duration of action
Lowers fasting and postprandial glucose levels
HbA1c: 1.5%
May cause hypoglycemia
Balfour, Faulds Drugs Aging 1998;13:173-80.
Oral Antihyperglycemic Agents:
Alpha-glucosidase inhibitors
• Slows gut absorption
of starch and sucrose
INTESTINE
– Acarbose
– Attenuates postprandial increases in blood glucose
levels
– GI side effects
– Not associated with hypoglycemia or weight gain
Salvatore, Giugliano Clin Pharmacokinet 1996;30:94-106.
Stepwise approach to type 2 diabetes
Nonpharmacologic therapy
Oral agent monotherapy
Oral agent combination therapy
Bedtime insulin and oral agents
Insulin 2–4 times/day
Goals of insulin therapy
• Achieve optimal glycemic control
• Minimize adverse effects:
– Weight gain
– Hypoglycemia
– Inconvenience
Insulin action
Regular
NPH
Onset
(min)
Peak
(hrs)
Duration
(hrs)
15-60
2.5-3.0
2-4
5-7
5-8
13-16
Regular – with meals
NPH - basal
Limitations of Regular Human Insulin
• Slow onset of activity:
– Should be given 30 to 45 minutes before meals
– Inconvenient for patients - less flexibility
• Insulin not peaking during peak absorption of food:
– Inadequate post-prandial control
• Long duration of activity:
– Lasts up to 8 hours
– Potential for late post-prandial hypoglycemia
– Need for additional snacks
Insulin action
Lispro
Regular
NPH
Onset
(min)
Peak
(hrs)
Duration
(hrs)
10-15
15-60
2.5-3.0
1-1.5
2-4
5-7
4-5
5-8
13-16
Objectives for the Development of Short-Acting Insulin
Analogues
Humalog s.c.
Insulin (mg/mL)
360
60
Pancreatic insulin OGT
300
50
240
40
Regular insulin
(–5 min.)
180
120
20
Regular insulin
(–30 min.)
60
30
10
0
0
0
60
120
240
180
Time (minutes)
300
360
Graph adapted from Pampanelli S et al. Diabetes Care, 1995: 18;11:1452-1459.
420
Post-prandial Glucose Control in 772 Patients
with Type 2 Diabetes Mellitus
2 hour post prandial glucose rise (mmol/L)
Anderson JH et al. Arch Int Med 1997;157:1249-55
4
3
regular-lispro
lispro-regular
2
1
0
0
1
2
3
4
5
6
months
2 hour pc blood glucose was significantly reduced with lispro
Hypoglycemia in 772 Patients
with Type 2 Diabetes Mellitus
Anderson JH et al. Arch Int Med 1997;157:1249-55
• hypoglycemia reduced by 7.3% with lispro insulin
( 3.43 to 3.18 episodes/30 days/pt, p<0.02)
• severe hypoglycemia was rare
• overnight hypoglycemia reduced by 36% with
lispro insulin (0.73 to 0.47 episodes/30 days/pt,
p<.001)
Lispro Insulin in Type 1 Diabetes
• Systematic review – 8 trials
• Lispro insulin vs. regular insulin
• 2576 patients with type 1 diabetes mellitus
• Follow-up: 4 – 12 months
• Severe hypoglycemia: 3.1% vs. 4.4%, p=0.024
Brunelle RL Diabetes Care 1998;21:1726-31.
Lispro
– Allows patients to inject at time of meal
– Significantly reduces post-prandial blood glucose levels
– Reduces the incidence of hypoglycemia
– Can improve the HbA1c
– Offers improved flexibility and convenience
Pre-mixed Insulin
– Convenient
– Less injections per day
– Adjustments in basal and meal time insulin more
difficult
– Preparations:
• 30/70 – 30% regular insulin/70% NPH insulin
• Other ratios available
• Mix25 – 25% lispro/75% NPH insulin
Insulin regimens
Many different potential regimens!
–
–
–
–
Oral + hs insulin (NPH)
Oral + AM insulin (NPH)
Pre-mixed insulin with breakfast and supper
Short-acting with meals + bedtime NPH
– Pre-mixed with breakfast, short acting at supper, and
bedtime HPH
Insulin regimens
All equivalent glycemic control.
Weight gain less with bedtime insulin.
Less hypoglycemia and weight gain with metformin
(vs. glyburide)
Regime will depend on patient preferences and
ability to achieve glycemic goals!
CDA Guidelines for Glucose Control
Glycated Hb
Normal
<100
Optimal Suboptimal Inadequate
<115
116-140
>140
(% of ULN)
HbA1C assay
Preprandial
glucose
(0.04-0.06) (<0.07)
(0.07-0.084)
(>0.084)
3.8-6.1
4-7
7.1-10
>10
4.4-7
5-11
11.1-14
>14
(mmol/L)
Postprandial
glucose
(mmol/L)
Meltzer et al CMAJ 1998;159(Suppl):S1-29. Gerstein HC et al CDA’s UKPDS Position Statement.
UK Prospective Diabetes Study
Blood Pressure
Control Study
Blood Pressure Control Study
- to determine whether a tight blood pressure control
policy can reduce morbidity and mortality in Type
2 diabetic patients
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
Mean Blood Pressure
mmHg
baseline
mean over 9 years
Less tight control
160 / 94
154 / 87
Tight control
difference
p
ACE inhibitor
161 / 94
1/0
n.s.
159 / 94
144 / 82
10 / 5
<0.0001
144 / 83
Beta blocker
difference
159 / 93
0/0
143 / 81
1/1
p
n.s.
n.s. / p=0.02
Therapy requirement
number of antihypertensive agents
None
one
two
LessTight Control Policy
> two
Tight Control Policy
% of patients
100
80
60
40
20
0
1
2
3
4
5
6
7
8
1
2
Years from randomisation
3
4
5
6
7
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
Myocardial Infarction
25%
Less Tight Blood Pressure Control (390)
% of patients with event
Tight Blood Pressure Control (758)
20%
15%
10%
5%
risk reduction
21% p=0.13
0%
0
3
6
Years from randomisation
9
Heart Failure
25%
% patients with event
Less Tight Blood Pressure Control (390)
Tight Blood Pressure Control (758)
20%
15%
risk reduction
56% p=0.0043
10%
5%
0%
0
3
6
Years from randomisation
9
Stroke
25%
Less Tight Blood Pressure Control (390)
% patients with event
Tight Blood Pressure Control (758)
20%
15%
10%
5%
risk reduction
44% p=0.013
0%
0
3
6
Years from randomisation
9
Microvascular endpoints
25%
% patients with event
Less Tight Blood Pressure Control (390)
Tight Blood Pressure Control (758)
20%
15%
10%
5%
risk reduction
37% p=0.0092
0%
0
3
6
Years from randomisation
9
UK Prospective Diabetes Study
Do ACE inhibitors or
Beta Blockers
have any specific advantages
or disadvantages?
Aggregate Clinical Endpoints
RR
p
0.5
Relative Risk
& 95% CI
1
2
Any diabetes related endpoint
1.10 0.43
Diabetes related deaths
1.27 0.28
All cause mortality
1.14 0.44
Myocardial infarction
1.20 0.35
Stroke
1.12 0.74
>
Microvascular
1.29 0.30
>
Favours Favours
ACE inhibitor Beta blocker
Renal Disease in Diabetes
Blood pressure control
ACE - inhibition
Angiotensin receptor blockade
Diabetes:
The Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Other
No. of dialysis patients
(thousands)
10%
700
Glomerulonephritis
13%
Hypertension
27%
Diabetes
50.1%
600
No. of patients
Projection
95% CI
500
400
520,240
300
281,355
200
243,524
100
0
r2=99.8%
1984
1988
1992
United States Renal Data System. Annual data report. 2000.
1996
2000
2004
2008
Blood pressure control
• Decreases development of microalbuminuria
• Decreases rate of decline in glomerular filtration rate
UKPDS: 29% RRR for microalbuminuria
Absolute risk reduction: 8.2%
Meta-analysis of RCTs of diabetic nephropathy:
• 10 mm Hg improvement – 0.18 ml/min/month
ACE-inhibition
• Role in patients with Type 1 diabetes and nephropathy
– Prevent death, dialysis, and transplantation
• Role in patients with microalbuminuria
– Reduce rate of diabetic nephropathy
• Role in patients with Type 2 diabetes at high risk of
cardiac complications
– Reduce risk of MI, stroke, and cardiovascular death
Type 1 Diabetes and nephropathy
Lewis and colleagues, 1993
• 409 patients
• Captopril vs. placebo
• Follow-up 3.5 years
• Outcome: Death, dialysis, renal transplant
• Placebo arm: 21%
• Captopril arm:11%
Microalbuminuria
•
•
•
•
Systematic review of randomized controlled trials
Follow-up: >1 year
RR for proteinuria: 0.35 (0.24 – 0.53)
ARR 16.3% NNT 6
• No demonstrated effect on renal function
HOPE
9297 patients: >55 years of age
- clinical vascular disease or diabetes mellitus + 1
other cardiovascular risk factor
- no history of heart failure
- randomly allocated to ramipril or placebo
- followed for a mean of 5 years
- outcome: MI, stroke, or CVS death
1137 patients: diabetes mellitus with no clinical
manifestations of cardiovascular disease
HOPE
Results:
- ramipril arm: 14.1%
- placebo arm: 17.7%
Relative risk: 78% (95% CI 70% - 86%)
Consistent across all subgroups, including patients
with diabetes and no CVS disease
MICRO-HOPE: ACEI Reduces the Risk of MI,
Stroke, and CV Death in Patients With Diabetes
30
25
20
25% RR
P=0.0004
19.8
15.3
15
Ramipril
Placebo
22% RR
P=0.01
12.9
10.2
10
5
0
Combined
HOPE Study Investigators. Lancet. 2000;335:253.
MI
33% RR
P=0.0074
6.1
4.2
Stroke
37% RR
P=0.0001
9.7
6.2
CV death
Angiotensin Receptor Blockers
• 3 recent publications
• Effect of angiotensin receptor blockers in patients
with Type 2 diabetes mellitus and nephropathy or
microalbubinuria
IRMA 2: IRbesartan MicroAlbuminuria Type 2
Diabetes Mellitus in Hypertensive Patients
• Irbesartan (150 mg and 300 mg) vs. other
antihypertensive medications
– (excl ACEIs, ARBs, dihydropyridine Ca++ ch. blockers)
• 590 patients
• Hypertension, type 2 diabetes, and microalbuminuria
• Follow-up: 2 years
IRMA 2: Results
• Nephropathy rate:
– 5.2% among patients treated with 300 mg irbesartan/day
– 9.7% among patients treated with 150 mg irbesartan/day
– 14.9% among those treated with conventional therapy
(P=0.0004)
• Reduction in microalbuminuria to normal levels
(33% vs 20%; P=0.006)
• BP control similar across study arms
IDNT: Irbesartan Type 2 Diabetic
Nephropathy Trial
Patients: 1715 patients with NIDDM, HT, proteinuria (≥900
mg/24 h), serum creatinine 88 – 265 µmol/l
Treatment regimen: Irbesartan 300mg, amlodipine 10mg, or
placebo (± conventional therapy); target BP 135/85
1 End points: Combined incidence of doubling of sCr, ESRD,
and death
2 End points: cardiovascular events
Follow-up: 2.6 years
IDNT: Results
• Incidence of the composite endpoint (CrX2, ESRD, death):
– Irbesartan:
32.6%
– Amlodipine: 41.1%
– Placebo:
39.0%
• Effects of irbesartan independent of effects on BP
• No effect on mortality or cardiovascular outcomes
RENAAL: Reduction of Endpoints in
NIDDM With the AII Antagonist Losartan
Patients: 1513 patients with NIDDM, nephropathy, serum
creatinine 115 - 265
Treatment regimen: Losartan vs placebo (± conventional therapy)
1 End point: Combined incidence of doubling of sCr, ESRD, and
death
2 End points: CV events, proteinuria
Follow-up: 3.4 years
RENAAL: Results
• Incidence of the composite endpoint (CrX2, ESRD, death):
– Losartan:
43.5%
– Placebo:
47.1%,
– RRR 16%, p=0.02
• Effects of losartan independent of effects on BP
• No effect on mortality or cardiovascular outcomes
Diabetes Clinical Cases
Case 1
60 y.o. ♂, mildly obese
• Inferior myocardial infarction 6 months ago
• Echocardiogram: mild left ventricular dysfunction
• Started on glyburide 5 mg bid post-discharge
• Fasting blood glucose values currently 8 – 10
Case 1 – Points for discussion
• High risk for cardiac complications
– Aggressive risk factor modification
• Diet and exercise review
• Role for insulin
• Role for metformin - UKPDS
Case 2
50 y.o. ♀; Type 2 DM for 6 years; uses 30/70 bid
• Poor glycemic control despite increasing doses
• Persistently elevated fasting blood glucose values
• Progressive weight gain
• Lab:
LDL 3.2
↑microalb/creat. ratio
Case 2 – Points for discussion
• Often difficult to achieve optimal control with 30/70 bid
– Insulin adjustment difficult
– Nocturnal hypoglycemia and Somogyi effect common
• NPH action (hrs):
Onset: 2.5-3.0
Peak: 5-7
Dur’n: 13-16
• ↑ LDL: Treat lipid abnormalities aggressively
• ↑ microalb/Cr ratio: 24-hour urine to confirm
– If abnormal: optimize glycemic control + ACE - inhibitor
Case 3
40 y.o. ♀; Type 1 diabetes for 15 years
• Regular with meals (fixed doses) and NPH qhs
• Sub-optimal glycemic control; HbA1c 8.5%
• Frequent hypoglycemia
• BP 150/80
• Urine: 1+ proteinuria
Case 3 – Points for discussion
• Lyspro insulin
– Less post-prandial hyperglycemia
– Less hypoglycemia
• Adjust insulin doses according to CHO content
• Probable nephropathy:
– 24-hour urine; ACE-inhibition; aggressive BP control
Case 4
65 y.o. ♂; Type 2 diabetes for 7 years
• Glyburide 10 mg bid; metformin 1000 mg bid
• Fasting blood glucose values: 10 – 12
• Lipid profile: ↑ TG, ↓ HDL, normal LDL
Case 4 – Points for discussion
• Diet and exercise review
• Consider insulin sensitizer
– e.g. pioglitazone, rosiglitazone
Case 5
75 y.o. ♀; Type 2 diabetes for 12 years
• Main complaint: pain in feet at night
• Physical examination: callus formation, ↓ monofilament
sensation
Case 5 – Points for discussion
• Neuropathic pain:
– Tricyclic antidepressant
– Gabapentin
– Capsaicin
• Foot care:
– Education – inspection, walking barefoot
– Footwear
– Nail care