Combined Therapy with
Insulin Plus Oral Agents
Is there Any Advantage?
Matthew C. Riddle, M.D.
Professor of Medicine
Oregon Health & Science University
Portland, Oregon
Is there Any Advantage in Combined Therapy?
Yes !
Gewiss!
Vraiment!
Most patients with type 2 diabetes
need combination therapy
to reach usual glycemic targets
. . . including those who need insulin
The Clinical Problem
Loss of Control with Monotherapy in the UKPDS
Conventional (diet)
Intensive (SU or insulin)
Median HbA1c (%)
9
8
7
6
0
0
3
6
9
12
Years From Randomization
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
18
Monotherapy in the UKPDS Obese Substudy
Percent with HbA1c < 7% on monotherapy
3 years
6 years
9 years
Diet
23
12
11
Sulfonylurea
45
28
21
Metformin
44
34
13
Insulin
34
37
24
Turner RC et al. UKPDS 49. J Am Med Ass 1999;21:2005
Monotherapy in the UKPDS Obese Substudy
“The majority of patients need
multiple therapies
to attain these target goals in the longer term.”
Turner RC et al. UKPDS 49. J Am Med Ass 1999;21:2005
Why combine oral agents with insulin?
Pharmacology
Physiology
Clinical trials
Why combine oral agents with insulin?
Pharmacology
The ratio of desired to undesired effects
may be improved
Dose-response Relationships for
Effects of Treatments
Undesired effect
Desired effect
% of maximal effect
% incidence
100
100
50
50
0
0
50
100
% of maximal dose
50
100
Dose-response Relationships for
Metformin
HbA1c reduction
% of maximal effect
100
h
h
50
GI symptoms
% incidence
100
h
h
h
0
?20-30%
50
5%
1000
2500
0
1000
Mg metformin daily
Garber AJ et al. Am J Med 1997;102:491
2500
Dose-response Relationships for
Glimepiride
HbA1c reduction
% of maximal effect
100
50
0
h
Hypoglycemia
% incidence
h
h
100
50
2
4
8
0
Mg glimepiride daily
Goldberg RB et al. Diabetes Care 1996;19: 849
4
8
Why combine oral agents with insulin?
Physiology
Glycemic variability and hypoglycemia
can be reduced by enhancing
the effectiveness of endogenous insulin
Three Main Oral agent + Insulin
Combinations
Sulfonylureas + Insulin
Metformin + Insulin
Thiazolidinediones + Insulin
Smooth Transition to Insulin
while Continuing Glimepiride
Placebo + 70/30 insulin titrated to 140 mg/dL
Glimepiride + insulin
FPG
300
mg/dL
250
*
100
Insulin Dosage
Units/Day
*
75
200
*
*
*
16
20
* *
*
50
†
150
25
100
0
0
4
* P <.001
8
12
16
20
24
Weeks of treament
0
4
* P <.001
† P <.05
8
12
Weeks of treament
Quicker control with 37% less injected insulin
Riddle MC et al. Diabetes Care. 1998;21:1052-57
24
Metformin or Glitazone + CSII in T2DM
Effect on Plasma Glucose
Continuous insulin infusion
Continuous insulin infusion plus metformin
Continuous insulin infusion
Continuous insulin infusion plus troglitazone
Metformin
Troglitazone
mg/dL
150
150
100
100
50
50
0
0
0800
1200
1600
Time of day
2400
0800
0800
1200
1600
Time of day
Equivalently excellent glycemic control
Yu et al. Diabetes 1999;48:2414-21
2400
0800
Metformin or Glitazone + CSII in T2DM
Effect on Plasma Insulin
Continuous insulin infusion
Continuous insulin infusion plus troglitazone
Continuous insulin infusion
Continuous insulin infusion plus metformin
pmol/L
Metformin
Troglitazone
1000
1000
800
31% insulin
dose reduction
600
800
600
400
400
200
200
0
0
0800
1200
1600
2000
Time of day
2400
0800
53% insulin
dose reduction
0800
1200
1600
2000
2400
Time of day
Reduced exogenous insulin requirement
due to enhanced response to endogenous insulin
Yu et al. Diabetes. 1999;48:2414-21
0800
Variability of FPG in 2 Studies
of glibenclamide and evening insulin
SD of sequential FPG measurements
Placebo/Ins Glibenclamide/Ins
Bedtime NPH
1.7 ± 0.2
1.1 ± 0.1
P < 0.05
Riddle MC et al.
Diabetes Care 1989;12:623-9
Suppertime 70/30
Riddle MC et al.
1.4 ± 0.3
0.8 ± 0.1
P < 0.05
Am J Med Sci 1992;:303:151-6
35 and 43% less variability with combination therapy
Glibenclamide is no longer a suitable
choice as secretagogue
Higher incidence of severe hypoglycemia in a populationbased study1
Glibenclamide
Glimepiride
5.60
0.86
per 1000 patient-year
Interference with cardiac ischemic preconditioning2
Glibenclamide
Glimepiride
Abolished preconditioning
No effect on preconditioning
Higher mortality in a population taking a secretagogue
with metformin3
Glibenclamide
Repaglinide
Gliclazide
Glimepiride
8.7
3.1
2.1
0.4
1 Holstein A et al. Diab/Metab Res Rev 2001;17: 467-73
2 Lee T-M & Chou T-F. J Clin Endocrinol Metab 2003;88: 531-7
3 Monami M et al. Diab/Metab Res Rev 2006;22: 477-82
% per year
Summary of physiologic studies
Secretagogues increase the proportion of insulin
from endogenous secretion
Sensitizers increase the response
to endogenous insulin
. . . both improve the effectiveness
of remaining endogenous insulin
Why combine oral agents with insulin?
Clinical trials
Better glycemic control achieved
Less weight gain
Improvement of Glycemic Control
with Combination Therapy
Previously insulin-treated T2DM patients
Regimen
Glycated Hb reduction
vs insulin alone
(despite insulin dose reductions)
Insulin + sulfonylurea
- 0.4%
7 studies
Insulin + metformin
- 1.3%
4 studies
Insulin + TZD
2 studies
Yki-Jarvinen H. Diabetes Care 2001;24: 738-67
- 1.3%
Initiation of Bedtime NPH Insulin ± Glipizide
N = 18 T2DM
Baseline on Glipizide 20 mg/d
After bedtime NPH titrated to FPG 120 mg/dL
FPG
300
mg/dL
HbA1c
10
248
%
220
9
200
140
113
8
- 0.7%
8.9
8.6
7.8
7.1
100
7
0
Bedtime NPH Bedtime NPH
+ glipizide
6
Bedtime NPH Bedtime NPH
+ glipizide
Better control with combination therapy
Shank M et al. Diabetes. 1995;44:165-72
Metformin + Intensified N + R Insulin
Insulin + Placebo Insulin + Metformin
Insulin dosage (U/d)
Baseline
6 months
Weight (kg)
Baseline
6 months
HbA1c (%)
Baseline
6 months
N = 22
N = 21
97
120
96
92
107
110
104
104
-3 kg
9.1
7.6
9.0
6.5
-1.1%
Better control and no weight gain with combination therapy
Aviles-Santa et al. Ann Intern Med 1999;131:182-8
Intensive Insulin Therapy ± Metformin
390 type 2 patients on insulin or insulin + metformin
Mean age 61 yr, duration 13 yr, BMI 30, A1c 7.9%
Randomized to
Insulin 2 to 4 injections + Placebo
Insulin 2 to 4 injections + metformin 850-2550 mg
Endpoints
At 48 months – CV morbidity and mortality
At 16 weeks – glycemic control
An early report after 16 weeks:
“ . . . unexpected favorable effects of metformin”
Wulffele MG et al. Diabetes Care 2002;25: 2133-40
Intensive Insulin Therapy ± Metformin
Insulin + placebo Insulin + metformin
Insulin u/d
Metformin mg/d
71
---
64
2163
A1c %
Endpoint
∆
Placebo adj ∆
7.6
- 0.3
---
6.9
- 0.9
- 0.6 <0.0001
Weight kg
∆
Placebo adj ∆
+ 1.2
---
- 0.4
- 1.6 <0.0001
Hypoglycemia/pt-mo
1.12
1.52
Wulffele MG et al. Diabetes Care 2002;25: 2133-40
NS
Unanswered questions
Will limitation of weight-gain accompanying
insulin treatment improve CV outcomes?
What are the roles of pramlintide and exenatide
combined with insulin?
Will using all available agents to get to A1c 6%
improve outcomes?
Pramlintide + Basal-prandial Insulin in T2DM
Open-label clinical experience study
Baseline
6 Months
230
210
Glucose
mg/dL
190
170
*
150
*
*
*
*
*
*
130
acB
pcB
acL
*P <0.05
pcL
acD
pcD
Karl D et al. Diabetes 2005; 54(S1):A12; in press Diab Res Clin Pract
hs
The ACCORD Trial
Can we get to 6% A1c and will that improve outcomes?
10,000 type 2 patients -- to be followed ~ 5.5 yr
Primary endpoint -- major cardiovascular events
Double 2x2 factorial design
– Intensive vs standard glycemic policy
(n=10,000)
– Intensive vs standard blood pressure policy
(n=5800)
– Statin treatment with or without added fibrate
(n=4200)
HbA1c target for intensive glycemic arm -6%, using any combination of agents, including
intensive insulin