Combined Therapy withInsulin Plus Oral Agents

Is there Any Advantage?

Matthew C. Riddle, M.D.

Professor of Medicine

Oregon Health & Science University

Portland, Oregon

Yes !Gewiss! Vraiment!

Most patients with type 2 diabetesneed combination therapy

to reach usual glycemic targets

. . . including those who need insulin

Is there Any Advantage in Combined Therapy?

The Clinical ProblemLoss of Control with Monotherapy in the UKPDS

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

9

8

7

6

00 3 6 9

Years From Randomization

12 18

Conventional (diet)

Intensive (SU or insulin)

Med

ian

Hb

A1

c(%

)

Monotherapy in the UKPDS Obese Substudy

Turner RC et al. UKPDS 49. J Am Med Ass 1999;21:2005

Percent with HbA1c < 7% on monotherapy3 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

“The majority of patients need

multiple therapies

to attain these target goals in the longer term.”

Monotherapy in the UKPDS Obese Substudy

Why combine oral agents with insulin?

Pharmacology

Physiology

Clinical trials

Why combine oral agents with insulin?

Pharmacology

The ratio of desired to undesired effectsmay be improved

Dose-response Relationships forEffects of Treatments

50 100

Desired effect Undesired effect

50

0

100

50

50

0

100

% of maximal dose

% of maximal effect

100

% incidence

Dose-response Relationships forMetformin

1000 2500

HbA1c reduction GI symptoms

50

0

100

1000

50

0

100

Mg metformin daily

% of maximal effect

2500

% incidence

?20-30%

5%

Garber AJ et al. Am J Med 1997;102:491

h

h

h

hh

Dose-response Relationships forGlimepiride

4 8

HbA1c reduction Hypoglycemia

50

0

100

4

50

0

100

Mg glimepiride daily

% of maximal effect

8

% incidence

2

Goldberg RB et al. Diabetes Care 1996;19: 849

h

h h

Why combine oral agents with insulin?

Physiology

Glycemic variability and hypoglycemiacan be reduced by enhancing

the effectiveness of endogenous insulin

Three Main Oral agent + Insulin Combinations

Sulfonylureas + Insulin

Metformin + Insulin

Thiazolidinediones + Insulin

Smooth Transition to Insulinwhile Continuing Glimepiride

Riddle MC et al. Diabetes Care. 1998;21:1052-57

mg/dL

0

300

*

* *****

*

250

200

150

100

4 8 12 16 20 24

Weeks of treament

FPG

Placebo + 70/30 insulin titrated to 140 mg/dL

Glimepiride + insulin

0

100

75

50

25

04 8 12

Insulin Dosage

16 20 24

Weeks of treament* P <.001 * P <.001† P <.05

Units/Day

†

Quicker control with 37% less injected insulin

Metformin or Glitazone + CSII in T2DMEffect on Plasma Glucose

Yu et al. Diabetes 1999;48:2414-21

0800 1200 1600 2400 0800

Metformin

Continuous insulin infusion

Troglitazone

100

50

0

mg/dL150

0800 1200 1600 2400 0800

Continuous insulin infusion plus metforminContinuous insulin infusion

Continuous insulin infusion plus troglitazone

100

50

0

150

Time of day Time of day

Equivalently excellent glycemic control

Metformin or Glitazone + CSII in T2DMEffect on Plasma Insulin

0800 1200 1600 2400 0800

Metformin

Continuous insulin infusion

1000

600

400

200

0

Troglitazone

800

1000

600

400

200

0

pmol/L

800

0800 1200 1600 2400 0800

Continuous insulin infusion plus metforminContinuous insulin infusionContinuous insulin infusion plus troglitazone

2000 2000

Time of day Time of day

31% insulindose reduction

53% insulindose reduction

Yu et al. Diabetes. 1999;48:2414-21

Reduced exogenous insulin requirementdue to enhanced response to endogenous insulin

Variability of FPG in 2 Studiesof glibenclamide and evening insulin

Placebo/Ins Glibenclamide/Ins

Bedtime NPH 1.7 ± 0.2 1.1 ± 0.1

Riddle MC et al. P < 0.05

Diabetes Care 1989;12:623-9

Suppertime 70/30 1.4 ± 0.3 0.8 ± 0.1

Riddle MC et al. P < 0.05

Am J Med Sci 1992;:303:151-6

35 and 43% less variability with combination therapy

SD of sequential FPG measurements

Glibenclamide is no longer a suitable choice as secretagogue

Higher incidence of severe hypoglycemia in a population-based study1

Glibenclamide 5.60 per 1000 patient-yearGlimepiride 0.86

Interference with cardiac ischemic preconditioning2

Glibenclamide Abolished preconditioningGlimepiride No effect on preconditioning

Higher mortality in a population taking a secretagoguewith metformin3

Glibenclamide 8.7 % per yearRepaglinide 3.1Gliclazide 2.1Glimepiride 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

Secretagogues increase the proportion of insulin from endogenous secretion

Sensitizers increase the responseto endogenous insulin

Summary of physiologic studies

. . . both improve the effectivenessof remaining endogenous insulin

Why combine oral agents with insulin?

Clinical trials

Better glycemic control achievedLess weight gain

Improvement of Glycemic Controlwith Combination Therapy

Yki-Jarvinen H. Diabetes Care 2001;24: 738-67

Previously insulin-treated T2DM patients

Regimen Glycated Hb reductionvs insulin alone

(despite insulin dose reductions)

Insulin + sulfonylurea - 0.4%7 studies

Insulin + metformin - 1.3%4 studies

Insulin + TZD - 1.3%2 studies

Initiation of Bedtime NPH Insulin ± Glipizide

Shank M et al. Diabetes. 1995;44:165-72

0

100

220

140

248

113

8.6

7.8

8.9

7.1

200

300

6

7

8

9

Baseline on Glipizide 20 mg/d

Bedtime NPH Bedtime NPH

+ glipizide

Bedtime NPH Bedtime NPH

+ glipizide

10FPG HbA1c

After bedtime NPH titrated to FPG 120 mg/dL

mg/dL %

Better control with combination therapy

- 0.7%

N = 18 T2DM

Metformin + Intensified N + R Insulin

Insulin + Placebo Insulin + Metformin

N = 22 N = 21

Insulin dosage (U/d)

Baseline 97 96

6 months 120 92

Weight (kg)

Baseline 107 104

6 months 110 104

HbA1c (%)

Baseline 9.1 9.0

6 months 7.6 6.5

-1.1%

Aviles-Santa et al. Ann Intern Med 1999;131:182-8

-3 kg

Better control and no weight gain with combination therapy

Intensive Insulin Therapy ± Metformin

390 type 2 patients on insulin or insulin + metforminMean age 61 yr, duration 13 yr, BMI 30, A1c 7.9%

Randomized to Insulin 2 to 4 injections + PlaceboInsulin 2 to 4 injections + metformin 850-2550 mg

EndpointsAt 48 months – CV morbidity and mortalityAt 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 71 64Metformin mg/d --- 2163

A1c %Endpoint 7.6 6.9∆ - 0.3 - 0.9Placebo adj ∆ --- - 0.6 <0.0001

Weight kg∆ + 1.2 - 0.4Placebo adj ∆ --- - 1.6 <0.0001

Hypoglycemia/pt-mo 1.12 1.52 NS

Wulffele MG et al. Diabetes Care 2002;25: 2133-40

Unanswered questions

Will limitation of weight-gain accompanyinginsulin 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

130

150

170

190

210

230

acB pcB acL pcL acD pcD hs

*

*

*

*

*

* *

Glucosemg/dL

Baseline

6 Months

*P <0.05

Karl D et al. Diabetes 2005; 54(S1):A12; in press Diab Res Clin Pract

The ACCORD TrialCan 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