Insulin Therapy in Type 2 Diabetes: Current and Future Directions.

Insulin Therapy in Type 2 Diabetes:Current and Future Directions

Issues in the Management ofType 2 Diabetes

• Type 2: Deterioration of beta cells over time

• Increasing prevalence with increasing risk factors, eg, obesity

• Hyperglycemia affects morbidity, mortality, and resources

• Tight glycemic control with insulin may reduce costly complications

• 30% to 40% of patients ultimately require insulin

• Regimen-related limitations with current insulin formulations and delivery systems

• Newer semisynthetic insulins and delivery systems may improve compliance and achieve better glycemic control with less hypoglycemia

Prevalence of Type 2 Diabetes Mellitus

MMWR. 1997;46:1014-1018.

29.8

25.2

20

25

30

35

1990 1992 1994

CDC NHIS Results

Rat

e (p

er 1

000

popu

latio

n)

Incidence of Type 2 Diabetes Mellitus

MMWR. 1997;46:1014-1018.

3.7

2.1

1

2

3

4

5

1990 1992 1994

CDC NHIS Results

Rat

e (p

er 1

000

popu

latio

n)

Risk Factors for Type 2 Diabetes

Nonmodifiable• Genetic factors

• Age

• Ethnicity

Modifiable• Weight

• Physical activity

Trend in Prevalence of Obesity*: NHANES Data

Kuczmarski RJ, et al. JAMA. 1994;272:205-211.

*BMI 27.3 mg/m2 for women; 27.8 kg/m2 for men

20

22

24

26

28

30

32

34

36

NHES (1960-1962)

NHANES I(1971-1974)

NHANES II(1976-1980)

NHANES IIIb(1988-1994)

US

Pop

ulat

ion

(%)

Link Between Obesity and Type 2 Diabetes:

Nurses’ Health Study

Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

0

20

40

60

80

100

120

<22 22-22.9

23-23.8

24-24.9

25-26.9

27-28.9

29-30.9

31-32.9

33-34.9

>35

BMI (kg/m2)

Age

-Adj

uste

d Rel

ativ

e Ris

k

Link Between Obesity and Type 2 Diabetes:

Nurses’ Health Study (cont’d)

Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

0

10

20

30

40

50

60

70

80

<22.0 22.0-24.9 25.0-28.9 29+

BMI (kg/m2) at Age 18 Years

Ag

e-A

dju

ste

d R

ela

tive

Ris

k

Loss of 5-10 kg

Loss or gain of 4.9 kg or less

Gain of 5-6.9 kg

Gain of 7-10.9 kg

Gain of 11-19.9 kg

Gain of 20 kg or more

ADA Treatment Guidelines

Biochemical Index Normal Goal Action Suggested

Preprandial glucose<90 mg/dL 80-120 mg/dL <80 or >140 mg/dL

Bedtime glucose <120 mg/dL 100-140 mg/dL<100 or >160 mg/dL

HbA1c <6%* <7% >8%

*Depending on assay norms

Medical Nutrition Therapy for Type 2 Diabetes

• Diet– Improved food choices– Spacing meals– Individualized carbohydrate

content– Moderate calorie restriction

• Exercise

Pharmacologic Therapy for Type 2 Diabetes

• Sulfonylureas (glyburide, glipizide, glimepiride)

• Biguanides (metformin)

• Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose)

• Benzoic acid analogues (repaglinide)

• Thiazolidinediones (troglitazone, rosiglitazone, pioglitazone)

• Insulin (human insulin, insulin analogues)

Treatment Algorithm

Nonpharmacologic therapy

MonotherapySulfonylureas/Benzoic

acid analogueBiguanide

Alpha-glucosidase inhibitors

ThiazolidinedionesInsulin

Combination therapy Insulin

Very symptomaticSevere hyperglycemiaKetosisLatent autoimmune diabetesPregnancy

Considerations in Pharmacologic Treatment of Type 2 Diabetes

• Efficacy (HbA1c lowering capacity)

• Mechanisms of action of drugs

• Impact on weight gain

• Complications/tolerability

• Frequency of hypoglycemia

• Compliance/complexity of regimen

• Cost

Tight Glycemic Control:Reducing the Risk of

Complications• Epidemiologic evidence in type 2 diabetes to link

microvascular disease and hyperglycemia — first suggested in DCCT

• Type 2 diabetes studies: Veterans Affairs Cooperative Study on Type 2 Diabetes (VA CSDM), United Kingdom Prospective Diabetes Study (UKPDS), and Kumamoto trial– Intensive blood glucose control with insulin, sulfonylurea, or

metformin reduced risk of micro- and macrovascular complications– Glycemic threshold to prevent onset and progression of

microvascular complications: HbA1c <6.5%, FBG <110 mg/dL,

2-hr postprandial glucose <180 mg/dL

Improvement in HbA1c in the VA CSDM

P<0.001 vs. placebo in intensive treatment group

Abraira C, et al. Diabetes Care. 1995;18:1113-1123.

6

7

8

9

10

0 3 6 9 12 15 18 21 24 27 30

Months

HbA 1

c (%

)

Standard

Intensive

VA CSDM: Results at Endpoint

Baseline Endpoint P Value

HbA1c 9.3% 6.9% <0.001

Fasting serum glucose 206 mg/dL 118 mg/dL <0.001

Insulin dose 22.9 U 133.0 U

Blood pressure* 136/81 mmHg 137/80 mmHg

Total cholesterol* 5.9 mg/dL 5.2 mg/dL 0.003

HDL cholesterol* 1.1 mg/dL 1.0 mg/dL

LDL cholesterol* 3.5 mg/dL 3.4 mg/dL

Triglycerides* 2.3 mg/dL 2.0 mg/dL 0.06

*Results at 2 years

Abraira C, et al. Diabetes Care. 1995;18:1113-1123.

The Kumamoto Trial: Effects of Conventional vs. Intensive Insulin

Therapy

Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.

32%

44%

28%32%

7.7%

19.2%

7.7%11.5%

0

10

20

30

40

50

PrimaryPrevention

SecondaryPrevention

PrimaryPrevention

SecondaryPrevention

Retinopathy Nephropathy

Cu

mu

lativ

e D

eve

lop

me

nt o

r P

rog

ress

ion

(%

)

Conventional

Intensive

UKPDS: Effect of Intensive Therapy on Glycemia

UKPDS Group. Lancet. 1998;352:837-853.

6

7

8

9

10

0 1 3 5 7 9Years

FP

G (

mm

ol/L

) or

HbA

1c

(%)

FPG, Conventional (N=1138)

FPG, Sulfonylurea (N=1573) or Insulin (N=1156)

HbA1c, Conventional

HbA1c, Sulfonylurea or Insulin

UKPDS 10-Year Cohort Data: Reductions With Intensive vs. Conventional Therapy

UKPDS Group. Lancet. 1998;352:837-853.

-6%

-10%

-16%(P= 0.052)

-25%(P= 0.0099)

-12%(P= 0.029)

-11%

-30

-20

-10

0

HbA1c All-Cause Mortality Diabetes-RelatedDeath

Any Diabetes-Related

Complication

MyocardialInfarction

MicrovascularComplication

Summary of Key Findings• VA CSDM:

– Glycemic control achievable with intensive insulin treatment: control maintained >2 years

– Intensive treatment not associated with severe hypoglycemia, weight gain, hypertension, or dyslipidemia

• Kumamoto trial:– Intensive insulin treatment reduced microvascular complications– Established glycemic threshold to prevent onset and progression

of complications• UKPDS:

– Diet therapy alone inadequate in two thirds of patients– Pharmacologic therapy plus nutrition/exercise necessary– Weigh benefit:risk ratio– No threshold for HbA1c reduction in reducing complications– Insulin does not increase macrovascular disease

EffectiveOnset Peak Duration

Insulin lispro <15 min 1 hr 3 hr

Regular 0.5-1 hr 2-3 hr 3-6 hr

NPH/Lente 2-4 hr 6-12 hr 10-16 hr

Ultralente 4-8 hr Varies 18-20 hr

Pharmacokinetics of Current Insulin Preparations

Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:1463-1495.

Clinical Efficacy of Insulin Lispro

• Worldwide clinical trials of insulin lispro in >10,000 patients with type 1 or type 2 diabetes

• 1-year parallel group comparisons or 6-month crossovers (3 months on each insulin) studies– Dosage regimen: insulin lispro 10 min before and

soluble human insulin 30 to 45 minutes before meals, with NPH or ultralente insulin as the basal insulin supplement

Strategies for Insulin Therapy in Elderly Patients

• Insulin therapy often considered a last resort in the elderly

• Therapeutic goals:– Relieve symptoms– Prevent hypoglycemia– Prevent acute complications of hyperglycemia

• Ways to facilitate insulin treatment:– Simple dose schedules– Premixed preparations– Improved, more convenient delivery systems

Combination Therapy: Oral Agents Plus Insulin

• Rationale– Combination of two agents with different mechanisms of action– More convenient and may be safer

• Sulfonylurea + Insulin– BIDS therapy: bedtime insulin/daytime sulfonylurea– Useful in patients early in course of disease

• Metformin + Insulin– Improves insulin sensitivity

• Alpha glucosidase inhibitor (acarbose) + Insulin– Decreases postprandial glycemia

• Thiazolidinediones + Insulin– Improves insulin resistance, improves insulin action in peripheral

tissues– Reduces insulin requirement

Meta-Analysis of Sulfonylurea/Insulin

Combination Therapy

Johnson JL, et al. Arch Intern Med. 1996;156:259-264.

* P< 0.05 vs. baseline value

1.4

-0.6-0.25

0.8

-2.5*

-1.1*

-3

-2

-1

0

1

2

Fasting Serum Glucose(mg/dL)

HbA1c (%) Weight (kg)

Ch

ange

Fro

m B

asel

ine

Val

ues Sulfonylurea + Insulin

Insulin Only

Comparison of Insulin RegimensAmong Oral Treatment Failures

Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.

-0.9-1.7*

2.2*

-1.9*

1.2* †

-1.8*

1.8*

-1.6*

2.9*

-0.5

-4

-2

0

2

4

6

8

10

Change in HbA1c (%) Weight Change (kg)

*P< 0.001 vs. control group†P< 0.05 vs. other insulin treatment groups

Morning NPH (N= 32)Evening NPH (N= 28)Twice-daily injections (N= 29)

Multiple-daily injections (N= 30)Control (N= 30)

Total Direct Costs of Type 2 Diabetes

Rathman W. Drug Benefit Trends. 1998;10:24-27.

15.6

1.8

6.2

37.2

0 10 20 30 40

Prescription Costs

Nursing Home

Outpatient Care

Hospital

US $ Billions

Total Indirect Costs of Type 2 Diabetes

Rathman W. Drug Benefit Trends. 1998;10:24-27.

27

11.2

8.5

0 10 20 30

Mortality

Long-TermMorbidity

Short-TermMorbidity

US $ Billions

Ideal Basal Insulin

• Closely mimic normal pancreatic basal insulin secretion

• No distinct peak effect

• Continued effect over 24 hours

• Reduce nocturnal hypoglycemia

• Once-daily administration for patient compliance

• Predictable absorption pattern

EffectiveOnset Peak Duration

Insulin lispro <15 min 1 hr 3 hr

Regular 0.5-1 hr 2-3 hr 3-6 hr

NPH/Lente 2-4 hr 7-8 hr 10-12 hr

Ultralente 4 hr Varies 18-20 hr

Insulin glargine* 1-2 hr Flat/Predictable 24 hr

*Investigational

Pharmacokinetics of Current Insulin Preparations Compared With Insulin

Glargine

Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:1463-1495. Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.

Structure of Insulin Glargine:A New Long-Acting Insulin

Analogue• Modifications to human insulin chain

– Substitution of glycine at position A21– Addition of two arginines at position B30– Unique release pattern from injection site

1

1

15105

5 10 15 20

20 Asn

25 30

Gly

Arg Arg

Substitution

Extension

Characteristics of Insulin Glargine

• Euglycemic clamp studies vs. NPH– Smooth continuous release from injection site– Longer duration of action– Continued effect at end of 24-hour clamp study

• No differences in the absorption rate from arm, leg, or abdominal sites

• No inflammatory reactions at any of the injection sites

• Flat insulin profile• As effective in lowering FPG levels as NPH insulin,

with significantly reduced nocturnal hypoglycemia

Blood Glucose Profile of Insulin Glargine in Normal Volunteers

Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.

70

75

8085

9095

100

105

110

-0.5 1 3 6 9 12 15 18 21 24

Time (hr)

Co

nce

ntr

atio

n (

mg/

dL)

NPH Insulin glargine (15 µg zinc) Insulin glargine (80 µg zinc)

Exogenous Insulin Concentration of Insulin Glargine in Normal

Volunteers

Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.

0

25

50

75

0 2 4 6 8 10 12 14 16 18 20 22 24

Hours after injections

Exog

eno

us

insu

lin

(pm

ol/L

)

NPH Insulin glargine (15 µg zinc) Insulin glargine (80 µg zinc)

Efficacy of Insulin Glarginein Type 1 and Type 2 Diabetes

Raskin P, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0404.Rosenstock J, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0357.

*P=0.0001

Improvement in FPG After 4 Weeks

-50.4-41.4

-14.4

-46.8-52.2*-60

-40

-20

0

InsulinglargineN= 168

NPHN= 88

Insulinglargine(30 µgzinc)

N= 55

Insulinglargine(80 µgzinc)

N= 51

NPHN= 49

Type 1 Type 2

Mea

n C

hang

e Fr

om B

asel

ine

(mg/

dL)

Safety of Insulin Glargine in Type 1 and Type 2 Diabetes

• Type 1 Diabetes– Similar incidence of hypoglycemia between insulin

glargine and NPH after 4 weeks of treatment– Pattern of adverse events and injection site reactions

also similar

• Type 2 Diabetes– No difference in frequency of hypoglycemia from NPH– No change in body weight

Other Long-Acting Insulin Analogues

• Glycemic objectives:– Provide constant, reproducible supply of basal insulin – Adequately suppress hepatic glucose production

• NovoSol Basal– First long-acting insulin analogue– Discontinued because of local inflammatory reactions

• In development– Di-arginyl human insulin analogue (Gly, Arg)– C16 fatty-acid-acylated analogue

Need for Novel Delivery Systems of Insulin

• Disadvantages of conventional subcutaneous injection:– Discomfort– Inconvenience– Systemic delivery– Inconsistent pharmacokinetics– Irreversible after injection

• Insulin pumps: too complex, limited experience and utility with type 2

• Insulin pen: beneficial but underutilized• Systems in clinical testing

– Inhaled formulation– Jet-injected systems

Insulin Pump

• CSII: uses portable infusion pump connected to an indwelling subcutaneous catheter to deliver short-acting insulin

• IIP shown to have significant advantages over multiple daily injections– Reduces glycemic variability, clinical hypoglycemia,

weight gain– Extreme for routine practice but may be useful in

special circumstances– Not currently available in the United States

Insulin Pump

Insulin Pen

• Benefits– More accurate dosing mechanisms – Faster and easier than conventional syringes– Improved patient attitude and compliance

• Advantages of newer insulin pens– LCD display to show dosage setting– Dosage settings change quickly and easily– Safety button automatically resets after drug delivery

Insulin Pen

Inhaled Insulin Formulations

Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.

Changes in Glycemic Parameters

-50-45-40-35-30-25-20-15-10

-50

HbA1c 2-hr PG

% C

han

ge F

rom

Bas

elin

e

Inhaled human insulin

Subcutaneously injectedinsulin

Continuous Glucose Sensors

• When available, may provide only mechanical means of achieving “normal” glucose homeostasis

• Will direct insulin delivery automatically on demand (“closed loop”)

• One technology uses reverse iontophoresis to noninvasively extract and measure glucose levels

• Technical challenge to develop

Conclusions

• Type 2 diabetes: gradual deterioration of glycemic control• Significant morbidity and mortality; tight glycemic control reduces

risk of complications• Earlier institution of insulin may help attain initial glycemic control • Objectives of insulin therapy:

– Achieve normal fasting glucose levels– Achieve normal postprandial glucose levels– Minimize hypoglycemia

• Intensive insulin therapy should:– Provide good glycemic control– Produce little hypoglycemia– Improve lipid profile– Reduce risks and costs of treating complications

Conclusions (cont’d)

• New delivery systems:– Reduce limitations of conventional insulin syringes– Improve patient compliance and disease

management

• New long-acting insulin analogues (eg, insulin glargine):– Produce flat insulin profile with no peaks– Allow once-daily administration– Significantly reduce nocturnal hypoglycemia