insulin therapy and other management issues in type 1 diabetes mellitus

Insulin Therapy and Other Management Issues in Type 1

Diabetes MellitusPhilip Raskin, MD

Jaime A. Davidson, MD

The University of Texas Southwestern Medical Center

Treatment Guidelines for Diabetes• American Diabetes Association1

– HbA1c <7.0%– Preprandial BG 70–130 mg/dL– Postprandial BG <180 mg/dL

• American Association of Clinical Endocrinologists2

– HbA1c ≤6.5%– Preprandial BG <110 mg/dL– Postprandial BG <140 mg/dL

• International Diabetes Federation– HbA1c <6.5%3,4

– Preprandial BG <110 mg/dL3,4

– Postprandial BG <160 mg/dL4

1. American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S11-S63. 2. AACE. Endocr Pract. 2011;17(suppl 2):1-53. 3. IDF. Global Guideline for Type 2 Diabetes. 2005. 4. IDF. Guideline for Management of PostMeal Glucose in Diabetes. 2011.

Type 1 Diabetes Mellitus

• Type 1 (immune-mediated beta cell destruction leading to absolute insulin deficiency)

• Dependent on exogenous insulin• Prone to ketoacidosis• Usually lean, but not always• Recent weight loss• Abrupt onset of symptoms, often before age

30• May occur at any age

Natural History of Type 1 Diabetes

CELLULAR (T CELL) AUTOIMMUNITY

LOSS OF FIRST PHASE INSULIN RESPONSE

(IVGTT)

GLUCOSE INTOLERANCE(OGTT)

HUMORAL AUTOANTIBODIES(ICA, IAA, Anti-GAD65, IA2Ab, etc.)

PUTATIVEENVIRONMENTAL

TRIGGER

CLINICALONSET

TIME

BET

A C

ELL

MA

SS

DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

With permission from Skyler JS, et al. Diabetes. 2011;60:1-8.

As Early as Possible in the Course of Diabetes

• Metabolic Memory: Benefits of good diabetes control are long-lasting in both type 1 and type 2 diabetes1,2

• Intensive diabetes control in older diabetic individuals with long-standing Type 2 diabetes and well-established microvascular and macrovascular complications can result in bad outcomes (ACCORD, etc)?3

When to Initiate Intensive Therapy in Type 1 Diabetes?

1. DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653.2. UKPDS Group. N Engl J Med. 2008;359:1577-1589.3. ACCORD Study Group. N Engl J Med. 2011;364:818-828.

DCCT Microvascular Complication Event Rates

1. DCCT Research Group. Ophthalmology. 1995;102:647-661. 2. DCCT Research Group. Kidney Int. 1995;47:1703-1720. 3. DCCT Research Group. Ann Intern Med. 1995;122:561-568.

RetinopathyProgression1

LaserRx1

Microalbuminuria2 Albuminuria2 ClinicalNephropathy3

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569.

Further Retinopathy Progression Over 7 Years of EDIC from the Level

at DCCT Closeout• Even after intensive therapy was stopped at

the end of DCCT, effects of intensive therapy persisted for >7 years

• Difference between conventional and intensive therapy accelerated even after the treatments ended

• After 7 years of EDIC– Risk reduction: 62% with intensive

therapy (95% CI 51%-70%, P <.001)

Meta-analysis: Improved Glucose =Reduction in Macrovascular Events

• With reduction in glucose, there is greater improvement in macrovascular events in glucose T1DM vs T2DM*

Stettler C, et al. Am Heart J. 2006;152:27-38.

Combined incidenceAny macrovascular event T1DM 0.38 (95% CI, 0.26–0.56)T2DM 0.81 (95% CI, 0.73–0.91)

Cardiac eventsT1DM 0.41 (95% CI, 0.19–0.87)T2DM 0.91 (95% CI, 0.80–1.03)

Peripheral vascular eventsT1DM 0.39 (95% CI, 0.25–0.62)T2DM 0.58 (95% CI, 0.38–0.89)

Cerebrovascular eventsT1DM 0.34 (95% CI, 0.05–2.57)T2DM 0.58 (95% CI, 0.4–0.74)

*Incidence rate ratios are shown for T1DM (based on 8 randomized studies) and T2DM (based on 6 randomized studies).

Insulin

Insulin Analog

Insulin produced by technology that uses recombinant DNA to produce an insulin molecule

that is slightly different from human insulin in structure as well as pharmacokinetic/

pharmacodynamic properties

Insulin Preparations

Agents

Regular, NPH

Human 70/30

Insulin aspart, glulisine and lispro, insulin glargine and detemir

Insulin lispro 75/25, 50/50Biphasic insulin aspart 70/30

Class

Human Insulin

Premixed HumanInsulin

Insulin Analogs

Premixed InsulinAnalogs

Time Action Profiles of Insulin Products

• Rapid-acting insulin analogs (insulin aspart, insulin glulisine, insulin lispro)– Duration of action: 4–6 hours

• Regular insulin– Duration of action: 8–10 hours

• NPH insulin– Duration of action: 12–18 hours

• Long-acting insulin analogs (insulin glargine, insulin detemir)– Duration of action: 20–24 hours

Rapid-Acting Analogs vs Regular Human Insulin

Insu

lin L

evel

(mU

/mL)

800

700

600

500

400

300

200

100

0

With permission from Woodworth, et al. Diabetes. 1993;42(suppl 1):54A.

0 1 2 3 4 5 6 7 8Time (hours)

0.05 U/kg (n = 6)0.1 U/kg (n = 9)

Regular Human Insulin

0.2 U/kg (n = 9)0.3 U/kg (n = 3)

800

700

600

500

400

300

200

100

0

0 1 2 3 4 5 6 7 8Time (hours)

Rapid-Acting Analogs

Glu

cose

Insu

lin R

ate

(mg/

min

)

Braak EW, et al. Diabetes Care. 1996;19:1437-1440.

Rapid-Acting AnaloguesTmax (hours)*

Regular Human Insulin

1.0

0.77

1.0

3.8

1.3

3.1

* 0.2 U/kg sc.

Comparison of Insulin Absorption by Injection Site

Management of Type 1 Diabetes

Intensive Diabetes Management

• Goals of Therapy• Tools of Therapy• Systems of Therapy

Defined by


• Near-normal glycemia• Near-normal glycohemoglobin• Prevention of complications• Absence of hypoglycemia

Goals


• Multiple-component insulin regimen• Daily blood glucose monitoring• Careful balance of food intake, activity, and

insulin dosage• An action plan for patient adjustment of the

above, and the use of insulin supplements• Defined target blood glucose levels

(individualized)

Elements of Management


• Frequent contact between patient and health care providers

• Patient education and motivation• Psychological support• Assessment (glycohemoglobin)

Elements of Management


• Basal• Meal-related

Components of Insulin Replacement

Basal Bolus Therapy

Plas

ma

Insu

lin (m

U/m

L)

Time4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Breakfast Lunch Dinner

Glargine/Detemir

75

50

25

0

Basal/Bolus Idealized Absorption of Analog Insulin

Bedtime

Lispro/Aspart/Glulisine

Courtesy of Davidson JA.

Insulin Pumps

Time of Day

20

40

60

80

100 B L D

0600 06000800 18001200 2400

Bolus

Continuous infusion for basal delivery

Bolus

mU/m

L

Bolus

Insulin Pump Delivery Rapid-Acting Analogs

B=breakfast; L=lunch; D=dinnerCourtesy of Davidson JA.

Insulin Pumps

Wearing the Insulin Pump


• Basal: 40%–60%• Premeal: 40%–60%

– If according to carbohydrate 0.8–1.2 units/gram carbohydrate

– If according to % of total daily dose 15%–25% before breakfast 15% before lunch 15%–20% before dinner

Insulin Dose Distribution

• Insulin dosage• Insulin timing• Meal size• Meal content


Preprandial Algorithms


• Supplements• Adjustments

Insulin Dose Changes


• Supplements– Compensatory– Anticipatory


• Compensatory supplements– Based on prevailing blood glucose– Corrects blood glucose outside “target”

range– Alters basic dose for that point in time

Intensive Diabetes ManagementInsulin Dose Changes


• Blood glucose– <50 mg/dL– 51–100 mg/dL– 101–150 mg/dL– 151–200 mg/dL– 201–250 mg/dL– 251–300 mg/dL– >300 mg/dL

• Fast-acting insulin– Decrease 2 units– Decrease 1 unit– Take usual dose– Increase 1 unit– Increase 2 units– Increase 3 units– Increase 4 units

Compensatory Supplements

Per Dr. Raskin.


• What is my blood glucose now?• Do I plan to eat more or less than usual?• Will I be more or less active after eating?• What has happened under these

circumstances previously?


Mealtime Questions


• Adjustments– Based on pattern over several days– ~10% increase or decrease in insulin

component preceding BG measurement– Change one component at a time


Insulin Timing

• Regular insulin usually 30–60 minutes before meals

• Rapid-acting analogs taken at mealtime or better yet 15 minutes before– Increase time interval if blood glucose above

target (further from meal)– Decrease time interval if blood glucose

below target (closer to meal)


Meal Size or Carbohydrate Content

• Decrease if blood glucose above target or less activity planned

• Increase if blood glucose below target or more activity planned


Criteria for Selection of Patients

• Suboptimal glycemic control• Motivation to pursue intensive therapy• Willing and able to perform frequent SMBG• Sufficient education and ability• Adequate psychological stability• Appropriate financial resources• Skilled medical staff available


Contraindications

• Hypoglycemia unawareness• Counterregulatory unresponsiveness• Age• Medical reasons, debilitated, short life

expectancy, malignancy, etc


Benefits of Insulin Pump Therapy

• Allows for flexibility in schedule• More physiologic and reproducible• Insulin delivery more predictable• Less hypoglycemia (exercise)


Self-Blood Glucose Monitoring

Essential Component of Intensive Management


Blood Glucose Monitoring

• Initially, check blood glucose before and 1.5–2 hours after each meal and at bedtime

• Weekly at 2:00 AM–3:00 AM

• Four blood glucose checks before each meal after targets are achieved

Effect of Memory Meter on HbA1c in Patients with Type 1 Diabetes

• N = 22 intensively treated T1DM patients (using insulin pump or 4 daily insulin injections)

• Monthly mean HbA1c across 12 months– HbA1c 6.9% ± 0.12% before memory meter– HbA1c 6.4% ± 0.10% while a memory meter was

used– P = .0004– Difference in slopes P = .046

• As the frequency of SMBG (tests/day) increased, HbA1c decreased: r = −0.61, P <.01

Strowig SM, Raskin P. Diabetes Care. 1998;21:1694-1698.

Hypoglycemia

Hypoglycemia

• Identify hypoglycemia patterns and relate to insulin peaks

• Look for causes — Lifestyle issues

Exercise Food Alcohol

— Medical causes Altered kidney or liver function Hormonal deficiencies (eg, pituitary or adrenal) Rapid gastric emptying Hypoglycemia unawareness

National Diabetes Information Clearinghouse (NDIC). Hypoglycemia. Accessed 1/29/13 at: http://diabetes.niddk.nih.gov/dm/pubs/hypoglycemia/#symptoms.

46

15 g CHO as juice, soda, or glucose tablets

Monitoring • GLYCOHEMOGLOBIN1

– 1–2 MONTHS DURING STABILIZATION– 2–4 MONTHS ROUTINELY

• BLOOD PRESSURE—every visit1

– Probably should be measured in both supine and standing positions2

• URINE PROTEIN/MICROALBUMIN—annually1,2

• EYE EXAMS—annually1,2

• FOOT EXAMS—annually1,2

• LIPIDS—annually1,2

1. American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S11-S63. 2. AACE. Endocr Pract. 2011;17(suppl 2):1-53.

Adherence

Adherence to Insulin in Pediatric Type 1 Diabetes

• Meta-analysis of 21 studies (N = 2492)• Increased adherence is associated with

decreased HbA1c values– Greater association pre-DCCT vs post-

DCCT, possibly due to increased complexity of regimens

Hood KK, et al. Pediatrics. 2009;124:e1171-e1179.

Adherence During Transition to Adolescence in Type 1 Diabetes

• 2-year longitudinal, multisite study of youth aged 9–11 (N = 225)• HbA1c increased (8.2 to 8.6%, P <.001)• Blood glucose monitoring frequency decreased

(4.9 to 4.5/day; P <.02) • Change in HbA1c associated with change in blood

glucose monitoring frequency (P <.001)

Rausch JR, et al. Diabetes Care. 2012;35:1219-1224.

Adherence to Insulin in Adults with Diabetes

• Internet survey of US adults (N = 502)• 57% reported skipping insulin injections

– 20% regularly skip insulin injections• Risk factors for intentional insulin omission

– Type 2 vs type 1 diabetes– Higher number of injections– Perceived injection burden

Interference with daily activities Pain Embarrassment

Peyrot M, et al. Diabetes Care. 2010;33:240-245.

Global Attitudes of Patients and Physicians in Insulin Therapy

(GAPP) Study• Multinational internet survey

– 1250 physicians– 1530 patients age ≥18 (n = 180 with type 1 diabetes)

• Patients – Overall: 33.2% reported being nonadherent ≥1 day in

previous month (mean 3.3 days)– US: 41.9% reported being nonadherent

2nd highest level among 8 countries in study• Physicians

– 72.5% reported that some patients do not take insulin as prescribed

Peyrot M, et al. Diabet Med. 2012;29:682-689.

Most Common Reasons for Insulin Omission/Nonadherence

• Was too busy• Was traveling• Skipped meals• Stress or emotional problems• Embarrassment• Difficult to take it at the same time every day

Peyrot M, et al. Diabet Med. 2012;29:682-689.

Conclusions

• People with T1DM require insulin on a daily basis for survival

• Intensive diabetes treatment can prevent the development and progression of microvascular complications in diabetes

• Because there is metabolic memory, intensive diabetes treatment should be initiated as early in the course of T1DM as is possible

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