Insulin Therapy and Other
Management Issues in Type 1
Diabetes Mellitus
Philip 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
PUTATIVE
ENVIRONMENTAL
TRIGGER
CELLULAR (T CELL) AUTOIMMUNITY
BETA CELL MASS
HUMORAL AUTOANTIBODIES
(ICA, IAA, Anti-GAD65, IA2Ab, etc.)
LOSS OF FIRST PHASE
INSULIN RESPONSE
(IVGTT)
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
GLUCOSE INTOLERANCE
(OGTT)
“PRE”DIABETES
CLINICAL
ONSET
DIABETES
TIME
With permission from Skyler JS, et al. Diabetes. 2011;60:1-8.
When to Initiate Intensive
Therapy in Type 1 Diabetes?
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
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
Retinopathy
Progression1
Laser
Rx1
Microalbuminuria2
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.
Albuminuria2
Clinical
Nephropathy3
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)
DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569.
Meta-analysis: Improved Glucose =
Reduction in Macrovascular Events
• With reduction in glucose, there is greater improvement
in macrovascular events in glucose T1DM vs T2DM*
Cardiac events
T1DM 0.41 (95% CI, 0.19–0.87)
T2DM 0.91 (95% CI, 0.80–1.03)
Peripheral vascular events
T1DM 0.39 (95% CI, 0.25–0.62)
T2DM 0.58 (95% CI, 0.38–0.89)
Combined incidence
Any macrovascular event
T1DM 0.38 (95% CI, 0.26–0.56)
T2DM 0.81 (95% CI, 0.73–0.91)
Cerebrovascular events
T1DM 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).
Stettler C, et al. Am Heart J. 2006;152:27-38.
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
Class
Agents
Human Insulin
Regular, NPH
Premixed Human
Insulin
Human 70/30
Insulin Analogs
Insulin aspart, glulisine and lispro,
insulin glargine and detemir
Premixed Insulin
Analogs
Insulin lispro 75/25, 50/50
Biphasic insulin aspart 70/30
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
Insulin Level (mU/mL)
800
Glucose Insulin Rate (mg/min)
Rapid-Acting Analogs vs Regular
Human Insulin
Regular Human Insulin
700
600
500
400
300
200
100
0
0
1
2
3
4
5
6
7
8
800
Rapid-Acting Analogs
700
600
500
400
300
200
100
0
0
1
2
Time (hours)
With permission from Woodworth, et al. Diabetes. 1993;42(suppl 1):54A.
3
4
5
6
7
Time (hours)
0.05 U/kg (n = 6)
0.2 U/kg (n = 9)
0.1 U/kg (n = 9)
0.3 U/kg (n = 3)
8
Comparison of Insulin Absorption
by Injection Site
Tmax (hours)*
Rapid-Acting Analogues
Regular Human Insulin
1.0
3.8
0.77
1.3
1.0
3.1
* 0.2 U/kg sc.
Braak EW, et al. Diabetes Care. 1996;19:1437-1440.
Management of Type 1 Diabetes
Intensive Diabetes Management
Defined by
• Goals of Therapy
• Tools of Therapy
• Systems of Therapy
Intensive Diabetes Management
Goals
• Near-normal glycemia
• Near-normal glycohemoglobin
• Prevention of complications
• Absence of hypoglycemia
Intensive Diabetes Management
Elements of Management
• 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)
Intensive Diabetes Management
Elements of Management
• Frequent contact between patient and health
care providers
• Patient education and motivation
• Psychological support
• Assessment (glycohemoglobin)
Intensive Diabetes Management
Components of Insulin Replacement
• Basal
• Meal-related
Basal Bolus Therapy
Basal/Bolus Idealized Absorption of
Analog Insulin
75
Plasma Insulin (mU/mL)
Breakfast
Lunch
Dinner
Bedtime
Lispro/Aspart/Glulisine
50
25
Glargine/Detemir
0
4:00
8:00
12:00
16:00
Time
Courtesy of Davidson JA.
20:00
24:00
4:00
8:00
Insulin Pumps
Insulin Pump Delivery
Rapid-Acting Analogs
Bolus
100
B
Bolus
Bolus
L
D
mU/mL
80
60
40
Continuous infusion
for basal delivery
20
0600
0800
1200
B=breakfast; L=lunch; D=dinner
Courtesy of Davidson JA.
1800
Time of Day
2400
0600
Insulin Pumps
Wearing the Insulin Pump
Intensive Diabetes Management
Insulin Dose Distribution
• 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
Intensive Diabetes Management
Preprandial Algorithms
• Insulin dosage
• Insulin timing
• Meal size
• Meal content
Intensive Diabetes Management
Insulin Dose Changes
• Supplements
• Adjustments
Intensive Diabetes Management
Insulin Dose Changes
• Supplements
– Compensatory
– Anticipatory
Intensive Diabetes Management
Insulin Dose Changes
• Compensatory supplements
– Based on prevailing blood glucose
– Corrects blood glucose outside “target”
range
– Alters basic dose for that point in time
Intensive Diabetes Management
Compensatory Supplements
• 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
Per Dr. Raskin.
• Fast-acting insulin
–
–
–
–
–
–
–
Decrease 2 units
Decrease 1 unit
Take usual dose
Increase 1 unit
Increase 2 units
Increase 3 units
Increase 4 units
Intensive Diabetes Management
Insulin Dose Changes
Mealtime Questions
• 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?
Intensive Diabetes Management
Insulin Dose Changes
• Adjustments
– Based on pattern over several days
– ~10% increase or decrease in insulin
component preceding BG measurement
– Change one component at a time
Intensive Diabetes Management
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)
Intensive Diabetes Management
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
Intensive Diabetes Management
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
Intensive Diabetes Management
Contraindications
• Hypoglycemia unawareness
• Counterregulatory unresponsiveness
• Age
• Medical reasons, debilitated, short life
expectancy, malignancy, etc
Intensive Diabetes Management
Benefits of Insulin Pump Therapy
• Allows for flexibility in schedule
• More physiologic and reproducible
• Insulin delivery more predictable
• Less hypoglycemia (exercise)
Intensive Diabetes Management
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.
15 g CHO as juice, soda, or glucose tablets
46
47
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 postDCCT, 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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