PRACTICAL INSULIN USEPRACTICAL INSULIN USEor,

how to think like a pancreas

Oliver Z. Graham, MDDepartment of Internal Medicine

Virtual Endocrinologist

“Truly understanding issues such as when touse regular insulin, when it would be better touse insulin lispro or aspart… simply requires a great deal of experience.”

--Irl Hirsch, MD, UC San Diego, Clinical Diabetes 2001

“It tends to be more difficult to manage a patient on insulin if you don’t really understandwhat you’re doing.”

--Oliver Z. Graham, MD, reflecting on personal Experience, Pittsburgh Health Center

Types of Insulin

Types of Insulin

Onset Peak Duration

Lispro/Aspart

5 min 45-60 m 3-5 hrs

Regular 30-45 m 2-3 hrs 6-8 hrs

NPH 2-3 hrs 6-8 hrs 16-20 hrs

Glargine 6 hrs Peakless 24 hrs

Types of Insulin:Lispro and Aspart (Humalog/Novolog)

Fast acting (works within 5 min) Better matches carbohydrate intake to

insulin dose Can take right before meals

Types of Insulin:Regular Slower onset and later peaking Must take 30-45 min before meals Doesn’t really match blood sugar levels,

especially with high carbo meals May lead to hyperglycemia immediately

after meals with hypoglycemia several hours thereafter

Types of Insulin:NPH Long acting, with peak at 6-10 hours May be used for AM dosing to cover

midday meals, used in PM to cover overnight

Commonly used BID as 70/30

Types of Insulin:Glargine (Lantus) A true basal insulin with a 24 hour,

peakless, predictable effect Simulates basal pancreatic insulin

secretion

70/30 (NPH/Regular) BID

2 Injections/day (ie 70/30)using regular/NPH Postprandial glucose levels for breakfast/dinner

covered by short acting insulins, lunch and overnight sugars covered by NPH

Advantage: 2 Injections/day Disadvantage:

– NPH given at supper does not last until breakfast, leading to high AM BS

– NPH in AM does not cover lunch BS well

Lispro/Glargine

4 Injections/day using Lispro/Glargine One dose basal insulin during day and overnight, with

rapid/short acting insulin covering meals Advantage:

– Allows for meal to meal adjustments of insulin in accordance to food intake, preprandial blood glucose levels, and exercise.

– With lispro, probably offers the tightest control of BS given its physiologic simulation of insulin secretion (the “poor man’s insulin pump”)

Disadvantage: – Its 4 injections

Case Study #1

See your handout for details

Question 1:

How would you go about improving John’s glycemic control?

Question #2:

If you choose insulin, should you start a long acting/short acting or both?

Relative contribution of fasting and postprandial glucose to A1C.

Starting Insulin 101

For HA1C > 9, FIX FASTING FIRST– Self monitoring on fasting glucose is easier

for most patients– Fasting glucose is primarily influenced by

stage of disease and meds• Diet and activity have limited influence on

fasting BS

– Controlling postprandial BS is difficult with poorly controlled fasting sugars

Starting Insulin 101

As you near target A1C (<7), post prandial control gets more important

Question #3:

If basal insulin, how/which do you start?– Lantus (glargine)?– NPH?

Lantus vs. NPH

Equally efficacious when added to orals in achieving HA1c value

Lantus associated with 41% lower risk of severe hypoglycemia (BS < 51)

How to start insulin gently

Continue oral agents at same dosage– Consider d/c sulfonyurea

Add single dose at 10 U or 0.15 U/kg– NPH at bedtime– Glargine anytime

How to start insulin gently, continued Have patient adjust dose by fasting BG

every 3-5 days– Increase 4 U if FBG > 140– Increase 2 U if FBG 120-140– No change if FBG < 120– Decrease dose by 2 U if FBG < 72 or sx

hypoglycemia Check in by phone in 1-2 weeks

Question #3:

What about Byetta (exanatide)? Would that be a reasonable alternative to insulin?

Byetta (exanatide)

Naturally occurring component of Gila Monster Saliva

Stimulates insulin release from pancreas, slows gastric emptying, inhibits glucagon release

Why use Byetta?

Most patients gain weight with DM tx– Insulin tx 4 lb increase for every 1% A1c

reduction With Byetta WEIGHT LOSS

– 12 pound loss at 2 years tx A1c reduction about 1.1% ? Animal studies suggest beta cell

regeneration

Why not use Byetta?

Expensive (1 year -- $2700) Long term data not available (lessons

from Avandia & Rezulin…) Nausea very common (50-60%) Because slows gastric emptying

CONTRAINDICATED in GASTROPARESIS

2 injections/day

Who might get Byetta?

Obese patients not at A1C target who are already on metformin, sulfonyurea or both or glitazone +/- metformin

Not FDA approved for pts on 3 oral agents or on insulin

How to use Byetta

Start 5 mcg BID prior to meals, titrate up to 10 mcg BID as tolerated at one month

Question #4:

Should John get Byetta?

Case study, continued

John has titrated up his Glargine to 40 U daily, and his A1c decreased to 7.8%. He then missed his next appointment, and comes back 6 months later.

Case study, continued

Current meds:– Lantus 40 U daily– Metformin 1000 BID – Glipizide 10 mg BID

HA1c 8.5% What do you do now? Are “lifestyle”

changes still worthwhile?

Exercise and DM

Studies show regular exercise – reduced A1c from 8.3 7.65%

Diet and DM

Caloric restriction and weight loss (even 5-10% of body weight) can lead to:– Improved glucose control– Improved sensitivity to insulin– Improved lipid profiles and BP

Case study, continued

Current meds:– Lantus 40 U daily– Metformin 1000 BID – Glipizide 10 mg BID

HA1c 8.5% He says his knees hurt and he doesn’t want

to start an exercise program. His diet is reasonable, but he is unable to lose more weight. How would you adjust his insulin at this time?

How to initially dose prandial insulin

– 1 unit for every 10 g carb (needs to learn carb counting) OR

– 5 units for a small meal– 8-10 units for a large meal

OR

– Start with 4 units largest meal, titrate up every three days (see algorithm)

OR

– Calculate insulin needs (0.1 U/kg prior to each meal) AND

– 1 unit additional correction factor for every 30-50 mg/dl above 100 mg/dl preprandial (see handout)

Case Study, continued

John really doesn’t want to do more than 2 injections/day. How do you manage his insulin now?

Insulin Regimens:2 Injections/ day Postprandial glucose levels for breakfast/dinner

covered by short acting insulins, lunch and overnight sugars covered by NPH

Advantage: 2 Injections/day Disadvantage:

– NPH given at supper does not last until breakfast, leading to high AM BS

– NPH in AM does not cover lunch BS well

Transition From One Regimen to Another

Case continued

John comes in two weeks later on the following DM meds:– 70/30 20 U BID– Metformin 1000 BID – Glipizide 10 mg BID

AM BS – 100, 90, 120, 111, 110 PM BS -- 150, 144, 179, 180, 168 What is your next step?

70/30 (NPH/Regular) BID

Dosage Titration for Once-Daily or Twice-Daily Insulin Regimens

Case Study #2

RR is a 32 year old type I diabetic who was first diagnosed at age 12. Her HgA1c have ranged between 10-12 over the past ten years, and she is now legally blind from diabetic retinopathy and has a creatinine of 2.6. Her current insulin regimen is N 22 (AM) N 18 (PM) as well as sliding scale regular prior to meals. There have been 3 episodes of hypoglycemia in the past 2 weeks. She now comes to your clinic for the first time in 6 months without a blood sugar log book and wants you to “fix her diabetes” as well as signing some paperwork for in home support services and giving her some vicodin for her neuropathy.

What do you think her target blood sugars should be?

Glycemic Goals forIntensive Insulin Therapy Preprandial: 90-130 1-2 Hours Postprandial: 160-180 Target HbA1c < 6.5 - 7

Intensive Insulin Therapy:Relative Contraindications Individuals with hypoglycemia awareness Individuals with recurrent, severe hypoglycemic

episodes Individuals with severe emotional disorders or

psychosocial stressors Individuals with alcohol or drug abuse problems Individuals with advanced, end stage diabetic

complications Individuals with medical conditions that can be

aggravated by hypoglycemia, I.e. cerebrovascular disease, angina, or cardiac arrhythmia

Intensive Diabetes Management, 1998

Intensive Insulin Therapy:Relative Contraindications, cont Individuals unable or unwilling to commit to the

personal effort and involvement required for intensive diabetes management

Individuals with concurrent illness and/or conditions that would functionally limit intensive management I.e. debilitating arthritis or severe visual impairment

Individuals with a relatively short life expectancy Individuals who live alone

Intensive Diabetes Management, 1998

Glycemic Goals for not-so-Intensive Insulin Therapy “Good control”: HbA1c<8 “Fair control”: pre-meal BG<200 “Do no harm control”: Avoid

hyper/hypoglycemic symptoms only One blood sugar target does not fit all

Feel proud of any HgA1c reduction

From “horrible control” to “poor control” – pat yourself on the back!!

Focus on the ABC’s

A1cBlood PressureCholesterol

Slide SourceHypertensionOnline

www.hypertensiononline.org

Diabetes: Tight Glucose Diabetes: Tight Glucose vsvs Tight BP Tight BP Control and CV Outcomes in UKPDSControl and CV Outcomes in UKPDS

StrokeAny Diabetic

EndpointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

% R

ed

uct

ion

In

Rela

tive

Ris

k

Tight Glucose Control(Average HA1c 7.9 vs 7.0)

Tight BP Control(Average 154/ 87 vs 144/ 82)

32%

37%

10%

32%

12%

24%

5%

44%

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission, Harcourt I nc.

*

*

*

**P <0.05 compared to tight glucose control

www.hypertensiononline.org

Slide SourceHypertensionOnline

www.hypertensiononline.org

17% decrease per 10 mmHg decrement in BPp<0.0001

0.5

1

5

110 120 130 140 150 160 170

UKPDS: Relationship Between BP Control UKPDS: Relationship Between BP Control And DiabetesAnd Diabetes--Related DeathsRelated Deaths

Mean systolic blood pressure (mmHg)

Haz

ard

rati

o

Adler AI , et al. BMJ . 2000;321:412-419.Reprinted by permission, BMJ Publishing Group. www.hypertensiononline.org

Organizational Guidelines – the consensus…. Per American Diabetes Association, JNC 7,

California Department of Health Services, National Kidney Foundation, Singapore Ministry of Health, Scottish Intercollegiate Guidelines Network and many others

IF DM GOAL BP < 130/80

Results From Statin Trials for Patients With Diabetes

Updated NCEP ATP III: Key Diabetes Recommendations

TLC remains an essential modality in clinical management of LDL-C lowering and the metabolic syndrome

Patients with diabetes are included in the high-risk category

Patients with diabetes plus CVD are at very high risk

– LDL-C goal of <70 mg/dL is a therapeutic option in these patients

In patients with diabetes but no CVD, LDL-C goal remains <100 mg/dL

– If at goal, initiation of lipid-lowering therapy is left to clinical judgment

In high-risk or moderately high-risk patients, drug therapy should achieve at least 30%-40% reduction in LDL-C levels

Grundy SM et al. Circulation. 2004;110:227-239.

TLC=therapeutic lifestyle changes; CVD=cardiovascular disease

ARE YOU LISTENING???ARE YOU LISTENING???Another Case Study

A 29 year old patient has a very hectic life with two children and also works part time at a drug store. Her time of meals, length of workday and levels of physical activity are variable.

Her current insulin regimen is 4R + 10N (8 AM), 8R + 14 N (Before dinner)

8 AM 12PM 6 PM 10PM 3 AM 156 111 97 63 147 98 59 301 182 124 86 87 91 191 115 46 62 165 108 132 235 78 246 89 92 57 178 97 67 164 181 106 78 138

What could account for the variability of the readings?

What affects Blood Sugars?Foods Inconsistent eating habits

– overeating or skipping meals– Altering timing of meals when on a fixed

dose insulin schedule– variations in the carbohydrate load,

glycemic index or fat content

DM and carbohydrates The amount of carbohydrates directly

affects post-prandial blood sugars. To achieve good control, patients either need to learn:

Carbohydrate Consistency: Eat the same amount of carbs at every meal for predetermined insulin dosage

Carbohydrate Counting: Count up the amount of carbohydrates in the meal, and adjust insulin dosage accordingly

DM Nutrition 101

Increase activity Decrease calories for weight loss Whole grains instead of refined grains

and starches Low saturated and hydrogenated fats Carb/meal consistency or carb counting

ARE YOU LISTENING???ARE YOU LISTENING???A Case Study

A patient who has been treated for type 1 DM for 6 years is on N25 R10 (8 AM), N15 R10 (6 PM). His BS are:

8 AM Noon 6 PM 10 PM

125 190

120 147 227

95 175 162

How would you change his regimen?

Adjusting InsulinIf glucose levels are out of target at

Check coverage provided by

Postbreakfast/prelunch Prebreak short insulin

Postlunch/presupper Prelunch short insulin and/or AM NPH

Postsupper/bedtime Presupper short insulin

Midafternoon Morning NPH or long acting insulin

Early morning Evening NPH or long acting insulin

ARE YOU LISTENING???ARE YOU LISTENING???A Case Study A patient who has been treated for Type I DM for 14

years has the following regimen: N42 + R12 (8 AM), N21 + R 15 (6 PM)

8 AM Noon 6 PM 10 PM

140 184 275 260

202 180 113 235

195 143 152 198

230 201 128 187

95 150 122 243How would you change his insulin regimen?How do you account for the blood sugar outliers?

ARE YOU LISTENING???ARE YOU LISTENING???A Case Study

His regimen :N42 + R12 (8 AM), N21 + R 15 (6 PM)

8 AM Noon 6 PM 10 PM

140 184 275 260

202 180 113 235

195 143 152 198

230 201 128 187

95 150 122 243Avg AM – 172 (excluding 95)Avg lunch 172Avg dinner 129 (excluding 275)Avg QHS 225 Change evening to N24 + R18, should improve daytime values

Adjusting insulin

Insulin adjustments should be based on average blood glucose readings, not the outliers

Changes should be made based on numbers over several days to over 1-2 weeks

Except for severe hypo/hyperglycemia, changes should be made in 10-20% increments (about 1-5U at a time)