using insulin in the primary care setting: interactive cases irl b. hirsch, md university of...
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Using Insulin in the Primary Care Setting: Interactive Cases
Irl B. Hirsch, MD
University of Washington School of Medicine
Dualities(Nov, 2011)
Research Grants: sanofi-aventis, Novo Nordisk, Halozyme, Mannkind
Consulting: Cellnovo, Roche, Johnson & Johnson, Abbott Diabetes Care
Teaching Point 1, Case 1
After 1 year of attempted weight loss and rising A1C levels since his diagnosis, Mr. Henry, 51 years-old, agrees it is time to start insulin. His BMI is 28 kg/m2, his weight is 80 kg, his A1C is 8.8%, and he is currently receiving metformin, glipizide, and sitagliptin.
Decision point 1- WHICH INSULIN/INSULIN REGIMEN DO YOU START?
6
7
8
9
0 4 8 12 16 20 24
Weeks of treatment
8.6 8.6
7.5 7.4
7.1 7.16.9 6.9 6.9 6.9
Glargine NPHMean A1c
%
58% ≤ 7%
Riddle MC et al. Diabetes Care 2003;26: 3080-86
Treat-to-Target Trial Change of A1c with systematic titration of basal insulin
Consistent results using the Treat-to-Target method with glargine as basal insulin
1. Riddle M et al. Diabetes Care 2003;26:30802. Gerstein HC et al. Diabetes Med 2006;23:736 3. Bretzel RG et al. Lancet 2008;371:10734. Yki-Järvinen H et al. Diabetes Care 2007;30:13645 Schreiber SA et al. Diabetes Obes Metab 2007;9:31
Baseline Study end
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
T-T-T1
n = 367INSIGHT2
n = 206APOLLO3
n = 174INITIATE4
n = 58Schreiber5
n = 12,216
Hb
A1C
(%
)
8.6 8.6 8.7 8.78.8
7.0 7.0 7.0 6.8 7.0
∆ -1.6 ∆ -1.6 ∆ -1.7 ∆ -2.0 ∆ -1.7Teaching Point 1: Most people can reach an A1C < 7% with
basal insulin alone with baseline A1C levels in the mid-8s
A1c change from baseline % of patients attaining <7% A1c
Baseline A1c affects results of basal insulin Rx
Riddle MC et al. Diabetes 2009;58(Suppl 1): A125
2193 patients with 24 weeks systematically titrated glargine added to OAD
75
-0.963
5647
34-1.4
-1.6
-2.0
-2.6
75% of participants with baseline A1c <8% attained 7%
TEACHING POINT 2: Final A1C (with basal insulin) is
dependent on baseline A1C!
Hypoglycemiaconfirmed <3.9 mmol/L (70 mg/dL)
Hypoglycemiarequiring assistance
Baseline A1c does not affect hypoglycemia risk2193 patients with 24 weeks systematically titrated glargine added to OAD
Riddle MC et al. Diabetes 2009;58(Suppl 1): A125
<8.08.0-8.4
8.5-8.99.0-9.4
≥9.5
Titration of insulin was stopped at appropriate levels of risk
50%
1.5%
Back to Mr. Henry
15 units of insulin glargine is started, and over the next 4 months his dose was titrated to 80 units daily
The metformin, glipizide, and sitagliptin remained unchanged; on glargine he has gained 3 kg
After being on the 80 unit dose for 8 weeks, 5 months after starting the insulin, his A1C is 7.3%. Fasting glucose levels are generally in the 130-140 mg/dL range.
What now? A) Bump glargine to 90 u; B) Split glargine to 40 u BID; C) SMBG to determine prandial insulin needs; D) add pioglitazone; E) wait another 4 weeks to recheck the A1C
What About Dose Response to Insulin Glargine in Obese Patients?
20 subjects with type 2 diabetes (A1C 8.3%, BMI 36 kg/m2) injected single injections of insulin glargine into abdomen at 0, 0.5, 1.0, 1.5, and 2.0 units/kg body weight
26-hour euglycemic clamp studies, so conclusions longer than this time period were not possible
Wang Z. Diabetes Care. 2010;33:1555-1560.
Glucose Infusion Rates (GIRs) for Different Glargine Doses Injected into Abdomen
1.5 units/kg 2.0 units/kg0.5 units/kg
placebo
1.0, 1.5, and 2.0 units/kg > GIR than 0.5 units/kg, but not than each other!
1.0 units/kg
TEACHING POINT 3: although it is possible duration of insulin action is prolonged with increasing doses of
glargine, there is no difference in insulin action the 24 h after injection once dose
is > 1.0 u/kg
WAIT A MINUTE! Mr. Henry now has a BMI of 29.5 kg/m2, uses
an insulin pen for his insulin glargine-and he needs all of his ‘scripts renewed. What size pen needles do you write for?
A) 4 mm 32 G B) 5 mm 31 G C) 8 mm 31 G D) 12.7 mm 29 G
Nano Mini Short Original
Distribution of Skin Thickness Values (in mm)by Body Site and BMI
1. Small differences within each body site: obese higher (P<0.001)
2. Mulitvariate analysis between sites and genders (P<0.001) but not age (NS)
2. Thigh lowest ST values
3. Greatest difference thigh/buttocks 0.6 mm
In perspective: a 10 kg/m2 change in BMI accounts for
a 0.2 mm change in ST
Gibney MA et al: Curr Med Res Opin. 2010 Jun;26(6):1519-30
Estimates of Intramuscular (IM) Injection Risk from ST/SCT Data*
Pen Needle Length (mm) IM (%)
4 mm 0.5
5 mm 2.0
6 mm 5.5
8 mm 15.5
12.7 mm 45.0 *Assume a 90-degree insertion without pinch-up. All injection sites combined (n = 1,208)
Gibney MA et al: Curr Med Res Opin. 2010 Jun;26(6):1519-30
Hirsch LJ. Curr Med Res Opin. 2010;26:1531–1541
Study Conclusions: 4 mm and 5 mm vs. 8 mm Insulin Needles
N= 328 Equivalent glycemic control REGARDLESS
of BMI No differences in hypoglycemia between
needle lengths Strong preference for shorter needles
Ease of use, pain, overall preference
Back to Mr. Henry
A1C=7.3%, injecting 80 units of insulin glargine with 4 mm needle q HS; also receiving maximum dose metformin, glipizide, sitagliptin
He is asked to increase testing to 2-3X/day Tries to limit carbohydrates to no more than
60 grams/meal (met with nutritionist)
SMBG RESULTSB’FAST LUNCH DINNER HS 0300 h
MON 128 285
TUES 118 196
WED 136 177 248
THURS 128 144 205
FRI 162 205 307
SAT 142
SUN 122 188 265
NOW WHAT?
What to do with the glargine? What to do with prandial insulin? What to do with metformin, glipizide, and
sitagliptin?
What’s Next? Glargine is reduced to 70 units q HS Insulin aspart is started at dinner, 10 units
(10-15 min prior to dinner) Correction dose for any pre-meal BG: ISF 30
above 150 150-180 +1 unit 241-270 +4 units 181-210 +2 units 271-300 + 5 units 211-240 + 3 units 301-330 + 6 units
Sitagliptin is stopped!
NOW WHAT TO SUGGEST?
B’FAST LUNCH DINNER HS 0300
MON 116 162 10+1
221 70G
TUE 125 142 10
207 70G
WED 107 196 10+2
238 70G
THU 158 185 10+2
224 70G
Why the Interest In Glycemic Variability?
Experimental data suggests an increase in oxidative stress and activation of inflammation
May be involved with pathogenesis of vascular complications
For those on insulin high variability predicts severe hypoglycemia
A marker of insulin deficiency and poor matching of prandial insulin to carbohydrate load
Which Patient Has More Variable Fasting Glucose Data?
60 54
148 286
70 203
165 112
110 69
185 68
210 138
144 192
75 114
138 52
Joe: HbA1c = 6.5%; on liraglutide
Mary: HbA1c = 6.5%; on metformin
Mean = 123 mg% Mean = 123 mg%
SD = 51 SD = 77
Standard Deviation Our clinically available measurement of
glycemic variability Many other statistical analysis are available
but correlation will be with CGM and outcomes, not SMBG
Can determine both overall and time specific SD Need sufficient data points
Minimum 5 but prefer 10
Calculation To Determine SD Target
Ideally SD X 3 < mean
SD X 2 < MEAN (T1DM)SD X 2 < MEAN (T1DM)
Significance of a High SD Insulin deficiency (especially good with fasting blood
glucose) Poor matching of calories (especially carbohydrates)
with insulin Giving mealtime insulin late (or missing shots
completely) Erratic snacking Poor matching of basal insulin, need for CSII?
CGM?
Caveats of the SD
Need sufficient SMBG data Low or high averages makes the 2XSD<mean
rule irrelevant
Other Tricks To Reduce GV
Enough testing Don’t over-treat the lows! Reduce carbs Pramlintide/exenatide Lag times
300
Timing of Rapid-Acting Analog Insulin Injection Alters PPG in Type 1 Diabetes Mellitus
Rassam AG, et al. Diabetes Care. 1999;22:133-136.Cobry E, et al. Diabetes Technol Ther. 2010;12:173-177.
8.6 kcal/kg breakfast
Minutes
BG
Lev
el
(mg
/dL
)
288
252
216
180
144
108
72
36
0-30 0 30 60 24090 270120 150 180 210
–30 m–15 m
0 m+15 m
Injection-Meal Interval (minutes)
Insulin Lispro
300
Standardized breakfast
Minutes
BG
Lev
el
(mg
/dL
)
288
252
216
180
144
108
72
36
0-30 0 30 60 24090 270120 150 180 210
–20 m0 m
+20 m
Insulin Glulisine Injection-Meal Interval (minutes)
Now…Back to Mr. Henry
He is currently taking insulin glargine, 50 u q HS with premeal insulin aspart, 2-5 u ac breakfast, 10-15 units ac lunch and dinner with an insulin sensitivity factor of 25 (1 unit corrects 25 mg/dL) above 150 before meals, 200 at HS.
A1C = 6.7% What does the meter download suggest?
Mr. Henry’s Download Statistics Summary (30 days)
Frequency of testing = 3.2X/dayFasting mean/SD: 114 + 24AC lunch mean/SD: 122 + 42AC dinner mean/SD 140 + 49HS mean/SD: 179 + 88Overall: 135 + 42
Conclusions:
1. Still too much basal insulin
2. Needs help with dosing at dinner (missing doses?)
3. Still making lots of insulin!
4. Need to look at downloaded “logbook” to understand specifics (insulin not yet downloadable) and if ISF is correct
Teaching Point 4
Downloading of glucose data is extremely helpful to see patterns not otherwise noted for those checking more than 2X/day. These downloads will become more accessible over the next few years with the use of tablets and smartphones
Mr. Spar Tan
A 56 year-old mildly mentally retarded Caucasian man presents with a random blood glucose found to be 435 mg/dL. There is no family history of diabetes.
He lives with his brother who mentions nocturia and 10 pound weight loss over the past month. The patient’s only complaint is erectile dysfunction.
Exam is significant for a BMI of 32 kg/m2, BP 155/95, HR 88, mild acanthosis nigricans, normal fundi and vibratory sensation on his great toes.
Mr. Spar Tan, cont
Glucose 435 mg/dL, all other electrolytes WNL except sodium of 133.
HbA1C 14.0% (normal 4-6%) Urine ketones: negative
What would you suggest at this time?A) Begin combination glipizide/pioglitazoneB) Begin basal-bolus insulinC) Begin basal insulin aloneD) Begin twice daily NPH/regular
Teaching Point(s) 5
Type 1 diabetes can occur at any age Type 1 diabetes can occur in obese patients While acute presentation can be seen in type
2 diabetes, it is more common in type 1 diabetes and while sorting out the specific etiology of the diabetes, initiating insulin is never the wrong therapy
The best two auto-antibodies for this age group is GAD65 and IA-2 (ICA-512)
Mr. Bill Dog
Ms. Duck is a 54 year-old woman who will be having a pancreatectomy . What will you tell her she will require for insulin therapy after his surgery?
A.Basal insulin aloneB.Pre-mix insulin, 0.5 u/kgC.Basal-bolus insulin, 0.7 u/kgD.Basal-bolus insulin, 0.25 u/kgE. GLP-1 receptor agonist
Teaching Point 6
Pancreatectomized patients are glucagon deficient, are very insulin sensitive, and are prone to severe hypoglycemia
Mr. Grass Lee Mr. Lee, a convicted tax evader from Iowa, now
is an 81 year-old nursing home patient. He has a known 10 year history of type 2 diabetes and suffers from Alzheimer’s Disease and heart failure from a previous MI
In the nursing home over the past year he has lost 12 pounds.
For his diabetes he receives glyburide 10 mg BID His A1C is 10.4%. BID glucose testing shows all
levels between 220 and 280 mg/dL Other lab: creatinine 1.4, BUN 25, LDL-C 59
Mr. Lee (cont)
What to do now? A) Nothing B) Add a GLP-1 agonist C) Add a thiazolidinedione D) Add basal insulin E) Begin basal-bolus insulin therapy
Teaching Point 7
Many elderly patients become severely insulin deficient and often insulin is required to prevent severe symptoms, most notably falling at night from using the bathroom
Mrs. PIA
You receive a call at 5pm on a Friday from Mrs Pia that she needs a new prescription for insulin syringes. She takes 60 units of insulin detemir at bedtime and insists she uses a short insulin needle
What kind of insulin syringe to you call for her?
Teaching Point 8 Insulin syringes come in 3 volumes: 1cc (100
units) ½ cc (50 units) and 0.3 cc (30 units)
Mr. Fred I. Zone
A 55 year-old man with well-controlled type 2 diabetes treated with metformin is started on prednisone, 40 mg/day for severe asthma.
Random fingerstick glucose his second day after starting the prednisone is 355 mg/dL
What insulin regimen would serve Mr. Zone the best? A) bedtime NPH D) premeal lispro B) bedtime glargine E) bedtime glargine,
premeal lispro C) BID 70/30 premix
Tough Case (if time!)
A 53 year-old man with 5 years of type 2 diabetes presents with a HbA1c of 9.9%. He and his wife are frustrated in that he limits his carbohydrate and exercises 6X/week. His BMI is 27 and his exam is unremarkable other than he wears hearing aids. His insulin dose is 60 units of insulin glargine twice daily and premeal insulin lispro 40-50 units before meals. He cramps with metformin and pioglitazone had no impact on his glucose levels. What would you do next?
Conclusions
Our insulins are far from perfect, but if we can be creative our patients can usually do well
Thank You!