Understanding the Ups and Downs of Blood Glucose Irl B

1
Understanding the Ups and Downs of Blood Glucose
Irl B. Hirsch, M.D. University of Washington
2
Question

• Who has the greatest risk of proliferative
  diabetic retinopathy (PDR) over the next 10 years
• A 55 y/o man with type 2 diabetes for 5 years, on
  oral agents, A1c 9.0
• An 18 y/o man with 5 years of type 1 diabetes, on
  BID NPH/R, A1c 9.0
• An 18 y/o man with 5 years of type 1 diabetes, on
  CSII, A1c 9.0

Why are the risks of PDR different?
3
Postprandial hyperglycemia ? glycemic variability
Dont forget about the ups and downs!
4
Oxidative StressWhat Should You Know?

• Oxygen is critical for life respiration and
  energy
• Oxygen is also implicated in many disease
  processes, ranging from arthritis, cancer, Lou
  Gehrigs disease as well as aging
• This dangerous form of oxygen is from the
  formation of free radicals or reactive oxygen
  species, or pro-oxidants
• Normally, pro-oxidants are neutralized by
  anti-oxidants

5
Oxidative Stress What You Should Know
Oxidative Stress Imbalance between pro-oxidants
(free radicals, reactive oxygen species) and
anti-oxidants
6
Oxidative Stress Why is it Important?
Free radicals (reactive oxygen species) are known
to fuel diabetic vascular complications
7
OK, What Turns On Oxidative Stress, Free
Radicals, and Reactive Oxygen Species

• High blood glucose
• Science is confirmed on this point
• Variability in blood glucose
• Science is highly suggestive on this point

8
How Does One Measure?

• Oxidative Stress
• Urinary isoprostanes best marker of oxidative
  stress in total body
• HbA1c of oxidative stress
• Glycemic variability
• Mean Amplitude of Glycemic Excursions (MAGE)
• Standard deviation on SMBG meter download

I Hirsch
9
JAMA 2951688-97, 2006
I. Hirsch
10
Why This Study is So Important

• Oxidative stress not related to A1c, fasting
  glucose, fasting insulin, mean blood glucose
• Stronger correlation of oxidative stress to MAGE
  than to postprandial glucose levels!
• MAGE both the UPS and the DOWNS of blood glucose

I. Hirsch
11
So What Is The Significance of the Understanding
of GV?

• it suggests that different therapeutic
  strategies now in use should be evaluated for
  their potential to minimize glycemic excursion,
  as well as their ability to lower A1c.
• wider use of real-time continuous glucose
  monitoring in clinical practice would provide the
  required monitoring tool to minimize glycemic
  variability and superoxide overproduction.

Brownlee M, Hirsch IB JAMA 2951707, 2006
I. Hirsch
12
What About Long-Term Glycemic Variability?

• Pittsburgh Epidemiology of Diabetes Complications
• 16-year follow-up of childhood T1DM, N408
• Results
• Risks of coronary disease over time related to
  A1c and variability of A1c!

Diabetes 55 (Supp 1) A1, 2006
13
What We KNOW

• Risk of complications are related to
• Glycemic exposure as measured as A1c over time
• Proven
• Genetic risks
• Clearly true, but little understanding
• Glycemic variability
• Supported by most but not all studies

14
Conclusion 1

• Glycemic variability may be an important
  mechanism increasing oxidative stress and
  vascular complications

So how do we best measure glycemic variability in
our patients with diabetes?
I. Hirsch
15

Whats a better way to assess glycemic
variability?
Meter Downloads!
I. Hirsch
16
Which Patient Has More Variable Fasting Glucose
Data?
Joe HbA1c 6.5 on CSII with insulin aspart
Mary HbA1c 6.5 on HS glargine and prandial
lispro
Mean 123 mg Mean 123 mg
SD 51 SD 63
I. Hirsch
17
Standard Deviation

• A measurement of glycemic variability
• Can determine both overall and time specific SD
• Need sufficient data points
• Minimum 5 but prefer 10

I. Hirsch
18
Calculation To Determine SD Target
SD X 2 lt MEAN

• Ideally SD X 3 lt mean, but extremely difficult
  with type 1 patients

I. Hirsch
19
Significance of a High SD

• Insulin deficiency (especially good with fasting
  blood glucose)
• Poor matching of calories (especially
  carbohydrates) with insulin
• Gastroparesis
• Giving mealtime insulin late (or missing shots
  completely)
• Erratic snacking
• Poor matching of basal insulin, need for CSII?

I. Hirsch
20
Other Significance of a High SD
Increased Oxidative Stress!
I. Hirsch
21
Caveats of the SD

• Need sufficient SMBG data
• Low or high averages makes the 2XSDltmean rule
  irrelevant

I. Hirsch
22
Caveats of the SD Low Mean
Mean 81 SD 29
I. Hirsch
23
Caveats of SD High Mean
Mean 217 SD 82
I. Hirsch
24
Putting it all together

• Typical new patient visit to UW DCC
• 27 y/o woman on CSII for 5 years
• Testing 4 to 5 times daily, A1c6.4
• Major problems with hypoglycemia unawareness
• Poor understanding of basic concepts of insulin
  use despite seen by specialists for 20 years
  (last appointment with endocrinologist was no
  more than 12 min for her new patient
  appointment)

25
Question
After thinking about glycemic variability and
oxidative stress

• Who has the greatest risk of PDR over the next 10
  years?
• A 55 y/o man with T2DM for 5 years, on oral
  agents, A1c 9.0 Mean/SD 210/50
• An 18 y/o man with 5 years of T1DM, on BID N/R,
  A1c 9 Mean/SD 210/100
• An 18 y/o man with 5 years of T1DM, on CSII, A1c
  9 Mean/SD 210/75

26
The Future of Glycemic Variability Measurements
For the Future

• SD used with SMBG for over a decade with meter
  downloads underutilized
• Interquartile ratio the range where the middle
  50 of the values in a distribution falls,
  calculated by subtracting the 25th from the 75th
  percentile
• Compared to SD, IQR not influenced by outliers
• MAGE gold standard (?) but requires continuous
  glucose sensing. May be more useful as we move
  into the CGM era

I. Hirsch
27
What We Need
Data comparing these tools to markers of
oxidative stress!
I. Hirsch
28
Conclusions

• Although there is no definitive proof from a
  randomized controlled trial, the data suggests
  that glycemic variability is a risk factor for
  microvascular complications
• We have the opportunity to quantitate GV now with
  meter downloads

I. Hirsch
29
What You Should Take Away From This Discussion
A1c is not the only factor contributing to the
complications of diabetes