The Importance of Glycemic Control, the Potential

Benefits of New Technologies, and the Need for

Additional Research in Medicare Populations
Presentation to the Medicare Coverage Advisory Committee
Aaron Kowalski Ph.D.
Director, Strategic Research Projects
Juvenile Diabetes Research Foundation (JDRF)
August 30, 2006

1
 About JDRF

 JDRF’s mission: to find a cure for diabetes and its

complications through research
 JDRF is the leading charitable funder of type 1
diabetes research worldwide ($140 million a year)
 JDRF was founded in 1970 by the parents of
children with type 1 diabetes, and JDRF's
volunteers -- who have a personal connection to the
disease -- are the driving force behind JDRF's
commitment

2
 Tight Glycemic Control is the
Recommended Standard of Care
 American Diabetes Association (ADA) (ADA, 2006.)
› Glycemic control is fundamental to the management of diabetes
› The HbA1c (A1c) goal for patients in general is an A1c goal of <7%
› The goal of therapy is to achieve an A1c as close to normal as possible
(representing normal fasting and postprandial glucose concentrations) in
the absence of hypoglycemia
 American Association of Clinical Endocrinologists (AACE) (AACE, 2002)
› A1c level of 6.5% or less
› The threat of hypoglycemia can often be minimized with more frequent
blood glucose monitoring
 American Geriatrics Society Panel for Improving Care for Elders with
Diabetes (Brown et al., 2003)
› A1c <7% for those with “good functional status”
› 8% for frail older adults, those with life expectancies less than 5 years
and in whom the risks of tight control outweigh the benefits

3
 Hemoglobin A1c Levels are Elevated in the
United States and Appear to Have Plateaued

 Reported at Diabetes Mellitus Interagency

Coordinating Committee (DMICC) (DMICC, 2005)
› CDC: NHANES III – Mean A1c 7.7%, NHANES II – Mean
A1c 7.6%, 60% >7.0%
› Kaiser: TRIAD – A1c’s have stayed the same or declined
slightly over the past 10 years
› VA : 59% of people with diabetes above A1c 7.0%

 Summary: Many factors, but tools may be

suboptimal for reducing A1c below 7.0%

4
 Hyperglycemia Causes Complications
in Type 1 and Type 2 Diabetes

 Lower A1c confers significantly reduced risk of

microvascular and macrovascular complications:
› Diabetes Control and Complications Trial (DCCT) – Type
1 (Diabetes Control and Complications Trial Research Group, 1993)
› Epidemiology of Diabetes Interventions and Complications
(EDIC) – Type 1 (DCCT/EDIC Research Group, 2000, Nathan et al., 2005)
› UK Prospective Diabetes Trial (UKPDS) – Type 2 (UKPDS
Group, 1998)

› Benefits were realized in as soon as three years

5
 There are Common Pathways in
Diabetes Complications
Peripheral & Autonomic Neuropathy
Glucose

Polyol
Pathway

Hexosamine
AGE Formation Pathway

Cellular
Oxidative ROS
Dysfunction
Stress
ROS Vascular
Nephropathy
Damage
Cell
Damage Retinopathy

Different complications (eye, kidney, nerve, blood vessels)

arise from limited number of triggers perturbing a limited
number of metabolic pathway(s) (Brownlee, 2001)
6
 Hypoglycemia Remains a Significant Burden

 Hypoglycemia
› Is a real obstacle to tight glycemic control (Report from
the American Diabetes Association Workgroup on Hypoglycemia, 2005, Cryer et al.,
2003)

› Is a source of significant morbidity in older adults

with diabetes (Kennedy et al., 2002)
› Elderly are at increased risk for hypoglycemic
coma (Ben-ami et al., 1999)
› Elderly have reduced awareness of the
autonomoic symptoms of hypoglycemia (Meneilly et al.,
1994)

7
 Significant Glycemic Variability is Found
in both Type 1 and Type 2 Diabetes

 Type 1 Patients (Bode et al., 2005):

› 9.6% (2.3 hours) hypoglycemic
› 30% (7.2 hours) hyperglycemic

 Type 2 Patients (Bode et al., 2005):

› 4.2% (1.0 hours) hypoglycemic
› 28.7% (6.9 hours) hyperglycemic

8
 Variability May Exacerbate Complications Pathways

 Intensive management may reduce risk of

developing complications by both reducing
A1c and by reducing variability (Brownlee and Hirsch,
2006)

 Monnier et al.(2006):
› Type 2 Patients – Mean Age 63.6
› Mean A1c – 9.6%
› Acute Glucose Swings Activate Oxidative Stress
Pathways

9
 Tight Glycemic Control Improves Outcomes for all
People with Diabetes – the Young and the Elderly

 Lower A1c equals:

› Less blindness, less renal failure, fewer amputations,
fewer strokes, fewer heart attacks

 And continues to be critical in the elderly

› Increased survival for those on dialysis (Oomichi et al., 2006)
› Decreased post-operative morbidity (Ben Ami et al., 1999)
› Prevents progression of retinopathy (Morisaki et al., 1994)
› Prolonged hospitalization with exacerbated congestive
heart failure (Bhatia et al., 2004)
› Better cognitive function (Meneilly et al., 1993, Gradman et al., 1993)

10
 Better Glycemic Control Increases Survival for
People with Diabetes on Dialysis

(Oomichi et al., 2006)

11
 Better Glycemic Control Reduces Post-Operative
Morbidity in Elderly People with Diabetes

› Dronge et al., 2006

› Median age = 71 years
› Primary outcomes = infectious complications,
including pneumonia, wound infection, urinary
tract infection, or sepsis
› CONCLUSION: Good preoperative glycemic
control (A1c levels <7%) is associated with a
decrease in infectious complications across a
variety of surgical procedures

12
 Better Glycemic Control Reduces Hospitalization
Time for Elderly People with Diabetes and CHF

› Bhatia et al., 2004

› Patients with diabetes admitted to a tertiary care center with
exacerbation of Congestive Heart Failure (CHF)
› Mean Age = 76.5
› In-hospital glycemic control strongly correlated positively with the
number of days of hospitalization
› Admission blood glucose level also showed a strong positive
correlation with the days of hospitalization
› Mean hemoglobin A1c correlated positively with the number of
days in the hospital
› 51 patients with uncontrolled diabetes (A1c >7%) were
hospitalized for a mean period of 6.3 +/- 3.2 days, in comparison
with a mean duration of 3.2 +/- 1.9 days for the 49 patients with
good outpatient glycemic control (A1c < or =7%)

13
 Better Glycemic Control Prevents the Progression
of Retinopathy in Elderly People with Diabetes

› Morisaki et al., 1994

› Non-insulin-dependent patients with diabetes ≥ 60 years
of age
› The progression rates of retinopathy as a function of the
mean A1c during the follow-up were as follows: lower than
7%, 2%; 7-8%, 20%; 8-9%, 40%; more than 9%, 61%
› Only A1c was a significant risk factor for progression of
retinopathy
› CONCLUSIONS: Control of diabetes mellitus is the
most important factor associated with prevention of
progression of retinopathy in elderly patients

14
 Better Glycemic Control Improves Cognitive
Function in Elderly People with Diabetes

› Meneilly et al.,1993: Improved glycemic control

in the elderly patient with NIDDM may have
beneficial effects on selective areas of cognition
› Gradman et al., 1993: Verbal learning and
memory may improve with improved glycemic
control

15
 New Technologies Hold Potential to
Improve Control

 Continuous Glucose Sensors Show Considerable

Promise in Preliminary Studies(Presentations 2005 and 2005, Garg
et al. 2006, Bailey et al., 2006)

 Preliminary Studies have shown:

› Statistically significant reductions in A1c (Presentations 2005 and 2005,
and Bailey et al., 2006)

› Statistically significant reductions in hypoglycemia (Garg et al.,

2006)

› Statistically significant increase in time spent in target

range (Garg et al., 2006A-B)
› Benefits in both type 1 and type 2 patients – young and
adults (Garg et al. 2006A-B, Bailey et al. 2006)

16
 New Technologies Provide Additional Information

 Provide both point-in-time and glucose

trends
 Alarm at hyper and hypoglycemic thresholds
 Tells people with diabetes whether their
glucose level is trending upwards or
downwards, allowing them to adjust their
insulin, diet and exercise to prevent highs
and lows

17
 JDRF Plans Prospective Studies in Elderly

 The JDRF Artificial Pancreas Project

› Aims to “close the loop” – tying insulin delivery to
continuous glucose sensing
› Aims to bring new technologies to people with
diabetes that will improve glycemic control and
diabetes outcomes
› Plans to fund outcome-based continuous sensor
trial in over 65 patients with IDDM
› Would like feedback on outcome prioritization

18
 Potential JDRF Studies will Examine
Diabetes Outcomes in Over 65 patients

 Randomized controlled trial

 Primary outcomes of A1c and Hypoglycemia
 Secondary outcomes of quality of life,
glycemic variability, time in target
 Economic analysis – i.e. fewer
hospitalizations, reduced morbidity
 JDRF-funded: Independent

19
 References

American Diabetes Association. Standards of medical care in diabetes -2006. Diabetes Care. 2006; 29
Suppl 1:S4-42.
Bailey T., Kaplan R., Schwartz S. Reduction in A1c with Real-Time Continuous Glucose Monitoring:
Interim Results from a 12-Week Clinical Study. ADA Late breaking Abstract 1-LB. 2006 Annual
Scientific Sessions.
Ben-Ami H, Nagachandran P, Mendelson A et al. Drug-induced hypoglycemic coma in 102 diabetic
patients. Arch Intern Med 1999; 159: 281–284.
Bhatia V, Wilding GE, Dhindsa G, Bhatia R, Garg RK, Bonner AJ, Dhindsa S. Association of poor
glycemic control with prolonged hospital stay in patients with diabetes admitted with
exacerbation of congestive heart failure. Endocr Pract. 2004; 10: 467-71.
Bode BW, Schwartz S, Stubbs HA, Block JE. Glycemic characteristics in continuously monitored
patients with type 1 and type 2 diabetes: normative values. Diabetes Care. 2005; 28: 2361-6.
Brown AF, Mangione CM, Saliba D, Sarkisian CA; California Healthcare Foundation/American
Geriatrics Society Panel on Improving Care for Elders with Diabetes. Guidelines for improving
the care of the older person with diabetes mellitus. J Am Geriatr Soc. 2003; 51(5 Suppl
Guidelines): S265-80.
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414:
813-20.
Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic
Complications. JAMA. 2006; 295: 1707-8.
Cryer P, Davis SN, and Shamoon, H.,. Hypoglycemia in Diabetes, Diabetes Care. 2003; 26: 1902-12.

20
 References

Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of
diabetes on the development and progression of long-term complications in insulin-dependent
diabetes mellitus. N Engl J Med 1993; 329: 977-986.
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a
trial of intensive therapy. N Engl J Med 2000; 342: 381-389.
DMICC HbA1c, Diabetes and Public Health December 12, 2005 Summary Minutes.
http://www.niddk.nih.gov/federal/dmicc/2005/12-12-05/summary.pdf
Dronge AS, Perkal MF, Kancir S, Concato J, Aslan M, Rosenthal RA. Long-term glycemic control and
postoperative infectious complications. Arch Surg. 2006; 141: 375-80.
Garg S., Zisser H., Jovanovic L. Improvement in Glucose Excursions Using a Seven-Day Continuous
Glucose Sensor: Managing the Extremes. Abstract Number: 393-P. ADA Annual Scientific
Sessions. 2006.
Garg S, Zisser H, Schwartz S, et. al. Improvement in Glycemic Excursions With a Transcutaneous,
Real-Time Continuous Glucose Sensor: A randomized controlled trial, Diabetes Care. 2006; 29:
44-50.
Gradman TJ, Laws A, Thompson LW, Reaven GM: Verbal learning and/or memory improves with
glycemic control in older subjects with non-insulin dependent diabetes mellitus. J Am Geriatr
Soc. 1993; 41: 1305-12.
Kennedy RL et al. “Accidents in patients with insulin-treated diabetes: increased risk of low-impact
falls but not motor vehicle crashes- a prospective register-based study.” J Trauma. 2002; 52:
660-6.
Meneilly GS, Cheung E, Tessier D, Yakura C, Tuokko H: The effect of improved glycemic control on
cognitive functions in the elderly patient with diabetes. J Gerontol. 1993; 48: M117-21.
Meneilly GS, Cheung E, Tuokko H. Altered responses to hypoglycemia of healthy elderly people. J
Clin Endocrinol Metab. 1994; 78: 1341-8.

21
 References

Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by
acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type
2 diabetes. JAMA. 2006; 295: 1681-7.
Morisaki N, Watanabe S, Kobayashi J, Kanzaki T, Takahashi K, Yokote K, Tezuka M, Tashiro J,
Inadera H, Saito Y, et al. Diabetic control and progression of retinopathy in elderly patients: five-
year follow-up study. J Am Geriatr Soc. 1994; 42: 142-5.
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B;
Diabetes Control and Complications Trial/Epidemiology of Diabetes. Interventions and
Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and
cardiovascular disease in patients with type 1 diabetes N Engl J Med. 2005; 353: 2643-53.
Oomichi T, Emoto M, Tabata T, Morioka T, Tsujimoto Y, Tahara H, Shoji T, Nishizawa Y. Impact of
glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year
observational study. Diabetes Care. 2006; 29: 1496-500.
Presentations at the 9-05 EASD meeting in Athens, Greece and the 11-05 Diabetes Technology
Meeting in San Francisco.
Report from the American Diabetes Association Workgroup on Hypoglycemia, 2005. Diabetes Care
28: 1245-9.
The American Association of Clinical Endocrinologists Medical Guidelines for the Management of
Diabetes Mellitus:The AACE System of Intensive Diabetes Self-Management—2002 Update.
Endocrine Practice. 2002; Vol. 8 (Suppl. 1).
UKPDS Group. Intensive blood glucose control with sulphonylureas or insulin compared with
conventional treatment and risk for complications in patients with type 2 diabetes. Lancet. 1998;
352: 837-853.

22