The Importance of Glycemic Control, the Potential Benefits

1
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
2
About JDRF

• JDRFs 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

3
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 lt7
• 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 lt7 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

4
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 gt7.0
• Kaiser TRIAD A1cs 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

5
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

6
There are Common Pathways in Diabetes
Complications
Peripheral Autonomic Neuropathy
Glucose
Polyol Pathway
Hexosamine Pathway
AGE Formation
Oxidative Stress
Cellular Dysfunction
ROS
ROS
Vascular Damage
Nephropathy
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)
7
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)

8
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

9
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

10
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)

11
Better Glycemic Control Increases Survival for
People with Diabetes on Dialysis
(Oomichi et al., 2006)
12
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 lt7) is associated with a decrease in
  infectious complications across a variety of
  surgical procedures

13
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 gt7)
  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 lt or 7)

14
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

15
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

16
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)

17
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

18
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

19
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

20
References

• American Diabetes Association. Standards of
  medical care in diabetes -2006. Diabetes Care.
  2006 29 Suppl 1S4-42.
• 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 281284.
• Bhatia V, Wilding GE, Dhindsa G, Bhatia R, Garg
  RK, Bonner AJ, Dhindsa S. Association of poor
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References

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