Diabetes Update - Integrating Clinical
Trials with EMR Practicalities
Michael Shannon, MD
PMG Endocrinology, Olympia WA
Outline of Talk
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Newly released and upcoming medications: the
incretins, DPP-IV inhibitors, and what’s coming
Revised ADA/EASD and AACE guidelines:
focus on potency, safety, cost
Introduction of EPIC project at Providence
Role of a Clinical Advancement Team in
promoting best clinical practices
The Diabetes Toolbox 2010
Drug Class (First in Class)
FDA Approval
Insulin
1922 (first use)
Sulfonylurea (chlorpropamide)
1958
Biguanides (metformin)
1995
Alpha-glucosidase inhibitor (acarbose)
1995
Thiazolidinedione (troglitazone)
Meglitinide (repaglinide)
Incretins (exenatide)
1997
1997
2005
DPP-IV Inhibitors (sitagliptin)
2006
What’s New and What’s Coming
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Incretins: GLP-1 agonists and analogs
Incretins: DPP-IV inhibitors
Sodium-Glucose Transport Proteins-2 (SGLT2) inhibitors: Dapagliflozin
Glucagon-Like Peptide-1
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Glucagon-like peptide-1 is an incretin, a gut
hormone that increases the release of insulin
Many effects of GLP-1:
Increases insulin sensitivity
 Inhibits glucagon release
 Inhibits gastric emptying
 Increases satiety and decreases food intake
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Native GLP-1 improves glucose control but
the short half-life limits its use (needs pump)
GLP-1 Agonists and DPP-IV Inhibitors
Mixed
Meal
Intestinal
GLP-1
Release
Active GLP-1
DPP4
Rapid Inactivation
Inactive
GLP-1
t1/2 = 1-2 min
GLP-1 Agonists and Analogs
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Exenatide: GLP-1 receptor agonist (BID)
Liraglutide: GLP-1 analog (QD)
Under development:
Once-weekly exenatide long-acting release (LAR)
 Taspoglutide
 Lixisenatide
 Others in various stages
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GLP-1 Inhibitors: Exenatide
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Modification of GLP-1 to prevent degrading
Modest benefit in HbA1c 0.7-1.1%
Significant nausea (52% vs 8% for insulin) and
emesis; RJ Heine et al, Ann Int Med 2005
Some weight loss as well
Significant heterogeneity in response in
clinical experience (some all-stars, some fail)
Safety warnings about pancreatitis, kidneys
Liraglutide
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Approved January 2010; once-daily injection
Associated with similar modest decrease in
HbA1c of 0.7% - 1.1% with slightly more
reduction in one trial (LEAD-6)
Less renal limitations than exenatide
Possible association with pancreatitis and there
is suggestion of rare thyroid tumors in rats so
special warnings for medullary thyroid cancer
DPP-IV Inhibitors
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Sitagliptin (Januvia) and saxagliptin (Onglyza)
and linagliptin (Tradjenta)
Associated with modest decrease in HbA1c of
0.5% - 0.8%; can be dosed with ESRD
Minimal side effects (possible more minor
infections)
All are pregnancy Category B – unclear why
Minimal long-term safety data – possible offtarget interactions with diverse DPP-IV targets
SGLT-2 Inhibitors
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Sodium-glucose cotransporter-2 is a protein that
aids in glucose reabsorption from the kidney
Natural mutation: familial renal glycosuria
Inhibition of this protein leads to increased
glucosuria – in early studies appears to reduce
A1c and body weight, with possible side effect
of increased UTIs and yeast infections
Several in development (dapagliflozin filed with
FDA, remogliflozin, sergliflozin)
Final Word on New Therapies
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None of these have been in wide use for long
Lessons of rosiglitazone: hemoglobin A1c is
a surrogate endpoint, not the true goal of care
None of these have any microvascular or
macrovascular endpoints (trials underway)
Most of these drugs cost upwards of $6/day
Interesting products – but what is their impact?
Is lowering A1c the goal of care?
Diagnosis is a fairly soft endpoint,
but death is unequivocal.
Edwin AM Gale, Lancet 2003
ADA/EASD DM2 Algorithm
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Updated in 2009 based on clinical trials and collective
clinical judgment and experience of authors

Evaluates glucose reductions, non-glycemic effects
that could reduce diabetic complications, safety,
tolerability, ease of use, and cost of each intervention
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Provides treatment algorithm with intervention tiers
DM Nathan et al, Diabetes Care 2009
ADA/EASD DM2 Algorithm
Tier 1: Well validated core therapies
At diagnosis:
Lifestyle
+
Metformin
Lifestyle + Metformin
+
Basal insulin
Lifestyle + Metformin
+
Intensive insulin
Lifestyle + Metformin
+
Sulfonylurea
STEP 1
STEP 2
Tier 2: Less well validated therapies
Lifestyle + Metformin
+
Pioglitazone
Lifestyle + Metformin
+
GLP-1 agonist
DM Nathan et al, Diabetes Care 2009
STEP 3
Lifestyle + Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle + Metformin
+
Basal insulin
Diabetes interventions by tiers
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Tier 1 Interventions (‘well-validated core’)
Lifestyle changes with diet and exercise (1.0-2.0)*
Metformin (1.0-2.0)
Insulin (1.5-3.5)
Sulfonylureas (1.0-2.0)
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Tier 2 Interventions (‘less well-validated’ core)
Thiazolidinediones (pioglitazone) (0.5-1.4)
GLP-1 agonists (exenatide) (0.5-1.0)
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Others (less A1c lowering, less evidence, or costlier):
α-Glucosidase inhibitors (0.5-0.8), Glinides (0.5-1.5)
Pramlintide (0.5-1.0), DPP-IV inhibitors (0.5-0.8)
DM Nathan et al, Diabetes Care 2009
Comments on treatment choices
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Tier 2 options may be considered when weight loss is
major goal (exenatide) or when hypoglycemia is
major concern (pioglitazone and exenatide, not rosi)
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α-Glucosidase inhibitors, glinides, pramlintide, and
DPP-4 inhibitors appropriate for selected patients
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Starting or intensifying insulin preferred to third oral
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Algorithm is cautious in use of newer treatments
DM Nathan et al, Diabetes Care 2009
AACE Algorithm
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Released by American Association of Clinical
Endocrinologists in October 2009
Stated by AACE to include a variety of choices
based on first-line, second-line, and third-line
therapies as well as secondary factors (weight,
risk of hypoglycemia)
Emphasizes wider choices
Ends up somewhat overwhelming algorithm
HW Rodbard et al, Endocrine Practice 2009
Diabetes Toolbox: A Critical Look
Drug Class
A1C%
Cost/Mo
Sulfonylureas (glimepiride, etc)
1.2-2.0
4-12
Metformin
1.2-2.0
4-12
Thiazolidediones (pio 45 qday)
0.8-1.4
245
GLP-1 agonist (exenatide 10 bid)
0.8-1.2
271
DPP-IV (sitagliptin 100 qday)
Human Insulin
Insulin Analogs (vials)
0.6-0.8
No limit
No limit
193
~25
~80
Insulin Analogs (pens)
No limit
~100
Drugstore.com
Indications for Insulin Therapy
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Severe hyperglycemia at diagnosis or at a
later point despite aggressive treatment
To meet glycemic goals - hyperglycaemia
despite maximum doses of oral agents
Decompensation of other organ systems that
limits use of other oral agents
Early cost-effective potent treatment
A Broader Toolbox Doesn’t Always
Improve Clinical Outcomes
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Diabetes is a progressive disease
More choices can decrease ability to intensify
care (SS Iyengar, 2000)
Use algorithms as a guideline (joint ADAEASD consensus statement or AACE/ACE)
Individual patients may have specific issues
that require tailoring algorithms to their needs
Guidelines need to be available and accessible!
From Trials and Guidelines to
Implementing Best Practices
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Providence Health & Services has 27 hospitals,
major health plan, ~2000 doctors
Despite this, limited ways to disseminate best
practices and learn from other regions
Two reasons for Clinical Advancement Teams:
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Collect local successes and share the team practices
and order sets that allow these successes
And… the entire system is going onto EPIC, for a
new EMR
28
Washington
Pneumonia Mortality: Prov
Centralia
Sepsis Mortality, NOT Present on
Admission, Prov Centralia
Mortality on Ventilator (use on Day
1), Prov Everett
Central Line Blood Stream
Infections, Prov Everett
Mortality on Ventilator (Use after
Day 1), Prov Sacred Heart, Spokane
Heart Failure Readmissions, Prov
Holy Family, Spokane
Sepsis Mortality, Present on
Admission, Prov Holy Family,
Spokane
29
Oregon
Pneumonia Readmissions, Prov Hood River
AMI Readmissions, Prov Milwaukie
Neonatal Morbidity/Mortality, Prov St Vincent, Portland
501-1500 grams)
(infants
Heart Failure Readmissions, Prov Milwaukie
TIE!
Out Patient Data
Percent of patients over 65 with documented pneumococcal
vaccination:
Winner: PMG South Eagle Point @ 91% [near Medford OR]
(Range: 26% - 91%; P H & S average: 51%)
Percent of ambulatory diabetics who have not had an LDL test drawn
in the past year:
Winner: PMG West Linn (in West Linn, OR--South of Portland) 29%
(range: 29% - 70%, P H & S average: 56%)
Present of ambulatory adult diabetics with most recent HgAic > 9%
who have not had a HgA1c drawn the past year:
Winner: tie between PMG North Plaza [by Providence Portland
medical Center Hospital in Portland]
AND PMG Teaching Clinic, Milwaukie (near Providence Milwaukie)
@ 12%
30
(range: 70- 12, P H & S average: 19)
Clinical Guidance for EHR Build
Clinical Advisory Council
Content Build
As Needed
Decisions
Workflow Build
Clinical Advancement
Teams
6 to 8 Collaborative
Build Sessions
As Needed
Decisions
• “Think Tanks” in 32 disciplines
• Mainly virtual every 2 weeks; one inperson orientation
•
•
•
Physicians
Travel to Seattle
April-August
Quick decisions, e.g. correcting an omission or
typographical error
Non-physician Clinicians
Clinical Advisory Council
Coordinates and oversees “Clinical Guidance” to support the Quality Strategic Framework.
Core subgroups
Safe Medication
Formulary Workgroup
Interdisciplinary
Content Review
Physician Content
Review Workgroup
Clinical Decision
Support Workgroup
Other task
forces /
workgroups
as needed
Clinical ROI Workgroup
Regulatory / Accreditation
Workgroup
32 specialty
Clinical
Advancement
Teams
Clinical Advancement Teams
ID
Wave 1: Early Readiness or
Long Review Cycles
ID
Wave 2: Shorter Review
Cycles
I
D
Wave 3: Delayed Readiness or
Short Cycles
1
Adult Primary Care
13
Dermatology
24
Behavioral Health
2
Hospital Medicine
14
Orthopedics
25
Occupational Medicine
3
Pediatrics
15
General Surgery
26
Rheumatology
4
Urgent / Immediate Care
16
Pulmonary / Sleep
27
Rehabilitation Medicine
5
Emergency Medicine
17
Neurology and Stroke
28
Infectious Disease / Travel
Medicine
6
Endocrinology and Diabetes Care
18
Neurosurgery and Spine
29
Otolaryngology and Audiology
7
Obstetrics
19
Nephrology
30
Wound Care
8
Women's Health / Breast Health /
Gynecology
20
Pain Management /
Anesthesiology
31
Radiology
9
Heart and Vascular
21
Urology
32
Ophthalmology
10
Oncology
22
Gastroenterology
11
Physiatry
23
Critical Care
12
Palliative Care
34
Who is on a
Clinical Advancement Team?
Clinical Advancement Teams
Physicians
Non-physician
Clinicians
Ambulatory
Inpatient
Endocrinology/Diabetes: 2 endos, 2 hospitalists,
3 PharmD, 3 PCPs, 3 nurse specialists, 4 CDEs, and one
laboratory specialist
Inclusive “Mountain” of
Subject Matter Experts
Clinical Champions
SME representatives
CA
T
Translate clinical input into the
EHR
Phone, email
Print outs
Quick conversations
Section meetings
hundreds of
Subject Matter
Experts
CAT Team: “People Skills” for EPIC
Clinical Champions
SME representatives
Translate clinical input into the
EHR
CAT Goals to Achieve
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Order sets that are usable and up to date (no,
they don’t still make insulin ultralente)
Workable dashboard for best clinical practices
When was my last diabetic eye exam?
 How few clicks to order a urine microalbumin?
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Extractable data for disease management
registries and (likely) for payor demands/ACO
Find local successes and disseminate them
ADA/EASD DM2 Algorithm
Tier 1: Well validated core therapies
At diagnosis:
Lifestyle
+
Metformin
Lifestyle + Metformin
+
Basal insulin
Lifestyle + Metformin
+
Intensive insulin
Lifestyle + Metformin
+
Sulfonylurea
STEP 1
STEP 2
Tier 2: Less well validated therapies
Lifestyle + Metformin
+
Pioglitazone
Lifestyle + Metformin
+
GLP-1 agonist
DM Nathan et al, Diabetes Care 2009
STEP 3
Lifestyle + Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle + Metformin
+
Basal insulin
Content to Review

Inpatient:
Diabetic Ketoacidosis Admission
 Insulin drip order set
 Subcutaneous Insulin order sets
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Outpatient:
Diabetes Outpatient Visit
 Thyroid disease
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Special groups: pediatrics, obstetrics
CAT Team: Identifying Barriers
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Fear of loss of autonomy
Fear of technology
changes to workflow
Generalized resistance to
intrusion on “the way it’s
always been” (territorial
behavior)
Many ways to contribute feedback
•
•
•
•
•
Add a comment to the online collaboration tool
Phone / email your Clinical Champion or
subject matter expert representative
Discuss at a sub-section meeting or team
meeting
Physician liaisons / point persons: print-outs
Quick conversations
Conclusion
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There are interesting new therapies available
and on the horizon, but all still have limited
long-term safety and hard endpoint data
The ADA/EASD guidelines support first-tier
use of metformin, sulfonylureas, and insulin,
with second-tier use of GLP-1 and pioglitazone
Providence will use EPIC to take best local
practices and spread success across system
Clinical Advancement Teams will draw out
local experts to grow best care in Providence
Diabetes Quality Metrics are Here
Pay for Performance is Evolving
EMR and Integration are Continuing
and our diabetes care can’t be “last in”