®
Professional Postgraduate Services
Release Date: August 2007
Valid Until: December 2007
Sponsor
This educational activity is a component
of the National Diabetes Education Initiative®
®
(NDEI ), sponsored by
Professional Postgraduate Services® (PPS).
Professional Postgraduate Services
is a business unit of KnowledgePoint360
Group, LLC, Secaucus, NJ.
Clinicians who wish to receive CME credit for
this educational activity should do the
following: (1) read the current issue; and (2)
complete the post-test and evaluation form
included to conclude this CME activity. You
may also complete the post-test andevaluation
form on our website, www.ndei.org. To apply
for CME credit,return the completed post-test
and evaluation form to:
®
Professional Postgraduate Services
CME Dept. T196
150 Meadowlands Parkway
Secaucus, NJ 07094-1505
You may also fax the completed materials to
1 (201) 430-1441. If you have any questions,
please call 1 (800) 606-6106 Ext. 6139.
Applicants will receive a certificate of participa-
tion from PPS by return mail within 6 to 8
weeks of the date of receipt of the completed
evaluation form and post-test. Online appli-
cants will automatically receive their CME
credit certificate upon completion of the online
post-test and evaluation form.
Target Audience
This educational activity is designed for
primary care physicians, internal medicine
specialists, endocrinologists, diabetologists,
cardiologists, and other healthcare profession-
als involved in the care and management of
patients with type 2 diabetes, insulin resis-
tance, and cardiovascular disease.
Learning Objectives
With information from the latest evidence-
based studies, participants should be able to:
• Identify patients with insulin resistance, type
2 diabetes, and/or cardiovascular disease
• Select the most appropriate therapeutic
regimen for patients with type 2 diabetes
and its macrovascular and microvascular
complications
• Identify risk factors for cardiovascular disease
in patients with type 2 diabetes and select an
appropriate therapeutic regimen
Accreditation
Professional Postgraduate Services® is accred-
ited by the Accreditation Council for Continu-
ing Medical Education to provide continuing
medical education for physicians.
Professional Postgraduate Services® designates
this educational activity for a maximum of
.75 AMA PRA Category 1 Credit™.
Physicians should only claim credit commensu-
rate with the extent of their participation in
the activity.
Grantor
This CME activity is supported by an
educational grant from
Takeda Pharmaceuticals North America, Inc.
Off-Label Disclosure
Some of the drug treatments discussed in this
issue may note uses not approved by the
Food and Drug Administration. Articles
containing such uses will be noted at the end
of the article.
®
CLINICAL INSIGHTS IN
Diabetes VOLUME 10, NUMBER 8 • AUGUST 2007
MAYER B. DAVIDSON, MD,* CO-EDITOR-IN-CHIEF; BERNARD ZINMAN, MD,† REVIEWER;
TERRENCE F. FAGAN,‡ MANAGING EDITOR AND CO-WRITER; MARK A. PALANGIO,‡ CO-WRITER;
MICHELE SALERNITANO,‡ CO-WRITER
Diabetic Retinopathy and the Risk of Coronary Heart
Disease: The ARIC Study
M
acrovascular disease is the primary Of the 1,524 participants, 214 (14.7%) had
pathogenic mechanism for coronary diabetic retinopathy. There were 209 incident
heart disease (CHD), a leading cause of CHD events during the 7.8 years of follow-up,
mortality in patients with type 2 diabetes. including 34 fatal CHD, 110 incident MIs, and
Microvascular disease also plays a prominent role 154 cardiac revascularization procedures. After
in diabetes complications, and diabetic retinopa- adjusting for multivariate risk factors, diabetic
thy is a marker of microvascular disease. retinopathy was associated with an HR of 2.07
To determine if diabetic retinopathy might for incident CHD and 3.35 for fatal CHD. CHD
also be a marker for incident CHD, Cheung and risk increased with the severity of retinopathy
colleagues examined the relation of diabetic (HR 1.96 for mild/moderate retinopathy vs HR
retinopathy to incident CHD in a population- 2.69 for moderate/severe retinopathy). Diabetic
based, prospective cohort of men and women retinopathy was also associated with cardiac
with type 2 diabetes in the Atherosclerosis Risk In revascularization (HR 1.93) and incident MI (HR
Communities (ARIC) Study. The ARIC Study 1.88), and it remained significant even after ad-
included 15,792 individuals aged 45 to 64 years justing for carotid artery intima-media thickness,
at first examination between 1987-1989, with a inflammatory markers, and nephropathy. The
second examination between 1990-1992, and a association was significant in men and women
third between 1993-1995, when retinal photo- with and without hypertension.
graphs were taken of all patients. The authors noted study limitations includ-
The 1,524 patients with diabetes in this ing the use of one retinal photograph per
study had at least 1 retinal photograph gradable patient (taken without pharmacologic pupil
according to the Early Treatment of Diabetic dilation) for grading, with a high proportion
Retinopathy Study severity scale, which catego- of photographs that couldn’t be graded, possibly
rized retinopathy as absent, mild/moderate leading to an underestimation of retinopathy
(nonproliferative), and severe (nonproliferative cases. They suggest, however, that a greater
and proliferative). Patients were free of preva- number of cases would make the CHD risk
lent CHD and stroke at the time of the retinal stronger in their study.
photograph. The authors conclude that the study demon-
During 7.8 years of follow-up after the strates an association of diabetic retinopathy
retinal photography, the researchers examined with incident CHD independent of diabetes
incident CHD events in the cohort—defined as a duration and control, cardiovascular risk factors,
fatal CHD event, an incident myocardial infarc- and large artery atherosclerosis. This supports
tion (MI), or a myocardial revascularization the concept that microvascular disease may con-
procedure. They compared unadjusted survival tribute to CHD risk. They suggest that diabetes
curves by retinopathy levels and determined the patients with retinopathy may warrant a more
hazard rate (HR) ratio for CHD/retinopathy robust cardiovascular assessment and follow-up.
relation using Cox regression, adjusting for sex,
race, age, research center, education, diabetes
duration and medications, 6-year mean arterial
blood pressure, cigarette smoking, antihyperten-
sive treatment, fasting glucose, A1C, body mass Cheung N et al. Diabetic retinopathy and the risk of coro-
index, triglycerides, and total and high-density nary heart disease: the Atherosclerosis Risk in Communities
lipoprotein cholesterol levels. Study. Diabetes Care. 2007;30:1742-1746.
* Dr Davidson is Director, Clinical Center of Research Excellence at Charles R. Drew University, Los Angeles, California. He has indicated
the following relevant financial relationships: consultant for Amgen Pharmaceuticals, Amylin Pharmaceuticals, Daiichi Sankyo, Inc. and
speaker’s bureau member with Amylin Pharmaceuticals, Eli Lilly and Company, and Merck & Co., Inc.
† Dr Zinman is Director, Leadership Sinai Center for Diabetes, Mt. Sinai Hospital, Toronto, Canada. He has indicated the following relevant
financial relationships: grant/research support from Eli Lilly & Company, GlaxoSmithKline, Merck & Co., Inc., Novartis Pharmaceuticals
Corporation, and Novo Nordisk A/S; retained consultant for Amylin, Eli Lily & Company, GlaxoSmithKline, Johnson & Johnson, Merck &
Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc, and Sanofi-Aventis; speaker’s bureau for Eli Lilly & Com-
pany, GlaxoSmithKline, Merck & Co., Inc., and Novartis Pharmaceuticals Corporation.
‡ PPS staff members Managing Editor Terrence Fagan, Senior Medical Writer Mark Palangio, Writer Michele Salernitano, Program
Manager Cynthia Fontan, and CME Program Manager Wadee’ah Terry have indicated no relevant financial relationships.
1
 ®
CLINICAL INSIGHTS IN DIABETES

COMMENTARY
BERNARD ZINMAN, MD, Director, Leadership Sinai Center for Diabetes, Mt. Sinai Hospital,
Toronto, Canada.
The article by Cheung et al clearly demonstrates that there is a relationship between microvascular complications,
in this case diabetic retinopathy, and coronary heart disease (CHD). Although possible, there is little evidence that
this association represents a cause-and-effect relationship between the microvascular and macrovascular compli-
cations of diabetes. Rather, there is robust data in type 1 diabetes studies—particularly from the DCCT/EDIC (Dia-
betes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) study—that
glycemic control, as assessed by A1C, plays an important pivotal role in the development of both microvascular
and macrovascular diabetes complications. In type 2 diabetes, the traditional cardiovascular risk factors are clearly
important determinants of CHD and need to be actively targeted. It is indeed interesting that Cheung et al were
able to demonstrate that, after adjusting for traditional risk factors, retinopathy was still associated with CHD.
Thus it is conceivable that other nontraditional metabolic determinants are contributing to this association.

On-Demand CME
Activity at www.ndei.org:
“A 54-Year-Old Taxi Driver
Who Presents for Reassessment
of His Type 2 Diabetes and
New Dyspnea on Exertion.”
For primary care physicians and
other healthcare professionals
involved in the care of patients
with type 2 diabetes. Earn .75 AMA
PRA Category 1 Credit™—Free.
On-Demand CME
Activity at www.ndei.org:
“Incretins and Glycemic Control:
Understanding the Science for
Better Diabetes Management.”
For primary care physicians,
endocrinologisits, and nurse
practitioners. Earn 2.5 AMA
PRA Category 1 Credits™ and 2.4
AANP contact hours—Free.
Incretin Levels and Effect Are Markedly Enhanced 1 Month
After Roux-en-Y Gastric Bypass Surgery in Obese Patients
With Type 2 Diabetes
S tudies have shown that the majority of
patients who undergo bariatric surgery lose
50% to 70% of excess body weight, and 77%
of patients who test positive for diabetes before
surgery are free of diabetes after surgery. Lafer-
rère and colleagues designed a study to deter-
mine the role of incretins in insulin improvement
in patients with diabetes who undergo
Roux-en-Y gastric bypass surgery (RY-GBP).
They selected 8 women patients with a
mean age of 45 years with type 2 diabetes of
20.1±12.9 months’ duration, with a body mass
index (BMI) >35 kg/m2 (obese) and an A1C of
6.9%±0.7%. These patients were not taking insu-
lin, thiazolidinediones, or β-blockers before RY-
GBP, or any diabetes medications after surgery.
Seven obese women without diabetes and tak-
ing no medications were recruited as control
subjects, with similar age, body weight, and BMI.
Only the women in the diabetes group under-
went RY-GBP surgery. Liver enzymes, thyroid
function, and blood pressure were measured
both at baseline and 1 month after RY-GBP
surgery.
Baseline measurements showed that fasting
and glucose-stimulated levels of glucagon-like
peptide-1 (GLP-1) and gastric inhibitory peptide
(GIP) were approximately equivalent between
patients with diabetes and control subjects be-
fore surgery. GIP is secreted by the K cells in the
proximal small intestine, and GLP-1 is secreted by
the L cells of the distal small intestine. These 2
incretins affect postprandial insulin secretion and
are impaired in patients with diabetes.
One month after RY-GBP surgery, a substan-
tial reduction in both body weight (9.2±7.0 kg;
P=0.008) and BMI (3.5±3.6 kg/m2; P=0.029) was
observed, along with reductions in both fasting
glucose (1.60±1.45 mmol/L; P=0.017) and 120-min
glucose (4.10±1.62 mmol/L; P<0.0001) levels,
which brought the 8 patients with presurgery
diabetes into the nondiabetic range. In addition,
a substantial increase in insulin levels was shown.
During the 1 month directly following the
RY-GBP surgery, investigators administered an
oral glucose tolerance test (OGTT) and an isogly-
cemic intravenous glucose test (IsoG IVGT), both
consisting of 50 g of glucose, in the morning on
2 separate occasions less than 5 days apart,
following a 12-hour overnight fast. Blood was
sampled periodically during the 3-hour testing
period. OGTT blood samples were compared
with those of the IsoG IVGT, and the difference
in β-cell responses (measured as insulin total area
under the curve [INS area under the curve {AUC}
0-180 min]) was considered the incretin effect.
Analysis found that GLP-1 AUC and peak GIP
increased significantly after RY-GBP surgery by
24.3±7.9 pmol·11-min-1 (P<0.0001) and 131±85
pg/mL (P=0.007), respectively. A significant in-
crease in the blunted incretin effect, from
7.6%±28.7% to 42.5%±11.3% (P=0.005), was also
observed.
Investigators concluded that RY-GBP surgery
had a very rapid effect on incretin production
and activity, occurring less than 1 month after
surgery. This incretin effect greatly increased
glucose-induced insulin secretion, which resulted
in a substantial improvement in diabetes man-
agement. Although promising, this study was
conducted on a very small group of women with
similar ethnic backgrounds. Further testing
should be conducted to assess these effects on a
larger and more diverse group of participants.
Laferrère B et al. Incretin levels and effect are markedly
enhanced 1 month after Roux-en-Y gastric bypass sur-
gery in obese patients with type 2 diabetes. Diabetes
Care. 2007;30:1709-1716.

2

NDEI Breakfast Symposium
Diabetes Expert Forum–The Role of
Incretin Therapy in Your Practice
Friday, October 5, 2007
Chicago, Illinois
6:00 AM-7:45 AM
CME Credit: 1.25 AMA PRA
TM
Category 1 Credits and
1.25 Prescribed credits.
Free registration online at
www.ndei.org.
CME/CE Dinner Meeting in
Orange,
ange, CA for Managed Care
Providers “Type 2 Diabetes,
Metabolic Syndrome, and CVD:
Clinical Implications of Recent
Pivotal Trials.”
Date: Wednesday, September 26, 2007
at 6:30 PM.
Speaker: Steven V. Edelman, MD.
Free registration online at
www.ndei.org.
CLINICAL INSIGHTS
No Impact on All-Cause Mortality With Various Oral
Antihyperglycemic Agents Relative to Sulfonylurea
P revious work has not revealed a definitive
relationship between oral antihyperglycemic
drug therapy and mortality. With this in mind,
Kahler and colleagues evaluated the impact of
several classes of oral antihyperglycemic agents
relative to sulfonylurea monotherapy on all-
cause mortality among a cohort of patients with
diabetes from the Veterans Health Administra-
tion (VHA). This retrospective cohort study used
data obtained from the VHA Diabetes Epidemi-
ology Cohort, which is an ongoing study of
virtually all VHA patients with diabetes since
October 1996.
Individuals using oral antihyperglycemic
agents were stratified into the following groups:
sulfonylurea monotherapy, metformin mono-
therapy, metformin plus sulfonylurea, thia-
zolidinedione (TZD) alone or in combination
with other oral agents, and no drug therapy.
Drug effects on all-cause mortality were esti-
mated using multivariate mixed models. The
analysis was restricted to individuals who re-
sponded to the 1999 Large Health Survey of Vet-
eran Enrollees (LHSVE) between April 1999 and
April 2000. Sensitivity analysis odds ratios were
adjusted for propensity score plus age, diabetes
duration, A1C, creatinine level, diabetes-related
physician visits, and utilization of lipid-lowering
and hypertension medications.
A total of 39,721 patients with diabetes
who responded to the LHSVE and received care
from 125 US medical facilities were included in
the study. Among this study population, 48.0%
of patients were in the reference (sulfonylurea
monotherapy) group, 7.5% were in the
metformin group, 34.8% were in the metformin
in combination with sulfonylurea group, 1.7%
AOA/ACOFP 112th Annual Convention & Scientific Seminar
Joint ACOFP/AOA Scientific Lecture and Din
Di nner
Sunday, September 30, 2007
San Diego, California
5:30 PM – 9:00 PM
CME Hours: 3.5 Extra Credit
Register online at: www.acofp.org/education/CA_07/index.html
3
®
IN DIABETES
were in the TZD group, and 8.0% were in the
no-drug-therapy group.
Mortality rates were 5.3% with sulfonylurea
monotherapy, 2.7% with metformin monother-
apy, 3.4% with metformin plus sulfonylurea,
7.1% with TZD alone or in combination with
other oral agents, and 4.1% with no drug ther-
apy. Adjusted odds ratios and 95% confidence
intervals for all-cause mortality were 0.87 (0.68–
1.10) for metformin monotherapy, 0.92 (0.82–
1.05) for metformin plus sulfonylurea, and 1.04
(0.75–1.46) for TZD, relative to sulfonylurea
monotherapy. Adjusting odds ratios without
A1C yielded similar findings, indicating the
robustness of the original results.
This analysis did not reveal any significant
drug effect on all-cause mortality for any oral
antihyperglycemic therapy relative to oral sul-
fonylurea monotherapy. The investigators
pointed out that this study had the distinctive
ability to control for various variables that are
usually not available in database studies. Limita-
tions of the study included use of administrative
databases and short duration of the follow-up
period. Additional study is needed to evaluate
whether long-term use of oral antihyperglycemic
drug therapy reduces all-cause and cause-specific
mortality.
Kahler KH et al. Impact of oral antihyperglycemic ther-
apy on all-cause mortality among patients with diabetes
in the Veterans Health Administration. Diabetes Care.
2007;30:1689-1693.
 ®
CLINICAL INSIGHTS IN DIABETES

Clinical Insights® in Diabetes Post-Test August 2007

1) In the ARIC Study, results showed that diabetic retinopathy was associated with increased risk of:
a. Stroke
b. Nephropathy
c. Coronary heart disease
d. Neuropathy

2) In a sub-study focusing on incretin levels in 8 obese women with diabetes, which of the following was
an effect in the participants 1 month following Roux-en-Y gastric bypass surgery?
a. Significant increase in incretin effects
b. Significant decrease in body weight
c. Reduction in glucose levels to nondiabetic range
d. All of the above

3) Relative to sulfonylurea oral monotherapy, Kahler and colleagues found a significant drug effect on
all-cause mortality with:
a. Metformin monotherapy
b. Thiazolidinedione monotherapy
c. Metformin plus sulfonylurea therapy
d. No significant drug effect was found

ANSWER KEY

NDEI MISSION STATEMENT

The National Diabetes Education
® ®
Initiative (NDEI ) is a multicomponent For more information about upcoming NDEI CME and CE activities, visit us at www.ndei.org or call
educational program on type 2 diabetes 1 (800) 606-6106. Visit www.ppscme.org for information on other CME or CE activities.
designed for endocrinologists, diabe-
tologists, cardiologists, primary care
Clinical Insights® in Diabetes, Monthly is co-edited by NDEI faculty members Mayer B. Davidson, MD, and Silvio E. Inzucchi, MD.
physicians, and other healthcare
professionals involved in the care and ®
management of patients with type 2 Clinical Insights in Diabetes monthly CME e-newsletter is available at no cost to you via email.
diabetes and insulin resistance. NDEI To subscribe to receive future issues via email, please visit us online at www.ndei.org or insert
programs address issues concerning your name and email address below and fax this page back to 1 (800) 471-7716.
insulin resistance and type 2 diabetes,
from the epidemiology and patho- Name: (Please print)



























physiology of the disease and its associ-
ated complications to the therapeutic Specialty:






























options for treatment and prevention.

Email Address:





























National Diabetes Education Initiative,
NDEI, and Clinical Insights are trademarks
used herein under license. You have received this email because we believe it may be of interest to you. If you would like your
®
name to be removed from the Clinical Insights newsletter email list, please click on the following link
Copyright © 2007 Professional www.pps-sso.com.
®
Postgraduate Services .
All rights reserved.

EM-T196-5-PHYCME-0807 4

4
 ®
CLINICAL INSIGHTS IN DIABETES

Activity Code: T196-5

Issue Date: August 2007
CME Credit Availability: Through December 2007

CME Activity Evaluation/Registration Form

Participants who wish to obtain CME credit for this educational activity, please complete the contact information below, sign this form, and
fax it with the completed post-test to 1 (201) 430-1441 or mail to: Professional Postgraduate Services®, CME Dept. T196, 150 Meadowlands
Parkway, Secaucus, NJ 07094-1505. You may download previous issues of Clinical Insights® in Diabetes e-newsletters by visiting us online at
www.ndei.org.
I have completed this activity as designed: _______________________________________________________________________________
(Signature)
PLEASE PRINT CLEARLY:
Name:




























Address:




























City:















State:

ZIP Code:





Phone:


-


-



Fax:


-


-




Email Address:


























Professional Classification: MD DO PharmD RN NP
Other __________________________________________________________________________________
Specialty: Endocrinology Cardiology Internal medicine Family medicine
Other ___________________________________________________________________________________________________

Strongly Strongly
1. The activity met the stated objectives in such a way that I am better able to: Disagree Disagree Agree Agree
a. Identify patients with insulin resistance, type 2 diabetes, and/or
1 2 3 4 5 6
cardiovascular disease
b. Select the most appropriate therapeutic regimen for patients with type 2
1 2 3 4 5 6
diabetes and its macrovascular and microvascular complications
c. Identify risk factors for cardiovascular disease in patients with type 2 diabetes
1 2 3 4 5 6
and select an appropriate therapeutic regimen
2. Overall, the activity was presented in a fair-balanced manner. Yes No*
* If you checked “No,” please explain.

3. Overall, the activity was free from commercial bias. Yes No*
* If you checked “No,” please explain.

4. In reflecting on your practice, what type of impact will this educational activity have?
This program has validated my practice in the treatment of type 2 diabetes and its cardiovascular complications.
Need more information before making a change.
(Please specify what information you would require.)

5. What is the largest challenge or unmet educational need in your practice?

6. What other clinical issues are you and your colleagues challenged by that could be addressed in a CME activity? (Please specify.)

Thank you for your participation. 5