International Forum for the Advancement of Diabetes
Research and Care, April 29–30, 2011, Athens, Greece
Geremia B. Bolli, M.D.,1Larry C. Deeb, M.D.,2,3Satish K. Garg, M.D., M.B.B.S., D.M.,4,*John L. Leahy, M.D.,5
Roger S. Mazze, Ph.D.,6David R. Owens, M.D., F.R.C.P., F.I.Biol.,7Matthew C. Riddle, M.D.,8
Phil Southerland, B.A.,9and Ellie S. Strock, A.P.R.N-B.C., F.A.A.N.P., C.D.E.10
The International Forum for the Advancement of Diabetes Research and Care brought together distinguished
international experts in diabetes to discuss diverse trends and emerging issues in diabetes therapy and man-
agement. The plenary sessions on the first day focused on trends in insulin therapy, the role of glucagon-like
peptide-1 receptor agonists in diabetes treatment, the relationship between diabetes and cardiovascular risk, and
the challenges associated with the development of clinically relevant treatment guidelines. Interactive breakout
sessions addressed the following topics: microvascular complications of diabetes; the need for a team approach
to patient education; optimal management of Asian people with diabetes; the role of continuous glucose
monitoring in assessing glucose variability; and lessons learned from biosimilar drugs. The plenary sessions on
the second day covered self-monitoring of blood glucose, treatment and prevention of type 1 diabetes, and
future directions for diabetes therapy. The meeting represented an excellent forum for the presentation of new
research and the exchange of ideas aimed at improving outcomes for people with diabetes.
on April 29 and 30, 2011. This was the third in a series of
successful meetings bringing together diabetes experts from
around the world to discuss current topics and future trends
in diabetes management. This year’s meeting, chaired by Ele
Ferrannini (University of Pisa, Pisa, Italy) and Jay Skyler
(University of Miami Leonard M. Miller School of Medicine,
Miami, FL), was attended by 400 people from 40 countries,
with a faculty comprising 27 international experts.
The opening plenary session discussed new insights into
insulin therapy, including insulin intensification strategies
and early use of insulin. The second session focused on the
potential role of glucagon-like peptide-1 (GLP-1) receptor
agonists in diabetes management, including preclinical data,
he 2011 International Forum for the Advancement of
Diabetes Research and Care was held in Athens, Greece,
the GetGoal trial program, and their use in combination with
basal insulins. The third plenary session commenced with a
roundtable discussion of the role of guidelines in the care of
people with diabetes, focusing on the challenges of making
guidelines clinically relevant as well as flexible enough to
individualize treatment and incorporate new therapeutic
advances. The roundtable was followed by presentations on
the relationship between insulin therapy and cardiovascular
diseases and the influence of genetic variation on cardiovas-
The first day concluded with parallel interactive breakout
sessions on various topics. One session focused on micro-
vascular complications, such as diabetic nephropathy, dia-
betic neuropathy, and foot ulcers, which are common and
debilitating complications of diabetes and whose occurrence
increases with the duration and severity of hyperglycemia.1,2
The growing burden of diabetes in Asia was discussed,
1University of Perugia, Perugia, Italy.
2Florida State University, Tallahassee, Florida.
3Tallahassee Memorial Hospital, Tallahassee, Florida.
4University of Colorado Denver, Barbara Davis Center for Childhood Diabetes, Aurora, Colorado.
5University of Vermont College of Medicine, Burlington, Vermont.
6WHO Collaborating Center, International Diabetes Center, St. Louis Park, Minnesota.
7Cardiff University, Cardiff, United Kingdom.
8Oregon Health & Science University, Portland, Oregon.
9Team Type 1, Atlanta, Georgia.
10International Diabetes Center, Minneapolis, Minnesota.
*Dr. Garg is Editor-in-Chief of Diabetes Technology & Therapeutics.
DIABETES TECHNOLOGY & THERAPEUTICS
Volume 13, Number 9, 2011
ª Mary Ann Liebert, Inc.
including the difficulties posed by genetic susceptibility,
underdiagnosis, and undertreatment. The efficacy and safety
of biosimilar drugs, with particular focus on how changes in
manufacturing may impact on clinical outcomes, were dis-
cussed in another session. Patient education and the role of
continuous glucose monitoring (CGM) in the assessment of
glucose variability were other topics covered by the breakout
The opening plenary session of the second day discussed
approaches to empowering people with diabetes to take
control of their disease. It started with a presentation of recent
advances in self-monitoring of blood glucose (SMBG) that
offer patients greater accuracy and convenience. The second
talk presented clinical evidence for basal–bolus therapy as a
safe and effective way to manage hyperglycemia in children
and adolescents with type 1 diabetes (T1D). Preventative
strategies for T1D were presented in the final talk of this
The Forum concluded with a look at the future of diabetes
treatment. The nearly completed ORIGIN study will provide
data on the impact of early insulin glargine therapy and x-3
fatty acids on cardiovascular outcomes in type 2 diabetes
(T2D). Current results from the field of b-cell replacement
were presented, including in vitro generation of b cells and in
vivo regeneration. The session concluded with a presentation
on the Juvenile Diabetes Research Foundation Artificial Pan-
The meeting provided a comprehensive update on clinical
research and treatment strategies that will help improve the
lives of people with diabetes both using currently available
therapies as well as with future developments in diabetes
New Insights into Fasting Blood Glucose
and Glycemic Variability
Satish K. Garg
Dr. Garg discussed new insights into fasting blood glu-
cose (FBG) and glycemic variability. The ‘‘glucose triad’’—
hemoglobin A1c (HbA1c), FBG, and postprandial blood
glucose (PPBG)—are well-established glycemic parameters
that are associated with cardiovascular complications of dia-
betes. Guidelines for the care of people with diabetes use
HbA1cas the gold standard for glycemic control, with most
guidelines recommending an HbA1clevel of <6.5% or 7.0%.
Recent data have shown that people with elevated FBG
have an increased risk of death from cancer, vascular causes,
and other causes, irrespective of the diagnosis with diabetes.3
People diagnosed with diabetes and with elevated FBG face a
twofold increase in the risk of coronary heart disease.3A 5-
year study comprising two arms—one arm treating fasting
hyperglycemia with basal insulin (targeting FBG), the other
arm treating postprandial hyperglycemia with prandial
insulin injections—did not demonstrate differences in car-
diovascular outcomes between study arms.4
Whether reductions in HbA1clevels are best achieved by
targeting FBG or PPBG, a subject of current debate, was ad-
dressed by Dr. Garg, who drew upon data from two stud-
ies.5,6A study by Monnier et al.6from 2003 analyzed diurnal
SMBG profiles of 290 non–insulin-treated T2D patients at
different levels of HbA1cto estimate the relative contributions
of FBG and PPBG to overall glycemia. Statistical analysis of
SMBG data suggested that in patients with lower HbA1cand
relatively good glycemic control, PPBG dominated hyper-
glycemic exposure. However, in those with HbA1c>8.4%,
FBG dominated hyperglycemicexposure, andtheinfluence of
PPBG decreased. This study provided the rationale for treat-
ing PPBG rather than FBG, unless HbA1cis high. A more
recent meta-analysis5compared the contributions of FBG and
more frequent SMBG measurements, a stricter definition of
hyperglycemia, and a larger sample size than in Monnier
et al.6and found that FBG dominated hyperglycemia across a
wider range of HbA1clevels than observed in the earlier
analysis (Table 1). According to Dr. Garg, focusing on fasting
hyperglycemia (even at lower HbA1cvalues) may allow more
patients to reach target HbA1clevels.
Furthermore, when these insulin-naive patients received
insulin therapy alone for 24–28 weeks, the contribution of
basal hyperglycemia to overall hyperglycemia decreased in
all patients but remained higher than previously observed,
regardless of their glycemic control at baseline.5Numerous
studies have indicated that treating to target FBG can result in
significant HbA1creductions. In T2D patients with similar
baseline levels of HbA1c, FBG at 6–12 weeks after initiating
insulin glargine predicts success in achieving HbA1c£7.0.7In
T2D patients with FBG levels titrated to 5.3mmol/L using
insulin glargine, the extent of PPBG excursion was correlated
with FBG (r=0.63, P<0.001), and PPBG excursions in patients
with T2D and FBG <5.3mmol/L were similar to those in
controls without diabetes.8These results suggest that better
control of FBG (i.e., lower FBG) reduces PPBG excursions.
An expansion of the glucose triad to a glucose tetrad—
HbA1c, FBG, PPBG, and glycemic variability—has recently
Table 1. Contribution of Basal and Postprandial Hyperglycemia to Hemoglobin A1c Levels at Baseline
and 24–28 Weeks After Initiation of Basal Insulin Across Groups with Varying Metabolic Control
Baseline After treatment intensification (24–28 weeks)
<8% 8–8.4%8.5–8.9% 9–9.4%
422 348 298245386
Average age of the patients is 59 years, with average duration of type 2 diabetes mellitus of 9 years with fasting blood glucose of 193mg/
dL and hemoglobin A1c (HbA1c) of 8.7%. Adapted from Riddle et al.5
BHG, basal hyperglycemia; PPHG, postprandial hyperglycemia.
968 BOLLI ET AL.
individuals with type 2 diabetes-results of the GINGER
study. Diabetes Obes Metab 2010;12:115–123.
42. Huxley R, Barzi F, Woodward M: Excess risk of fatal coro-
nary heart disease associated with diabetes in men and
women: meta-analysis of 37 prospective cohort studies. BMJ
43. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE,
Cull CA, Hadden D, Turner RC, Holman RR: Association of
glycaemia with macrovascular and microvascular compli-
cations of type 2 diabetes (UKPDS 35): prospective obser-
vational study. BMJ 2000;321:405–412.
44. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA:
10-year follow-up of intensive glucose control in type 2 di-
abetes. N Engl J Med 2008;359:1577–1589.
45. Action to Control Cardiovascular Risk in Diabetes Study
Group: Effects of intensive glucose lowering in type 2 dia-
betes. N Engl J Med 2008;358:2545–2559.
46. ADVANCE Collaborative Group: Intensive blood glucose
control and vascular outcomes in patients with type 2 dia-
betes. N Engl J Med 2008;358:2560–2572.
47. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N,
Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R,
Warren SR, Goldman S, McCarren M, Vitek ME, Henderson
WG, Huang GD: Glucose control and vascular complica-
tions in veterans with type 2 diabetes. N Engl J Med
48. Rhoads GG, Kosiborod M, Nesto RW, Fonseca VA, Lu SE,
Zhang Q, Foody JM: Comparison of incidence of acute
myocardial infarction in patients with type 2 diabetes mel-
litus following initiation of neutral protamine Hagedorn
insulin versus insulin glargine. Am J Cardiol 2009;104:
49. Alvarsson M, Sundkvist G, Lager I, Henricsson M, Berntorp
K, Fernqvist-Forbes E, Steen L, Westermark G, Westermark
P, Orn T, Grill V: Beneficial effects of insulin versus sul-
phonylurea on insulin secretion and metabolic control in
recently diagnosed type 2 diabetic patients. Diabetes Care
50. Alvarsson M, Sundkvist G, Lager I, Berntorp K, Fernqvist-
Forbes E, Steen L, Orn T, Holberg MA, Kirksaether N, Grill
V: Effects of insulin vs. glibenclamide in recently diagnosed
patients with type 2 diabetes: a 4-year follow-up. Diabetes
Obes Metab 2008;10:421–429.
51. Chen K, Lindsey JB, Khera A, Lemos JA, Ayers CR, Goyal A,
Vega GL, Murphy SA, Grundy SM, McGuire DK: In-
dependent associations between metabolic syndrome, dia-
betes mellitus and atherosclerosis: observations from the
Dallas Heart Study. Diabetes Vasc Dis Res 2008;5:96–101.
52. Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, Hu Y, Zhou Z,
Yan X, Tian H, Ran X, Luo Z, Xian J, Yan L, Li F, Zeng L,
Chen Y, Yang L, Yan S, Liu J, Li M, Fu Z, Cheng H: Effect of
intensive insulin therapy on beta-cell function and glycaemic
control in patients with newly diagnosed type 2 diabetes: a
multicentre randomised parallel-group trial. Lancet 2008;
53. Freemantle N, Balkau B, Danchin N, Admane K, Marre M,
Home P, Blonde L: Cardiovascular (CV) risk evaluation in
people with type 2 diabetes (T2D) on insulin therapy
(CREDIT) study—CV disease and CV risk at baseline [ab-
stract]. Diabetes 2009;58(Suppl 1):A474.
54. McEwan P, Sharplin P, Baldwin M, Evans M: Clinical
effectiveness of oral antidiabetic drugs and insulin in the
management of type 2 diabetes in UK primary care—a UK
population based study. Diabetologia 2008;51(Suppl 1):S69.
55. Riddle M, Vlajnic A, Zhou R, Orloff D, Rosenstock J: Base-
line A1C predicts the likelihood of reaching the 7.0% A1C
target with structured titration of add-on insulin glargine:
patient-level analysis of 12 studies in type 2 diabetes mellitus
[abstract]. Diabetes 2009;58(Suppl 1):A125.
56. Gerstein, HC, Yusuf S, Riddle MC, Ryden L, Bosch J:
Rationale, design, and baseline characteristics for a large
international trial of cardiovascular disease prevention in
people with dysglycemia: the ORIGIN Trial (Outcome Re-
duction with an Initial Glargine Intervention). Am Heart J
57. Tews D, Werner U, Eckel J: Enhanced protection against
cytokine- and fatty acid-induced apoptosis in pancreatic
beta cells by combined treatment with glucagon-like pep-
tide-1 receptor agonists and insulin analogues. Horm Metab
58. Thorkildsen C, Neve S, Larsen BD, Meier E, Petersen JS:
Glucagon-like peptide 1 receptor agonist ZP10A increases
insulin mRNA expression and prevents diabetic progression
in db/db mice. J Pharmacol Exp Ther 2003;307:490–496.
59. Distiller LA, Ruus R: Pharmacokinetics and pharmacody-
namics of a new GLP-1 agonist AVE0010 in type 2 diabetes
patients [abstract]. Diabetes 2008;57(Suppl 1):A154–A155.
60. Ratner RE, Rosenstock J, Boka G: Dose-dependent effects of
the once-daily GLP-1 receptor agonist lixisenatide in patients
with Type 2 diabetes inadequately controlled with metfor-
min: a randomized, double-blind, placebo-controlled trial.
Diabet Med 2010;27:1024–1032.
61. Gerich J, Fonseca V, Alvrdo-Ruiz R, Raccah D, Zieleniuk I,
Boka G, Miossec P: Monotherapy with GLP-1 receptor ago-
nist, Lixisenatide, significantly improves glycaemic control in
type2diabeticpatients [abstract]. Diabetologia2010;53:A830.
62. Seino Y, Min K, Niemoller E, Takami A: Lixisenatide sig-
nificantly improves glycemic control in Asian patients with
T2DM insufficiently controlled on basal insulin–SU [ab-
stract]. Diabetes 2011;60(Suppl 1):A278.
63. Rosenstock J, Raccah D, Koranyi L, Maffei L, Boka G,
Miossec P, Gerich JE: Efficacy and safety of lixisenatide once-
daily vs exenatide twice-daily in type 2 DM inadequately
controlled on metformin (GetGoal-X) [abstract]. Diabetes
64. Arnolds S, Dellweg S, Clair J, Dain MP, Nauck MA, Rave K,
Kapitza C: Further improvement in postprandial glucose
control with addition of exenatide or sitagliptin to combi-
nation therapy with insulin glargine and metformin: a proof-
of-concept study. Diabetes Care 2010;33:1509–1515.
65. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS,
Kwan AY, Hoogwerf BJ, Rosenstock J: Use of twice-daily
exenatide in basal insulin-treated patients with type 2 dia-
betes: a randomized, controlled trial. Ann Intern Med 2011;
66. Philis-Tsimikas A, Walker C, Rivard L, Talavera G, Reimann
JO, Salmon M, Araujo R: Improvement in diabetes care of
underinsured patients enrolled in Project Dulce: a community-
based, culturally appropriate, nurse case management and
peer education diabetes care model. Diabetes Care 2004;27:
67. International Diabetes Federation: IDF Diabetes Atlas, 4th
ed. 2009. www.diabetesatlas.org (accessed July 28, 2011).
68. Rickheim PL, Weaver TW, Flader JL, Kendall DM: Assess-
ment of group versus individual diabetes education: a ran-
domized study. Diabetes Care 2002;25:269–274.
69. Baksi AK, Al-Mrayat M, Hogan D, Whittingstall E, Wilson P,
Wex J: Peer advisers compared with specialist health
978 BOLLI ET AL.
professionals in delivering a training programme on self-
management to people with diabetes: a randomized con-
trolled trial. Diabet Med 2008;25:1076–1082.
70. Raiff BR, Dallery J: Internet-based contingency management
to improve adherence with blood glucose testing recom-
mendations for teens with type 1 diabetes. J Appl Behav
71. Tildesley HD, Mazanderani AB, Ross SA: Effect of Internet
therapeutic intervention on A1C levels in patients with type 2
72. Mazze RS: Staged diabetes management: improving diabe-
tes care world wide. Diabetes Voice 2003;48:10–13.
73. Zwar NA, Hermiz O, Comino EJ, Shortus T, Burns J, Harris M:
Do multidisciplinary careplansresult in bettercare forpatients
with type 2 diabetes? Aust Fam Physician 2007;36:85–89.
74. Mazze RS, Strock ES, Simonson GD, Bergenstal RM, eds.:
Introduction to staged diabetes management. In: Staged
Diabetes Management: A Systematic Approach, revised 2nd
ed. Minneapolis, MN: IDC Publishing, 2006:1–25.
75. Sidorov J, Shull R, Tomcavage J, Girolami S, Lawton N, Harris
R: Does diabetes disease management save money and im-
prove outcomes? A report of simultaneous short-term savings
and quality improvement associated with a health mainte-
nance organization-sponsored disease management program
among patients fulfilling health employer data and informa-
tion set criteria. Diabetes Care 2002;25:684–689.
76. Sidorov J, Gabbay R, Harris R, Shull RD, Girolami S, Tom-
cavage J, Starkey R, Hughes R: Disease management for
diabetes mellitus: impact on hemoglobin A1c. Am J Manag
77. Ceriello A, Ihnat MA: ’Glycaemic variability’: a new thera-
peutic challenge in diabetes and the critical care setting.
Diabet Med 2010;27:862–867.
78. Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE,
Testa R, Boemi M, Giugliano D: Oscillating glucose is more
deleterious to endothelial function and oxidative stress than
mean glucose in normal and type 2 diabetic patients. Dia-
79. Su G, Mi S, Tao H, Li Z, Yang H, Zheng H, Zhou Y, Ma C:
Association of glycemic variability and the presence and
severity of coronary artery disease in patients with type 2
diabetes. Cardiovasc Diabetol 2011;10:19.
80. Mazze RS: The future of self-monitored blood glucose: mean
blood glucose versus glycosylated hemoglobin. Diabetes
Technol Ther 2008;10(Suppl 1):S-93–S-101.
81. Mazze RS, Strock E, Wesley D, Borgman S, Morgan B,
Bergenstal R, Cuddihy R: Characterizing glucose exposure
for individuals with normal glucose tolerance using contin-
uous glucose monitoring and ambulatory glucose profile
analysis. Diabetes Technol Ther 2008;10:149–159.
82. Patton SR, Williams LB, Eder SJ, Crawford MJ, Dolan L,
Powers SW: Use of continuous glucose monitoring in young
children with type 1 diabetes: implications for behavioral
research. Pediatr Diabetes 2010;12:18–24.
83. Mazze RS, Strock E, Borgman S, Wesley D, Stout P, Rac-
chini J: Evaluating the accuracy, reliability, and clinical
applicability of continuous glucose monitoring (CGM): is
CGM ready for real time? Diabetes Technol Ther 2009;
84. Mazze R, Strock E, Morgan B, Wesley D, Bergenstal R,
Cuddihy R: Diurnal glucose patterns of exenatide once
weekly: a 1-year study using continuous glucose monitoring
with ambulatory glucose profile analysis. Endocr Pract 2009;
85. Di Flaviani A, Picconi F, Di Stefano P, Giordani I, Malan-
drucco I, Maggio P, Palazzo P, Sgreccia F, Peraldo C, Farina
F, Frajese G, Frontoni S: Impact of glycemic and blood
pressure variability on surrogate measures of cardiovascular
outcomes in type 2 diabetic patients. Diabetes Care
86. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder
RG, Cooper ME, Brownlee M: Transient high glucose causes
persistent epigenetic changes and altered gene expression
during subsequent normoglycemia. J Exp Med 2008;205:
87. Chemtob CM, Hochhauser CJ, Shemesh E, Schmeidler J,
Rapaport R: Does poor early metabolic control predict sub-
sequent poor control in young children with type 1 diabetes:
an exploratory study. J Diabetes 2011;3:153–157.
Address correspondence to:
Geremia B. Bolli, M.D.
Department of Medicine
University of Perugia
Ellisse, Building A, Floor +1, Room #17
Hospital S.M. della Misericordia
06129 Sant’Andrea delle Fratte
ADVANCEMENT OF DIABETES RESEARCH AND CARE979