Diabetes Research and Clinical Practice - Volume 120 - Supplement 1

liraglutide, a GLP-1 receptor agonist, suppressed the progres-

sion of nephropathy. These results indicated that GLP-1 has a

crucial role in protection against diabetic nephtropathy(2).

We have next examined the effects of linagliptin, a DPP-4

inhibitor, on KKTa-Akitamice. Linagliptin treatment increased

urinary sodium excretion, in addition to suppression of albu-

minuria. Increased urinary sodiumexcretionwas still observed

in GLP-1 receptor-deficient KKTa-Akita mice but not observed

in liraglutide-treated KKTa-Akita mice, indicating that

increased urinary sodium excretion is GLP-1-independent.

SDF-1 expression was increased in glomerular podocytes and

distal nephrons in diabetic mice and linagliptin further

augmented renal SDF-1 expression. As treatment with SDF-1

receptor antagonists with KKTa-Akita mice reduced urinary

sodium excretion, DPP-4 inhibition, independent of GLP-1

receptor signaling, contributes to protection of the diabetic

nephropathy through SDF-1-dependent amelioration of renal

hemodynamics(3).

References

(1) Yamada Y.,

et al. J Diab Invest

(2016).

(2) Fujita H.,

et al. Kidney Int

(2014).

(3) Takashima S.,

et al. Kidney Int

(in press)

S18-4

GLP-1 receptor agonists and cardiovascular safety

Yu-Yao HUANG

Medical Nutrition Therapy and Endocrinology &

Metabolism, Chang Gung Memorial Hospital and Chang Gung

University, Taoyuan, Taiwan

Clinical treatment with glucagon-like peptide-1 receptor

agonists has shown benefits in weight reduction, blood

pressure lowering, improving dyslipidemia and cardiovascular

surrogate biomarkers. Nevertheless, long-term cardiovascular

outcome trials (CVOT) for three DPP4-inhibitors (the SAVOR-

TIMI53, EXAMINE, and TECOS trials) all showed non-inferior

results for major adverse cardiovascular events (MACE) com-

pared to standard treatment. Moreover, a slight increase in the

risk of heart failure was observed in the SAVOR-TIMI53 trial,

raising concerns of cardiovascular safety in incretin-based

therapy. More recently, two CVOTs of GLP-1 receptors have

been reported. The ELIXA trial showed non-inferior results,

while the LEADER trial demonstrated beneficial cardiovascular

effects. Compared to the EMPA-REG trial in which reductions

were found in cardiovascular mortality and heart failure, the

LEADER trial reported that liraglutide treatment significantly

reduced both cardiovascular mortality and the risk of MACEs.

In this talk, we review the published trials in detail and

examine the findings related to cardiovascular safety and

treatment efficacy.

Injectable Antidiabetic Agents (II): Insulin

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New developments in basal insulin therapies

Avivit CAHN

Hebrew University of Jerusalem, Jerusalem, Israel

Diabetes mellitus is a growing epidemic worldwide. Insulin

therapy has been used for nearly a century now, saving the

lives and improving the care of millions of patients. Insulin

therapy has undergone significant evolution over the years

attempting to mimic normal physiology and accommodate to

the normal daily routine of our patients. The long-acting

insulin analogs glargine and detemir showed lower variability

and longer duration of action compared to the earlier NPH

insulin and can be administered only once a day. Novel ultra-

long acting basal insulins introduced to the market in recent

years further enhanced these benefits due to their even longer

half-life. Insulin degludec forms hexamers and di-hexamers

in the subcutaneous tissue resulting in a depot from which

the monomers are slowly released. Clinical studies in patients

with type 1 and type 2 diabetes demonstrated similar reduc-

tions in HbA1c with degludec vs. glargine with lower rates of

nocturnal hypoglycemia. Insulin glargine U-300 forms a sub-

cutaneous depot with a smaller surface area compared to

insulin glargine U-100 creating a prolonged release and a

flatter PK/PD profile. Similar HbA1c reduction and lower rates

of hypoglycemia were observed with the use of glargine U-300

compared to glargine U-100 in patients with type 1 and type 2

diabetes. PEGylation of insulin lispro resulted in a prolonged

half-life of insulin as well, yet due to concerns regarding its

liver safety and local lipohypertrophy and lipodistrophy,

further development of this compound was terminated.

Insulin formulations remain a major topic of research and

development including combinations of ultra-long acting

basal insulin with short acting insulin, as well as with GLP-1

receptor agonists recently launched. Novel methods of further

enhancing insulin action, or creating

“

smart

”

glucose-respon-

sive insulins are being explored and hopefully the future will

hold better, safer and more efficient methods of insulin

treatment.

S28-3

New era in insulin therapy: the ultra-fast acting insulins

Eda CENGIZ

Pediatric Endocrinology and Diabetes, Yale School of

Medicine, New Haven, CT, USA

Insulin had its evolution throughout the years since its dis-

covery in 1921. The introduction of insulin analogs allowed

flexibility with before meal time insulin injections and

improved after meal blood sugars. Despite the advances in

the field of insulin therapy, the rapid acting insulin analogs are

not fast enough to control after meal blood sugars. Moreover,

the prolonged and late effects of rapid acting insulins lead

to the undesirable late hypoglycemic episodes hours after an

insulin bolus. The late and slow insulin action remain

important obstacles for achieving a fully automated artificial

pancreas systems. If the ultimate goal of developing insulin

analogs is to recapitulate the physiologic pattern of insulin

secretion and action from a healthy beta cell, it is fair to say

that the evolution of insulin is not complete yet. Advances in

newer insulin formulations with improved pharmacokinetics

(PK) and pharmacodynamics (PD) will galvanize artificial

pancreas insulin therapy system research and overcome

challenges in daily management of diabetes to restore near-

physiologic glycemic control. This talk will summarize impli-

cations of slow action of insulin analogs and highlight the

results of key studies on new generation ultra-fast acting

insulins, innovative insulin delivery devices and their impact

on the artificial pancreas systems.

S28-4

Development of glucose-responsive

“

smart

”

insulin

Hung-Chieh CHOU

Department of Biochemistry, University of

Utah, UT, US

The development of exogenous insulin to treat diabetes has

dramatically improved overall patient survival for people

with diabetes. However, although currently available insulin

analogs reduce blood glucose levels, this blood glucose lower-

ing action is not regulated in a glucose dependent fashion.

Insulin analogs can cause severe hypoglycemia and remain

bioactive even in low glucose levels. Thus, hypoglycemia is the

rate-limiting step in the insulin therapy. To reduce the risk of

hypoglycemia, a glucose-responsive insulin (GRI) analog is

needed that is active when blood glucose levels are high, yet

is inactivatedwhen blood glucose levels start to decline. Such a

“

smart insulin

”

will eliminate the barrier of hypoglycemia

for insulin-treated people with diabetes. We developed a novel

GRI through manipulation of the C-terminus of the insulin

Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1

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