GLP-1 RA Vs Insulin after 2

OADs Failure
 Mrs. X
Woman, aged 62 years
Profession: Nurse
Physical examination:
Height: 160 cm
Weight: 75 kg; BMI: 29.2 kg/m2
BP: 142/90
History:
T2DM, bilateral DME, hypertension, and dyslipidemia diagnosed 2 years
ago
Metformin initiated at diagnosis of T2DM;
Intensified with Glimepiride 1 year ago;
Bilateral DME treated with laser photocoagulation; resolved

2
 Mrs. X
Recent relevant laboratory results:
A1C: 8.5%
A1C range in past year: 7.4%-8.5%
FPG range: 120-140 mg/dL
PPG range: 160-220 mg/dL
eGFR: 58 mL/min/1.73 m2
Medications:
Metformin 1000 mg once daily
Glimepiride 2 mg once daily
Rosuvastatin 20mg OD
Telmisartan 40mg-Amlodipine 5mg OD
Concerned about persistently elevated blood glucose values

3
What should be next line of
treatment?
Progressive Natural History of T2DM

5
Injectable Agents Play Prominent Roles in Current
Treatment Algorithms
ADA 2017 Guideline
Injectable Agents Play Prominent Roles in Current
Treatment Algorithms
 Current Algorithms Recommend Sequential
Addition of Injectable Agents
Patient Status ADA 20171 AACE 20172
First line Severe hyperglycemia (A1C Basal insulin Basal insulin
>9%-10%, with symptoms)
Second line Unable to attain glycemic Either basal insulin GLP-1 RA
targets with metformin or a GLP-1 RA
Third line Unable to attain glycemic Either basal insulin GLP-1 RA
targets with 2 antihyperglycemic or a GLP-1 RA
agents

Insulin can be added before adding a GLP-1 RA, or a GLP-1 RA can be added before
adding insulin; more studies are needed to determine the optimal order of
initiation3

1. ADA. Diabetes Care. 2017;40(Suppl 1):S1-S135; 2. Garber AJ, et al. Endocr Pract. 2017;23:207-238;
8
Expected Reduction in A1C in Combination With Metformin
(Change From Baseline)

9
Insulin and GLP-1 RAs Have Complementary
Modes of Action and Effects

10
 NICE- type 2 guidelines positioning for GLP-1

Consider adding a GLP-1 mimetic (exenatide) as third-line therapy to

first-line metforminand a second-line sulfonylurea when control of
blood glucose remains or becomes inadequate
A body mass index (BMI) 35.0 kg/m2in those of European descent
(with appropriate adjustment for other ethnic groups) and specific
psychological or medical problems associated with high body weight, or
A BMI < 35.0 kg/m2, and therapy with insulin would have significant
occupational implications or weight loss would benefit other significant
obesity-related co morbidities.

National Institute for Health and Clinical Excellence. Type 2 diabetes: Newer agents for blood
glucose control in type 2 diabetes. Short Clinical Guideline 87. London: NICE; 2009

11
 Facilitating Patient Success With
Injectable Therapies

Educate patients about the eventual need for

injectable therapies at diagnosis1
Validate patient concerns and offer solutions2
Select the smallest available needles to increase
injection comfort3,4
Administer first injection in the office to teach injection
technique, demonstrate painlessness of small needles4

1. American Diabetes Association. Diabetes Care. 2017;40(Suppl 1):S1-S135; 2. Borgsteede

SD, et al. Int J Clin Pharm. 2011;33:779-787; 3. Frid A, et al. Diabetes Metab. 2010;36(Suppl
2):S3-S18; 4. Kruger D, et al. Diabetes Educ. 2010;36(Suppl 3):44S-72S.
12
Therapeutic Intensification for T2DM with GLP-1 RAs
 What is your greatest obstacle
to initiating therapy with GLP-1 receptor agonists?

A. Not being up-to-date on current safety and efficacy

evidence supporting use of these agents in T2DM
B. Cost of medication/managed care issues
C. They offer no advantages over current
antidiabetic agents
D. Unfamiliarity with placement of this class within
treatment guidelines
E. Patients fear of injections or other patient-related
factors
What GLP-1 agonists do?
 Physiology of postprandial glucose regulation

Meal

Insulin
Insulin
Glucagon
Rising plasma glucose stimulates
pancreatic -cells to secrete insulin1 Gastric
emptying
Glucagon
Plasma glucose inhibits glucagon
secretion by pancreatic -cells1 PPG

Gastric emptying Hepatic

glucose Glucose
Delaying and/or slowing gastric output + uptake
emptying is a major determinant
of postprandial glycaemic excursion2
PPG = postprandial glucose
DeFronzo RA. Med Clin North Am 2004;88:787-835
1

Horowitz M et al. Diabet Med 2002;19:177-94

2
 Glucagon-like peptide-1 and incretin effect

-cell -cell

Food
GLP-1
intake

Incretin Pancreatic
effect islet

GLP-1 is a major intestinal hormone mediating the incretin effect

GLP-1 potentiates insulin release and reduces glucagon secretion in
glucose-dependent manner
Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940; and Wang Q, et al. Diabetologia. 2004;47(3):478-487.
 GLP-1 Actions in Peripheral Tissue
Heart Neuroprotection
Brain Appetite
Stomach
Stomach
Gastric
emptying

Cardioprotection
Cardiac output
GI Tract GLP-1

Liver _ Insulin secretion

-cell neogenesis
-cell apoptosis
Glucose +
Glucagon secretion
production Glucose
Uptake
Drucker DJ. Cell Metab. 2006;3:153-165.
Muscle
 The incretin effect
oral glucose load (50 g) iv glucose infusion
Plasma glucose Plasma insulin
15 270 80

60
10 180
mU/L
mmol/L mg/dL 40 Incretin
5 effect
90
20

0 0
0
10 5 60 120 180
10 5 60 120 180
Time (min) Time (min)

Insulin response is greater following oral glucose than iv glucose, despite

similar plasma glucose concentrations

Nauck MA et al. Diabetologia 1986;29:4652. Healthy volunteers n=8

 GLP-1 restores insulin and glucagon responses
in type 2 diabetes

GLP-1 Saline
Glucose (mmol/L) C-peptide (nmol/L) Glucagon (pmol/L)
17.5 3.0 30
Infusion Infusion Infusion
15.0 2.5 25

12.5 2.0 * 20
*
*
*
10.0 1.5 *
15
*
* *
7.5 *
1.0 10
*
*
5.0
0.5 5 *
*
* *
*
2.5
0.0 0

0.0 30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240
Time (min) Time (min) Time (min)

GLP-1(736 amide) infused at 1.2 pmol/kg/min for 240 min. *p<0.05 Adapted from Nauck MA et al. Diabetologia 1993;36:7414.
 GLP-1 delays gastric emptying

Subcutaneous injection of GLP-1 delays gastric emptying

by about 30 min in type 2 diabetes
GLP-1 or placebo
Liquid meal
400 ml GLP-1
Placebo
Gastric
volume
(ml)

*p<0.000
1

GLP-1 from

Adapted (7-36 amide)

Nauck MA et al.1.5 nmol/kg
Diabetologia sc
1996;39:154653
Time (min)
Options in GLP-1 RA Therapy Have Recently
Expanded

22
 Actions of GLP-1 agonists

Promote 1st phase insulin secretion

Reduce glucagon release
Delay gastric emptying
Weak satiety effect
Thus lowering blood glucose with modest weight loss
without hypoglycaemia
Therapeutic Characteristics and Outcomes for
Currently Available GLP-1 RAs: HbA1c
Therapeutic Characteristics and Outcomes for
Currently Available GLP-1 RAs: Weight
 Change in A1c Seen With Exenatide
in Phase 3 Clinical Trials Placebo BID
Exenatide 5 g BID
Exenatide 10 g BID
0.2
Change in A1c (%)

0.1 0.1
METa SFUb MET + SFUc

*
-0.4*
-0.5*
- 0.8 -0.6*
-0.8* -0.8*
-0.9*
n 113 110 113 123 125 129 247 245 241
Baseline 8.2 8.3 8.2 8.7 8.5 8.6 8.5 8.5 8.5
Mean (SE): *P < .005
a
DeFronzo R, et al. Diabetes Care. 2005;28:1092-1100. MET = metformin; SFU = sulfonylurea
b
Buse JB, et al. Diabetes Care. 2004;27:2628-2635.
c
Kendall D, et al. Diabetes Care. 2005;28:1083-1091.
Exenatide vs Insulin Glargine as
Add-on Therapy in T2DM
Exenatide group (n = 275)
Insulin glargine group (n = 260)
A1c Level (%)

Heine RJ, et al. Ann Intern Med. 2005;143:559-569.

 Cardiovascular Disease
and Diabetes

Cardiovascular disease is the most common

cause of death in adults with diabetes
Increased incidence of atherosclerosis
Increased incidence of hypertension and lipid
abnormalities
Increased macrovascular complications such as
stroke and myocardial infarction
Higher cost of managing cardiovascular disease
in diabetes than nondiabetic counterparts

Cefalu WT, et al. Diabetes Care. 2015;39(1):S1-S112.

 Cardiovascular Risk Reduction
Risk reduction strategies for cardiovascular disease in
diabetes focus on:
Medical nutrition therapy
Improvement of glucose control
Weight loss and weight maintenance
Blood pressure control
Lipid-lowering strategies
Lifestyle interventions are the cornerstone of
cardiovascular risk reduction; however, many patients will
need pharmacological help to maintain goals
 Incretin-based Therapies and
Blood Pressure

Effects of incretin-based therapies on blood pressure:

Small decreases in both systolic and diastolic blood
pressure
Possible reduction in albuminuria, proteinuria, and
glomerular injury
Increased urinary water and sodium secretion
Protective effects on endothelium in postprandial state
Shown to reduce postprandial oxidative stress and
biomarkers of cardiovascular disease

Cernea S, Raz I. Diabetes Care. 2011;34 Suppl 2:S264-S271.

Therapeutic Characteristics and Outcomes for Currently
Available GLP-1 RAs: Cardiovascular Variables

31
 Liraglutide and Blood Pressure

Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Gallwitz B, et al. Int J Clin Pract. 2010;64(2):267-276.
 Exenatide and Lipids

Open label 3-year RCT to evaluate exenatide effect

on cardiovascular markers (n=151)
Triglycerides decreased 12% (P = .0003)
Total cholesterol decreased 5% (P = .0007)
LDL decreased 6% (P < .0001)
HDL increased 24% (P < .0001)

Klonoff DC, et al. Curr Med Res Opin. 2008;24(1):275-286.

Cardiovascular Safety of GLP-1 RAs
Effects on MACE

34
 Cardiovascular Risk Reduction:
Body Weight

Many conventional glucose-lowering medications associated

with weight gain
Studies show that weight maintenance is difficult with lifestyle
alone
Benefits of weight loss:
Weight loss of 5% to 10% associated with reduction in blood pressure,
lipids, and improvement in glycemic control (Look AHEAD trial)
Modest weight loss linked to as much as a 28% risk reduction in
cardiovascular disease and mortality
Additional benefits of weight loss include remission or reduced severity of
obstructive sleep apnea

Van Gaal L, Scheen A. Diabetes Care. 2015;38(6):1161-1172.

 GLP-1 RA and Weight Loss

GLP-1 RA (eg, exenatide, exenatide ER,

liraglutide, albiglutide, dulaglutide)
Dose-dependent weight loss
Over 85% of patients lose weight

Davidson JA. Cleve Clin J Med. 2009;76(Suppl 5):S28-S38.

 Effects of Exenatide in Sulfonylurea-Treated
Patients: Weight

Buse JB, et al. Diabetes Care. 2004;27:2628-2635.

 Liraglutide and Weight Loss:
LEAD Trials
LEAD-3 trial:
Weight reduction of up to 2.5 kg with liraglutide compared with a
weight gain of 1.1 kg with glimepiride (P = 0.0001)
Weight loss sustained throughout a 52-week study
LEAD-5 trial:
Liraglutide produced a greater reduction in A1c and body weight
(loss of 1.8 kg) than insulin glargine (gain of 1.6 kg)
LEADER trial:
Compared with placebo, liraglutide treatment resulted in:
13% risk reduction for MACE (non-fatal MI, non-fatal stroke, and CV death)
22% risk reduction for CV death
15% reduction in all-cause mortality

Sesti G. Diabetes Care. 2011;34(Suppl 2):S272-S275.

Marso SP, et al. N Engl J Med. 2016 Jun 13 [Epub ahead of print].
 Exenatide vs Insulin Glargine for
Weight Loss
Change in body weight (kg) during 26 week treatment with exenatide or insulin glargine

1
Exenatide group (n=275)

0 Insulin glargine group (n=260)

*
-1 *
*
-2 *
*
*
-3
0 2 4 8 12 18 26
Weeks

* P < .0001 exenatide compared with insulin glargine

Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Heine RJ, et al. Ann Intern Med. 2005;143(8):559-569.
Lixisenatide and Glargine
 Insulin Vs GLP-1
Insulin GLP-1
Appropriate treatment for Appropriate treatment for
Type 2 symptomatic overweight Type 2 patients
patients with Hba1c >9% Considerations/Barriers
Considerations/Barriers Weight loss
Weight increase Minimal titration
Titration of dose Less considerations re
Driving/employment driving/employment
considerations Side effects
Side effects

41
 Choice of GLP-1 receptor agonist:
short acting versus long acting
The pharmacological profile and half-life of a GLP-1 receptor agonist
influences its effects on postprandial and basal (fasting) glycaemia

SHORT ACTING LONG ACTING

GLP-1 receptor agonists or GLP-1 receptor agonists
Lixisenatide OD, Exenatide BD Liraglutide OD, Exenatide/Dulaglutide
QW
Effect on Effect on Effect on Effect on

FPG PPG FPG PPG

FPG = fasting plasma glucose PPG =

postprandial glucose
Fineman MS et al. Diabetes Obes Metab 2012;14:675-88
Differences with Short and Long acting GLP-1 agonists
Short and Long acting GLP-1 (other effects)
 When to use GLP1-agonists

HbA1c>58 mmol/l +oral agents;

Overweight.
With metformin/Pioglitizone/SGLT2 inhibitors.
Stop DPP4 and Sulphonylureas.
Or with basal insulin;
To avoid further weight gain.
To reduce hypoglycaemia.
 How to use GLP1-agonists

With Oral Treatment;

Use least expensive agent (lixisentatide).
Continue with Metformin and/or Pioglitazone.
Add SGLT2 inhibitor if post-prandial hyperglycaemia.
Move from lixisenatide/exenatide to a Glutide;
if nauseous or sub-optimal response.
Transfer to biphasic insulin (Humulin M3);
if no weight loss or improved glycaemic control.
With OD human basal (Humulin I);
with dose increasing by 10% alternate days to reduce
FBG < 6mmol.
 The Steps Needed to Administer GLP-1 RAs
Vary by Agent

aConsult individual prescribing information for detailed reconstitution instructions; bAlthough

dulaglutide instructions for use do not include a specific dwell time, patients should press and hold the
pen firmly against the skin until a loud click is heard; this period of time accounts for the dwell time
and needle retraction incorporated into the pen technology.

47
 Benefits and Limitations of GLP-1 RAs to
Intensify Therapy
Benefits
High efficacy
Low risk of hypoglycemia
Potential for weight loss
Some agents (eg, liraglutide)
reduce CV events
Offers regimen flexibility:
agents available with twice-
daily, once-daily, and once-
weekly administration
Limitations
Risk of transient GI side effects
Subcutaneous injection: education needed3
May be unsuitable for patients with a history
of pancreatitis
Some agents (eg, exenatide) unsuitable for
patients with severe renal impairment3
Some agents (eg, albiglutide, dulaglutide,
exenatide QW, liraglutide) unsuitable for
patients with a personal or family history of
certain rare thyroid tumors
Variable access across insurance policies;
prior authorization may be required
48
 Facilitating Patient Success With GLP-1 RAs

Weight loss is associated with higher adherence to

therapy
Adherence is improved with less-frequent injections
Other predictors of patient preferences for GLP-1
RAs may include:
Greater efficacy
Fewer adverse effects
Shorter (eg, 4-5 mm) and thinner (eg, 31-32 G) needles
Steps needed to prepare an injection

49
 Conclusion
The incretin effect is severely reduced in patients with T2DM
Incretin-based agents act to stimulate insulin secretion, suppress
glucagon secretion, slow gastric emptying, and stimulate beta cell
proliferation
Benefits of incretin-based therapies include:
Reduced A1c, FPG, PPG
Improvement in markers of pancreatic beta cell function
Cardiovascular benefits
Weight loss or weight-neutral effects
Reduced blood pressure
Improved lipid parameters
GLP-1 RAs provide safe and effective glycemic control targeting
the underlying pathophysiologic defects and the comorbidities
associated with T2DM, which may modify the natural course of
the disease and long-term outcomes
 Conclusion (contd)
Treatment considerations:
When prescribing medications for the management
of T2DM, decision making should include a
personalized approach taking into account the
patients clinical circumstances, comorbidities,
preferences, and costs
Regardless of the specific therapy selected, the goal
should be to safely achieve glycemic control at the
earliest possible stage with the least risk for adverse
effects to improve outcomes and reduce
complications
52