Download Session 8: Use of Incretin

Please Complete
the Pre-Activity Survey
This activity is supported through an
educational grant from
Novo Nordisk.
Learning Objectives
Upon completion of this educational activity, the
participant should be able to:
1. Outline differences and similarities in the mechanisms
of action for both major classes of incretin-based
therapies.
2. Describe the effects of DPP-4 inhibitors on glycemic
targets, including A1c levels and postprandial glucose.
3. Discuss the effects of GLP-1 receptor agonists on
glycemic targets, including A1c levels and postprandial
glucose.
4. Review the effects of GLP-1 receptor agonists and
DPP-4 inhibitors on cardiovascular risk factors
including lipid levels, blood pressure, and body weight.
Pathophysiology of
Type 2 Diabetes (T2DM)
Obesity
• Accumulation of
cellular energy
• Increased serum
FFAs
• Altered adipocyte
hormone production
Decreased insulin
action in:
• Muscle
• Liver
• Adipose tissue
• Other tissues
• Increased insulin
secretion from betacells
• Abnormal insulin
secretion
FFA = free fatty acids
FPG = fasting plasma glucose
PPG = postprandial glucose
Adapted by Lillian McVey from Campbell RK. Clin Ther. 2011;33(5):511-527.
•
•
•
•
Increased PPG
Increased FPG
Dyslipidemia
Fatty liver
Progressive beta cell
dysfunction:
• Decreased insulin
production
• Beta cell death
• Decreased incretin
secretion/action
• Abnormal insulin
processing
The Importance of Glycemic
Control in Type 2 Diabetes
 Good glycemic control associated
with:
- Delayed progression of disease and
associated morbidity/mortality
 Decreased rates of microvascular and
neuropathic complications
 Risk reduction for cardiovascular disease
Cefalu WT, et al. Diabetes Care. 2016;39(Suppl 1):S1-S110.
Summary of ADA Glycemic
Recommendations
Glycemic Recommendations for Nonpregnant Adults With Diabetes
A1c
<7.0% (53 mmol/mol)*
Preprandial capillary plasma glucose
Peak postprandial capillary plasma
glucose**
80-130 mg/dL* (4.4-7.2 mmol/L)
<180 mg/dL* (10.0 mmol/L)
* More or less stringent glycemic goals may be appropriate for individual patients. Goals should be
individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD
or advanced microvascular complications, hypoglycemia unawareness, and individual patient
considerations.
** Postprandial glucose (PPG) may be targeted if A1c goals are not met despite reaching preprandial
glucose goals. PPG measurements should be made 1-2 hours after the beginning of the meal,
generally peak levels in patients with diabetes.
Only 37% of adults with T2DM achieve A1c <7.0%
Cefalu WT, et al. Diabetes Care. 2016;39(Suppl 1):S1-S110.
Saydah SH, et al. JAMA. 2004;291:335-342.
Individualizing Glycemic Targets
more stringent
Patient/Disease Features
Risks potentially associated with
hypoglycemia and other drug
adverse effects
Disease duration
A1c
7%
low
less stringent
high
newly diagnosed
long-standing
Life expectancy
long
short
Usually not
modifiable
Important comorbidities
absent
few/mild
severe
absent
few/mild
severe
Established vascular
complications
Patient attitude and expected
treatment efforts
Resources and support system
highly motivated, adherent,
excellent self-care capacities
readily available
less motivated, nonadherent,
poor self-care capacities
Potentially
modifiable
limited
Cefalu WT, et al. Diabetes Care. 2016;39(Suppl 1):S1-S110. Copyright © 2016 by the American Diabetes Association, Inc. All rights reserved. Used with permission.
Inzucchi SE, Bergenstal RM, Buse JB, et al. Diabetes Care. 2015;38:140-149.
Incretins: History
 Incretin hormones were discovered during trials to
identify the phenomenon that has been called the
“incretin effect”
 La Barre – 1930s
- Used the term “incretin” to describe gut activity that
stimulated pancreatic endocrine secretion
- Identified that insulin response was greater if glucose was
administered orally vs intravenously
 Nauck – 1986
- Demonstrated that a glucose infusion to achieve plasma
glucose levels identical to those achieved with oral glucose
led to an insulin response that was only one-quarter as high
La Barre J, Still EU. Am J Physiol. 1930;91:649-653.
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63(2):492-498.
Incretins
 Secreted within minutes
after meal ingestion in
response to activation of
neural circuits that connect
the GI tract with the
hypothalamus
DPP-4
causes
breakdown
of GLP-1
Appetite
Gastric
emptying
GLP-1
Cardioprotection
Cardiac output
- Gastric inhibitory
polypeptide (GIP)
- Glucagon-like peptide-1
(GLP-1)
 Broken down in GI tract by
enzyme dipeptidyl
peptidase-IV (DPP-4)
Glucose
production
Image courtesy of Shannon Reedy Idzik, DNP, CRNP, FAANP. Used with permission.
Insulin secretion
Beta cell
neogenesis
Beta cell
apoptosis
Glucagon
secretion
Glucose
uptake
The Incretin Effect
 In patients with T2DM:
- The incretin effect is severely reduced
 Insulinotropic effects of GIP are virtually absent
 Insulinotropic effects of GLP-1 are at least
partially preserved
 Endogenous GLP-1–mediated insulin secretion does
not compensate for loss of insulinotropic activity of
GIP
 Defective glucagon suppression produces
hyperglucagonemia (fasting and post-nutrient
state)
- Defective incretin-mediated stimulation
contributes to defective insulin secretion
Nauck M. Diabetes Obes Metab. 2016;18(3):203-216.
Incretin-based Medications
 GLP-1 receptor agonists (RAs)
- Produce effects similar to those of native
GLP-1
 Stimulate insulin secretion
 Suppress glucagon secretion, appetite, and food
intake
 Slow gastric emptying
 Stimulate pancreatic beta cell proliferation
- Resistant to DPP-4 degradation
 DPP-4 antagonists
- Augment endogenous GLP-1 by inactivating
the enzyme responsible for its degradation
Nauck M. Diabetes Obes Metab. 2016;18(3):203-216.
Incretin-based Therapies
GLP-1 RAs
DPP-4 Inhibitors
Drug
Starting dose
Drug
Starting dose
Exenatide
INITIAL: 5 mcg SC twice
daily
Alogliptin
INITIAL: 25 mg PO once
daily
Liraglutide
INITIAL: 0.6 mg SC once
daily x 1 week, then
increase to 1.2 mg SC once
daily
Linagliptin
INITIAL: 5 mg PO once
daily
Saxagliptin
INITIAL: 2.5 mg or 5 mg PO
once daily
Sitagliptin
INITIAL: 100 mg PO once
daily
Exenatide
extendedrelease
INITIAL: 2 mg SC once
weekly
Albiglutide
INTIAL: 30 mg SC once
weekly
Dulaglutide
INITIAL: 0.75 mg SC once
weekly
Beneficial Effects of
Incretin-based Therapies
Effect
GLP-1 RAs*
DPP-4 Inhibitors**
Reduction in A1c
0.5%-1.5%
0.5%-0.9%
Reduction in FPG
7-74 mg/dL
11-29 mg/dL
Reduction in PPG
41-47 mg/dL
49-68 mg/dL
↓1-4 kg
↓0.9-↑1.4 kg
Yes
Yes
Effect on weight
Improvement in markers of pancreatic
beta cell function?
*Exenatide 5-10 mcg SC twice daily, Liraglutide 1.2-1.8 mg once daily
**Sitagliptin 100 mg PO once daily, Saxagliptin 2.5-5 mg PO once daily, Linagliptin 5 mg PO once daily
Cobble M. Diabetol Metab Synd. 2012;4(1):8.
Incretin-based Therapies in
Current Guidelines
 According to 2015 AACE/ACE
guidelines:
- GLP-1 RAs now second drug of choice in
patients with A1c <7.5%
- Metformin and GLP-1 RA combination is
first line dual therapy for patients with A1c
≥7.5%
Garber AJ, et al. Endocr Pract. 2015;21(4):438-447.
GLP-1 RAs
Advantages
• Lack of hypoglycemia
when used as
monotherapy
• Weight loss
• Reduces PPG values
• Combination of injectable
therapies of basal insulin
and a GLP-1 RA is a
strategy
1.AstraZeneca Pharmaceuticals. BYETTA® (exenatide) injection
prescribing information. Accessed July 1, 2016.
2.Novo Nordisk. VICTOZA® (liraglutide) injection prescribing
information. Accessed July 1, 2016.
3.GlaxoSmithKline. TANZEUM™ (albiglutide) perscribing
information. Accessed July 1, 2016.
4.Eli Lilly. TRULICITY® (dulaglutide) injection prescribing
information. Accessed July 1, 2016.
Disadvantages
• Injectable
• AEs: headache, nausea
(often transient), diarrhea
• Dosage modification with
renal dysfunction needed
(albiglutide, dulaglutide)
• Contraindicated in severe
renal impairment
(exenatide)
• May be associated with
pancreatitis
• Associated with thyroid cell
cancer in rodents
• May be associated with
renal insufficiency
DPP-4 Inhibitors
Advantages
• Oral
• No hypoglycemia when
used as monotherapy
• Weight neutral
• Generally well tolerated
•
•
•
•
1.Takeda Pharmaceuticals. NESINA (alogliptin) prescribing
information. Accessed July 1, 2016.
2.Boehringer Ingelheim. TRADJENTA® (linagliptin) prescribing
information. Accessed July 1, 2016.
3.AstraZeneca Pharmaceuticals. ONGLYZA® (saxagliptin)
prescribing information. Accessed July 1, 2016.
4.Merck. JANUVIA® (sitagliptin) prescribing information. Accessed
July 1, 2016.
•
Disadvantages
Dosage modification
required with renal
impairment (sitagliptin,
saxagliptin, alogliptin)
CYP3A4 interactions
(saxagliptin, linagliptin)
May be associated with
pancreatitis
May worsen heart failure
(saxagliptin)
May cause severe joint
pain
GLP-1 RAs vs DPP-4 Inhibitors:
Head-to-Head Trials
Parameter
GLP-1
RAs
DPP-4 Inhibitors
Comments
Greater glycemic
control
X
Compared with sitagliptin, liraglutide, exenatide
once weekly, and dulaglutide produced significantly
greater reductions in A1c and other glycemic
parameters
Greater reductions
in body weight
X
Compared with sitagliptin, GLP-1 RAs produced
significantly greater reductions in body weight
Greater tolerability
X
Higher incidence of mild-to-moderate
gastrointestinal AEs associated with GLP-1 RAs
Greater
improvements in
beta cell function
X
Exenatide, liraglutide, and dulaglutide treatment
resulted in more favorable improvements in beta
cell function vs sitagliptin
Greater reduction in
postprandial
triglycerides
X
Exenatide twice daily produced greater reductions
in postprandial triglycerides compared with
sitagliptin
Greater treatment
satisfaction
X
Likely driven by weight reduction, despite need for
injection with liraglutide vs oral sitagliptin
Nauck M. Diabetes Obes Metab. 2016;18(3):203-216.
Effects of Incretin-based Therapies
on Cardiovascular Risk Factors
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
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.
Incretin-based Therapies and
Weight Loss
 GLP-1 RA (eg, exenatide, exenatide ER,
liraglutide, albiglutide, dulaglutide)
- Dose-dependent weight loss
- Over 85% of patients lose weight
 DPP-4 (eg, sitagliptin, linagliptin,
alogliptin, saxagliptin)
- Meta-analysis results of 13 studies show
weight neutrality or weight loss
Davidson JA. Cleve Clin J Med. 2009;76(Suppl 5):S28-S38.
Exenatide and Weight Loss
Change in body weight (kg) in placebo-controlled trials, open-label extensions
(10 µg exenatide twice daily)
-3.5 ± 0.2kg
-4.4 ± 0.3kg
Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Blonde L, et al. Diabetes Obes Metab. 2006;8(4):436-447.
Exenatide vs Insulin Glargine for
Weight Loss
Change in body weight (kg) during 26 week treatment with exenatide or insulin glargine
2
1
Exenatide group (n=275)
Insulin glargine group (n=260)
0
*
*
-1
*
-2
*
*
*
-3
0
2
4
8
12
Weeks
18
26
* 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.
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].
Cardiovascular Risk Reduction:
Blood Pressure
 Increasing levels of systolic blood pressure
(starting as low as 115 mmHg) linked with
progressive increase in risk of macrovascular
and microvascular events
 Current clinical recommendations for blood
pressure goals in diabetes:
- <140/90 mmHg (with some exceptions)
 Most patients with diabetes and hypertension will
require multiple pharmacological agents to
obtain adequate blood pressure control
Fox CS, et al. Diabetes Care. 2015;38(9):1777-1803.
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.
Sitagliptin and Blood Pressure
**After 12 weeks of monotherapy
Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Mistry GC, et al. J Clin Pharmacol. 2008;48(5):592-598.
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.
Cardiovascular Risk Reduction:
Lipids
 Common lipid abnormalities in T2DM include
elevated triglycerides, decreased HDL, and
elevated LDL
 LDL particles are oftentimes small and dense
 Small/dense LDL particles are more atherogenic
 LDL lowering should be the primary target with
reduction in triglycerides a secondary endpoint
 Moderate or high-intensity statin therapy should be
initiated for adults 40 to 75 years of age
Cefalu WT, et al. Diabetes Care. 2015;39(1):S1-S112.
Stone NJ, et al. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934.
Cardiovascular Risk Reduction:
Lipids
 Major vascular events reduced by 21%
with every 39 mg/dL reduction in LDL-C
in people with T2DM
(RR 0.79 [99% CI 0.72–0.86]; P < 0.0001)
 All-cause mortality reduced by 9% with
every 39 mg/dL reduction in LDL-C
(RR 0.91 [99% CI 0.82–1.01]; P = 0.02)
Kearney PM, et al. Lancet. 2008;371(9607):117-125.
Incretin-based Therapies
and Lipids
 GLP-1 RAs
- Reduce postprandial triglycerides,
FFA, and LDL
 DPP-4 inhibitors
- Reduce fasting LDL and triglycerides
- Small increase in HDL
- Parallels weight loss
Cefalu WT, et al. Diabetes Care. 2015;39(1):S1-S112.
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.
mg/dL
Sitagliptin and Lipids
Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Mistry GC, et al. J Clin Pharmacol. 2008;48(5):592-598.
Considerations for Treatment Plans
Containing Incretin-based Therapies
Clinical Case
 58-year-old female with newly diagnosed T2DM presents
for a 3-month follow-up
 Patient has been implementing lifestyle changes and
weight loss for the past 3 months to improve her glycemic
control
 Patient is motivated to improve nutritional choices and
increase her physical activity levels; to date, she has lost a
total of 10 pounds (4.4% TBW) and feels encouraged to
continue with her weight loss program
 Comorbidities include:
‒
‒
‒
‒
Class 2 obesity
Hypertension
Dyslipidemia
Osteoarthritis
 Patient’s A1c is 7.9%
TBW = total body water
Clinical Case
Physical Exam:
BMI = 37 (5'5", 223 lbs)
Waist circumference = 50"
BP = 145/86 mmHg
Pulse = 76 bpm
FBG = 173 mmol/L
A1c = 7.9%
Total cholesterol = 187 mg/dL
Triglycerides = 278 mg/dL
HDL = 44 mg/dL
LDL = 88 mg/dL
Medications:
Lisinopril 40 mg daily
Norvasc 5 mg daily
Meloxicam 15 mg daily
Cyclobenzaprine 10 mg as needed
Loratadine 10 mg daily
Lifestyle changes:
• Daily monitored caloric intake between 1400-1500 kcal/d
• Daily steps averaged 5000-6000 per day
(up from 3000 steps per day at start)
• Joined a gym and plans on attending 2 times per week
ADA Recommendations for
Managing Diabetes
 Metformin, if not contraindicated and if tolerated, is the preferred initial
pharmacological agent for T2DM (A rating)
 Consider initiating insulin therapy (with or without additional agents) in
patients with newly diagnosed T2DM and markedly symptomatic and/or
elevated blood glucose levels or A1c (E rating)
 If non-insulin monotherapy at maximum-tolerated dose does not achieve
or maintain the A1c target over 3 months, then add a second oral agent,
a GLP-1 RA, or basal insulin (A rating)
 A patient-centered approach should be used to guide the choice of
pharmacological agents; considerations include efficacy, cost, potential
side effects, weight, comorbidities, hypoglycemia risk, and patient
preferences (E rating)
 For patients with T2DM who are not achieving glycemic goals, insulin
therapy should not be delayed (B rating)
“Recommendations are assigned ratings of A, B, or C, depending on the quality of evidence. The E rating for expert opinion is a separate
category for recommendations in which there is no evidence from clinical trials, clinical trials may be impractical, or evidence is conflicting.
Recommendations with an A rating are based on large, well-designed clinical trials or high-quality meta-analyses. Recommendations with
lower levels of evidence may be equally important but are not as well-supported.”
Chamberlain JJ, et al. Ann Intern Med. 2016;164(8):542-552.
Relative
Function (%)
Glucose (mg/dL)
Natural History of T2DM
350
300
Postprandial Glucose
250
Fasting Glucose
200
150
100
50
Insulin Resistance
250
200
150
100
50
Insulin Level
β-Cell Failure
At Risk for T2DM
0
-15
-10
-5
0
Obesity IFG* Diabetes
5
10
15
20
25
Time (y)
Uncontrolled hyperglycemia
IFG = impaired fasting glucose
Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Kendall DM, Bergenstal RM. ©2005. International
Diabetes Center at Park Nicollet, Minneapolis, MN. All rights reserved. Used with Permission.
30
Considerations and Controversies in the
Selection of Monotherapy, Dual, and Triple
Therapies for the Treatment of T2DM






Target A1c
Duration of diabetes
Preservation of beta cell function
Comorbidities and patient-centered approach
Selection of initial, dual, and triple therapies
Early combination therapy vs the traditional stepwise
approach
 Responder vs nonresponder
 Emerging clinical trial outcomes on newer treatment
options
Cefalu WT, et al. Diabetes Care 2014;37:2647-2659.
Comparison of ADA and AACE Guidelines
A1c goal
ADA
AACE
<7% (6-6.5% if healthy, 7.5%8% if not)
<6.5% in new onset; >7% if
multiple comorbidities, labile
glycemia
Use of A1c in choice of agents If >9%, consider dual therapy
If >7.5%, >9%, >8%, or <8%,
in initial insulin dose selection
SMBG targets
Preprandial <130 mg/dL
Peak PPG <180 mg/dL
FPG <110 mg/dL
2-h PPG <140 mg/dL
Classes listed
MET, SU, DPP-4 inhibitor,
GLP-1 RA, SGLT-2 inhibitor
(other classes are mentioned
but are not recommended)
Use all approved classes
(emphasize avoiding SU);
MET, GLP-1 RA, DPP-4
inhibitor, SLGT-2 inhibitor,
TZD, AGI, BAS, BCR-QR,
pramlintide
Choice of agents
Consider efficacy, then safety,
weight, hypoglycemia, cost,
renal disease
Consider safety, then efficacy,
weight, hypoglycemia, side
effects
Insulin intensification
After basal, 1 bolus or mixed,
may consider GLP-1 RA
After basal, either GLP-1 RA,
SGLT-2, DPP-4, or add bolus;
mixed insulin discouraged
Bloomgarden ZT, Handelsman Y. J Diabetes. 2016;8(1):4-6.
Targeting the Preservation or
Rejuvenation of Beta Cell Function
 Progressive deterioration in cell function and mass occurs
with duration of diabetes
- Approximately 50% loss of normal at the time of diagnosis
- Reduction in beta cell mass of about 60% at necropsy
 Reduction of beta cell mass is thought to be attributable
to accelerated apoptosis
 Major clinical factors affecting progressive loss of beta
cell function and mass:
- Glucotoxicity
- Lipotoxicity
- Adipocyte-secreted cytokines and hormones
 Pro-inflammatory cytokines (TNF-, IL-6, and IL-1 receptor
antagonists) are produced and secreted by fat tissue, increased in
obesity, and have been causally linked to insulin resistance
 Leptin
- Islet cell amyloid deposition
Wajchenberg BL. Endocr Rev. 2007;28(2):187-218.
Targeting the Preservation or
Rejuvenation of Beta Cell Function
(cont’d)
 Impaired cell function and possibly cell mass
appear to be reversible, particularly at early
stages of the disease where the limiting threshold
for reversibility of decreased beta cell mass has
probably not been passed
 Interventions found to preserve or rejuvenate
beta cell function:
-
GLP-1 RA
DPP-4 inhibitors
Thiazolidinediones (TZDs)
Insulin
Wajchenberg BL. Endocr Rev. 2007;28(2):187-218.
Summary of Effects of GLP-1 RA and
DPP-4 Inhibitors
GLP-1 RA
DPP-4 Inhibitors
Administration
injection
oral
GLP-1 concentrations
pharmacological
physiological
Mechanism of actions
GLP-1
GLP-1, GIP
Activation of the portal
glucose sensor
no
yes
Insulin secretion
↑↑↑
↑
Glucagon secretion
↓↓
↓↓↓
Fasting glucose
↓
↓↓↓
Weight reduction
yes
no
Gastric emptying
↓
+/-
Nausea and vomiting
yes (approx 45%)
no
Expansion of β cell mass
yes
yes
Potential immunogenicity
yes
no
Druker DJ, Nauck MA. Lancet. 2006;368(9548):1696-1705.
Factors to Consider When
Choosing Medications for T2DM
Clinician factors
Patient factors
Adherence factors
Efficacy
Patient preference
Complexity
Cost
Cost
Multiple doses
Tolerability
Health beliefs
Polypharmacy
Impact on body weight
Health literacy
Side effects
Comorbidities
Adherence
Potential adverse
effects
Risk of hypoglycemia
Fear
Patient preference
Duration of diabetes
System factors: Inadequate follow-up or support
Cefalu WT, et al. Diabetes Care. 2014;37:2647-2659.
Clinical Case
 Considerations for a personalized approach to
treatment:
- Newly diagnosed (58-year-old)
- Comorbidities:
 Class 2 obesity (BMI = 37 kg/m2)
 Hypertension not at treatment goal on 2 antihypertensives
 Atherogenic dyslipidemia (elevated TG, low HDL, Pattern B)
- Personal preferences:
 Nearly 5% total body weight loss in the past 3 months
 Highly motivated to continue with weight loss efforts
 Concerned about weight gain with diabetes medications
Considerations When Prescribing
Medications for T2DM
Met
SU
TZD
DPP-4
inhibitor
GLP-1
RA
SGLT-2
inhibitor
Basal insulin
Efficacy
(A1c lowering)
high
(1 - 2)
high
(1 - 1.5)
moderate
(0.5 - 1)
moderate
(0.5 - 1)
high
(1 - 1.5)
high
(1 - 1.5)
highest
(1.5 - 3.5)
Hypoglycemic
risk
none
high
low
rare/low
low
low
high
Effect on body
weight
loss or
neutral
gain
gain
neutral
loss
loss
gain
Tolerability
GI
effects
hypoglycemia
edema,
HF,
fractures
rare
GI
effects
GU
infections,
dehydration
hypoglycemia
Cost
low/free
low
low
high
high
high
variable - high
Uccellatore A, et al. Diabetes Ther. 2015;6:239-256.
Hawes EM, et al. Journal of Family Practice. 2016;65(2):85-89.
Adverse Effects and Patient Education
Adverse Effect
Patient Education
Nausea, vomiting,
diarrhea
• Often transient nature
• Possibility that drug needs to be withdrawn in a minority of patients
• Potential pharmacotherapy for side effects
Injection site reactions
and nodules
• Information about nature of this side effect (immunological responses
potentially related to antibody formation)
• Possibility that repeated episodes may suggest the need to discontinue
this treatment
Increased risk for
hospitalization for
heart failure (?)
• Information on recognition of symptoms
• Clinical significance of study findings are undetermined
• Caution for those at high risk
Increased risk for
acute pancreatitis (?)
• Discussion of this as an unresolved issue
• Early signs and symptoms of pancreatitis, behavioral advice in such a
case (seek medical advice, discontinue treatment)
• Advice for alternative treatment in the case of past episodes of pancreatitis
Increased risk for medullary
thyroid carcinoma (?)
• Information about the low likelihood in the face of the rarity of this disease
• Advice for alternative treatment in the case of a personal or family history
or with a given genetic background (multiple endocrine neoplasia
syndrome type 2)
Cefalu WT, et al. Diabetes Care. 2014;37:2647-2659.
Clinical Case
 Started on liraglutide 0.6 mg per day
with a titration schedule to 1.2 mg in 1
week
 Educated on common adverse effects
 Encouraged to continue with her
lifestyle program
 Follow-up scheduled for 2 to 3 weeks
Common Barriers to Adherence
Patient-based
Barriers
Health Care System–
based Barriers
 Cost/insurance
coverage
 Education/
knowledge
 Adverse effects
 Complexity of
treatment
 Clinician’s attitudes
toward treating
diabetes
 Time constraints
 Management of
multiple comorbidities
 Patient’s
insurance/finances
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 and DPP-4 inhibitors 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 (cont’d)
 Treatment considerations:
- When prescribing medications for the
management of T2DM, decision making should
include a personalized approach taking into
account the patient’s 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
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