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Medication Update in the
Treatment of Type 2 Diabetes
Rick Hess, PharmD, CDE, BC-ADM
Associate Professor
Gatton College of Pharmacy, Department of Pharmacy Practice
East Tennessee State University
Johnson City, Tennessee
Objectives

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Compare and contrast incretin-based hormone therapies
available for the treatment of type 2 diabetes (T2DM)
Evaluate the safety and efficacy of incretin-based
therapies in the treatment of T2DM
Describe the role of sodium-glucose co-transporter 2
(SGLT2) inhibition in the treatment of T2DM
Evaluate the safety and efficacy of SGLT2 inhibitors in
the treatment of T2DM
Discuss the clinical implications with incretin-based
therapies and SGLT2 inhibitors options on appropriate
patient selection
Relative Function
Glucose (mg/dL)
Type 2 Diabetes is a Complex and Progressive Metabolic Disorder 350
300
250
200
150
100
50
Postmeal Glucose
Obesity - Inactivity
Genetics
Fasting Glucose
Insulin Resistance
250
200
150
100
50
Progressive -Cell Defect (glucose specific)
Prediabetes (IFG, IGT)
Metabolic Syndrome
0
-15 -10
-5
Insulin Response
Amylin Response
Diabetes
Diagnosis
0
Onset
5
10 15
Years
20
25
30
Adapted from Kendall DM, et al. 2004 International Diabetes Center, Minneapolis, MN
Page 1
Diabetes Medication Timeline
Lancet. 2014 Mar 22;383(9922):1068-8
Islet -cell
Decreased
Incretin Effect
Increased
Lipolysis
Impaired
Insulin Secretion
Islet -cell
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
Decreased Glucose
Uptake
Increased
HGP
Diabetes 2009;58(4):773-795
Neurotransmitter Dysfunction
Diabetes Medications &
Effects on Blood Glucose
Medication/Class
Blood Glucose Effect
-glucosidase inhibitors
Postprandial
Metformin
Fasting
DPP – 4 Inhibitors
Postprandial
GLP – 1 RA
Short-acting = Postprandial
Long-acting = Fasting and Postprandial
Glinides
Postprandial
Amylinomimetic (Pramlintide)
Postprandial
Sulfonylureas
Fasting and Postprandial
TZDs
Fasting and Postprandial
SGLT2 inhibitors
Fasting and Postprandial
Basal Insulin
Fasting
Bolus Insulin
Postprandial
Page 2
Diabetes Drugs Impact Multiple Endpoints
Drug
-glucosidase
inhibitors
Weight
HTN
Dyslipidemia
Hypoglycemia
Risk
Neutral
Improved
Neutral/
Improved
Low
Loss/Neutral
Neutral
Improved
Low
GLP-1 RA
Loss
Improved
Improved
Low
Insulin
Gain
Neutral*
Improved
High
DPP-4 inhibitors
Glinides
Gain
Neutral
Neutral
Moderate
Loss/Neutral
Neutral
Improved
Low
SGLT2 inhibitors
Loss
Improved
?
Low
Sulfonylureas
Gain
Neutral
Variable
Moderate
TZD
Gain
Improved
Improved
Low
Metformin
*Hyperinsulinemia is associated with hypertension
J Diabetes Complications. 2013;27(3):280-286.
The Perfect Drug to Treat Diabetes:
Does it exist??


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Efficacy
Safety
Cardiovascular effects
Glycemic durability
Affordability
AACE Diabetes Management Algorithm
LIFESTYLE MODIFICATION
(Including Medically Assisted Weight Loss)
ENTRY A1c < 7 . 5%
ENTRY A1c ≥ 7 . 5%
ENTRY A1c > 9 . 0%
MONOTHERAPY*
NO SYMPTOMS
SYMPTOMS
Metformin
GLP-1 RA
DUAL THERAPY*
DPP4-i
AG-i
TZD
SGLT-2 **
SU/GLN
or other
first-line
agent
TZD
** SGLT-2
Colesevelam
Basal insulin
BromocriptineQR
* Order of medications listed are a suggested hierarchy of usage
* * Based upon phase 3 clinical trials data
DPP4-i
AG-i
SU/GLN
If not at goal in 3
months proce e d
to triple therapy
TRIPLE
THERAY
GLP-1 RA
Basal insulin
MET
INSULIN
± OTHER
AGENTS
OR
TRIPLE THERAPY *
** SGLT-2
TZD
If A1c > 6.5%
in 3 months add
second drug
(Dual Therapy)
DUAL
THERAPY
GLP-1RA
DPP4-i
MET
or other
first-line
agent
Colesevelam
BromocriptineQR
ADD OR INTENSIFY INSULIN
AG-i
SU/GLN
If not at goal in 3
months proce e d
to or intensify
insulin therapy
P RO G RE S S IO N
O F
LEGEND
=
Fe w adverse e ve nts
or possible benefits
= Use with caution
D IS EA S E
Copyright © 2 0 1 3 AACE May not be reproduced in any form without express written permission fro m AACE.
Reprinted with permission from American Association of Clinical Endocrinologists. Garber AJ, Abrahamson, MJ,
Brazilay JI, et al. AACE Comprehensive Diabetes Management Algorithm. Endocr Pract. 2013;19:327-336.
Page 3
Management Of Hyperglycemia In Type 2 Diabetes
A Patient Centered Approach
Diabetes Care 2012. Jun;35(6):1364-79
After metformin,
then what?
The Incretin‐Based Therapies IN‐CRET‐IN = INtestine seCRETion INsulin Definition: gut derived factors that increase glucose stimulated insulin secretion
Two hormones:
(1) glucagon‐like peptide‐1 (GLP‐1)
(2) glucose‐dependent insulinotropic polypeptide (GIP)
Diabetologia 1985 28: 5645 Page 4
The Incretin Effect
Role of Incretins in Glucose Homeostasis
Ingestion of food
Glucose‐dependent
 Insulin from beta cells
Release Incretin Hormone
PPG
levels
Beta cells
Alpha cells
Active
GLP‐1 & GIP
Glucose production by liver
Glucose dependent
 Glucagon from
alpha cells
DPP‐4 enzyme
Inactive
GLP‐1
Glucose uptake by muscles
Inactive
GIP
DPP‐4 = dipeptidyl‐peptidase 4; GLP‐1 = glucagon‐like peptide‐1; GIP = glucose‐dependent insulinotropic polypeptide; PPG = Postprandial blood glucose Endocr Rev. 1999;20:876–913. Curr Diab Rep. 2003;2:365–372.
Diabetes Care. 2003;26:2929–2940
Diabetes Metab Res Rev. 2002;18:430–441.
Meal
Glucose
(mg %)
Insulin
(µU/mL)
Glucagon
(pg/mL)
360
330
300
270
240
110
80
Type 2 diabetes (n=12)
Normal subjects (n-=11)
120
90
60
30
0
140
130
120
110
100
90
-60
Delayed/depressed
insulin response
Nonsuppressed glucagon
0
60
120
180
240
Time (min)
N Engl J Med. 1970;283:109-115.
Page 5
GLP‐ 1 Dose‐Response Relation
Lancet 2009;373:438‐9
Comparison of DPP-4 Inhibitors
Dose
Januvia
(sitagliptin)
Onglyza
(saxagliptin)
Tradjenta
(linagliptin)
Nesina
(alogliptin)
100mg daily
5mg daily
5mg daily
25mg daily
Take ONCE DAILY with or without food
Administration
Selectivity
>2,600 x
<100 x
> 10,000 x
Half-life
12.4 hrs
2.8 hrs
12 hrs
> 10,000 x
21 hrs
Elimination
13% hepatic
87% renal
CYP 3A4
40-67% hepatic
33-60% renal
90% excreted
unchanged
40% hepatic
60% renal
Renal
Impairment
Renal dose adjustment
ClCr 30-50 (50mg/day)
ClCr <30 (25mg/day)
Renal dose adjustment
ClCr <50 (2.5mg/day)
No renal dose
adjustment
Renal dose adjustment
ClCr 30-60 (12.5mg/day)
ClCr <30 (6.25mg/day)
Drug
Interactions
Digoxin
Strong CYP 3A4
inhibitors or inducers
Rifampin
None
Effect on
Body
Weight
Weight Neutral
Precaution
Nasopharyngitis, URIs
Lower dose of SU or insulin to reduce hypoglycemia
Pancreatitis, Severe hypersensitivity reactions
Pharmacotherapy.2010;30(5):463-84, Tradjenta(R) [package insert]. Ridgefield, CT: Boehringer Ingelheim
Pharmaceuticals Inc; 2012, Nesina(R) [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2013,
P T. 2011 December; 36(12): 807-812, 842
DPP- 4 Inhibitors: Comparison Trials
Drug/Daily Dose
Comparison
Sitagliptin 100mg
Placebo
Saxagliptin 5mg
Placebo
Linagliptin 5mg
Placebo
Alogliptin 25mg
Placebo
Concurrent
Therapies
A1c change
from baseline
None
- 0.48 to 0.70%
Metformin
- 0.67 to 1.00%
None
- 0.46%
Metformin
- 0.69%
None
- 0.60 to 0.70%
Metformin
- 0 .60%
None
- 0.60%
Metformin
- 0.40 to 0.60%
Pharmacotherapy.2010;30(5):463-84, Tradjenta(R) [package insert]. Ridgefield, CT: Boehringer Ingelheim
Pharmaceuticals Inc; 2012, Nesina(R) [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2013
Page 6
DPP-4 Inhibitor vs. Active Comparator:
Change in HbA1c (%) From Baseline
vs. Metformin
vs. Sulfonylurea
vs. Pioglitazone
vs. GLP-1 RA
BMJ 2012;344:bmj.e1369
Prolonging GLP-1 RA activity
Nat. Rev. Endocrinol.
2012;8:28-742
Comparison of GLP-1 RAs
Tanzeum
(Albliglutide)
Bydureon
(exenatide LAR)
Byetta
(exenatide)
Victoza
(liraglutide)
0.6mg SQ QD x 1
week then 1.2mg SQ
QD. May increase to
1.8mg SQ QD
Dose
30mg weekly
May increase to 50mg
weekly
2mg SQ weekly
5mcg SQ BID x 1
month then 10mcg SQ
BID
Food Interaction/
Administration
None
At least 4 days apart
None
At least 4 days apart
0-60 min. ac
at least 6 hrs apart
None
Half-life
5 days
~2 weeks
2.4 hrs
13 hrs
Elimination
Proteolytic enyzmes
Renal
Renal
Proteolysis by DPP4
and endopeptidases
A1c reduction
~0.6 – 0.8%
~1.5%
~ 0.8 – 1.3%
~ 0.9 – 1.5%
Mean change in
weight
- 0.4 – 1.2kg
(@ 52 weeks)
~2.3kg
(@ 24 weeks)
- 1.6 – 3.6kg
(@ 30 weeks)
- 0.2 – 2.8kg
(@ 26 weeks)
Nausea
11.1%
11 – 27%
18 – 44%
8 – 34%
CI and warnings
Thyroid C-cell tumors
pancreatitis
Thyroid C-cell tumors
ClCr <30
pancreatitis
ClCr <30
pancreatitis
Thyroid C-cell tumors
pancreatitis
Diabetes Care. 2005;28:1092-1100, Diabetes Care 2004;27:2628-35, Diabetes Care 2005;28:1083-91, Diabetes
Med. 2009;26:268-78, Diabetes Care 2009;32:84-90, Lancet 2009;373:473-81, Diabetes Care 2009;32:1224-30,
Diabetologia 2009;52:2046-55, Pharmacotherapy.2010;30(6):609-24, Tanzeum(R) [package insert]. Wilmington,
DE :GlaxoSmithKline; 2014
Page 7
GLP-1 RAs Comparison Trials
Lancet 2009;374:39-47
Lancet 2008;372:1240-1250
J Clin Endocrinol Metab 2011;96(5):1301-1310
Lancet 2013;381:117-24
Lancet Diabetes Endocrinol 2014 2(4):289-97
Concerns with Incretin-Based Therapies

Drug-Induced Pancreatitis
◦ FDA Alert (Oct. 2007)
 30 postmarketing reports of acute pancreatitis
◦ FDA Alert (Aug. 2008)
 6 cases of hemorrhagic or necrotizing pancreatitis
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Increased risk of pancreatitis and pancreatic-duct
metaplasia
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Medullary thyroid cancer
Immune dysfunction
Hypersensitivity reactions
Drug costs
◦ FDA Drug Safety Communication (March 2013)
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http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm. Accessed April 6th 2013
http://www.fda.gov/cder/drug/InfoSheets/HCP/exenatide2008HCP.html Accessed March 5th 2009
Diabetes Care.2010;33:428-33, Pharmacotherapy.2010;30(6):609-24
Glucose: From Blood to Urine
(180 g/day)
SGLT2: Major transporter of glucose in the kidney
• Low affinity, high capacity for glucose
• Nearly exclusively expressed in the kidney
90%
(180 g/day)
10%
(0 g/day)
Nat Rev Endocrinol. 2012;8:495-502.
Physiol. Rev. 1994;74:993-1026.
Page 8
Comparison of SGLT2 Inhibitors
Dose
Invokana
(canagliflozin)
Farxiga
(dapagliflozin)
Jardiance
(empagliflozin)
100mg daily and
may increase to 300mg
daily if GFR > 60
5mg daily
may increase to 10mg daily
If GFR > 60
10mg daily
may increase to 25mg daily
If GFR > 60
Take in the morning with or without food
Administration
Renal Impairment
Drug Interactions
Max dose 100mg daily
if GFR 45 – 60
Rifampin
Increase dose to 300mg daily
Do not use if GFR < 60
Max dose 10mg daily
if GFR 45 – 60
None
None
Effect on Body
Weight
Weight Loss
Precautions
Hx of genital infections, hyperkalemia, hypotension, Increased LDL
Lower dose of SU or insulin to reduce hypoglycemia
Hx of bladder CA (dapagliflozin only)
Invokana® [package insert]. Janssen Pharmaceuticals, Inc.Titusville, NJ, 2013
Farxiga® [package insert]. Bristol-Myers Squibb Company, Princeton, NJ, 2014
Jardiance® [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, 2014
SGLT2 Inhibitors Reduce A1c
Monotherapy

Canagliflozin
◦ 26 weeks, 300 mg/d

Dapagliflozin
◦ 24 weeks, 10 mg/d

Empagliflozin
◦ 24 weeks, 25 mg/d
Treatment
Group
Baseline
-1.03% vs placebo
8.0%
-0.89% vs placebo
8.0%
-0.85% vs baseline
7.9%
Diabetes Obes Metab. 2013;15:372-382.
Diabetes Care. Oct 2010; 33(10): 2217–2224
The Lancet Diabetes & Endocrinology 2013;1: 208-19
SGLT2 Inhibitors Reduce A1c
Added to Metformin

Canagliflozin
Treatment
Group
Baseline
-0.77% vs placebo
8.0%
-0.52% vs baseline
7.7%
-0.6% vs baseline
7.9%
◦ 26 weeks, 300 mg/d
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Dapagliflozin
◦ 52 weeks, up to 10 mg/d

Empagliflozin
◦ 24 weeks, 25 mg/d
Diabetologia. 2013;56(12):2582-2592
Diabetes Care. 2011;34:2015-2022
Jardiance® [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, 2014
Page 9
SGLT2 Inhibitors Reduce Body Weight
Monotherapy
• Canagliflozin
Treatment
Group
Baseline
-2.9 kg vs placebo
86.9 kg
-1.0 kg vs placebo
94.2 kg
-2.8 kg vs baseline
78 kg
– 26 weeks, 300 mg/d
• Dapagliflozin
– 24 weeks, 10 mg/d
• Empagliflozin
– 24 weeks, 25 mg/d
Diabetes Obes Metab. 2013;15:372-382.
Diabetes Care. Oct 2010; 33(10): 2217–2224
Jardiance® [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, 2014
SGLT2 Inhibitors Reduce SBP
Monotherapy
All in mmHg:
• Canagliflozin
Treatment
Group Baseline
SBP
-5.4 vs placebo
128.5
-2.7 vs placebo
Not Reported
-3.4 vs baseline
Not Reported
– 26 weeks, 300 mg/d
• Dapagliflozin
– 24 weeks, 10 mg/d
• Empagliflozin
– 24 weeks, 25 mg/d
Diabetes Obes Metab. 2013;15:372-382.
Diabetes Care. Oct 2010; 33(10): 2217–2224
Jardiance® [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, 2014
Canagliflozin: Infections
Monotherapy, 26 weeks
14
Urinary Tract
Infections
Genital Infections
12
Patients (%)
10
8
6.2
7.2
6.6
6
5.1
4.2
4
2
2.1
0
N=
PBO
100 mg
300 mg
PBO
100 mg
300 mg
192
195
197
192
195
197
Diabetes Obes Metab. 2013;15:372-382.
Page 10
Dapagliflozin: Infections
Monotherapy, 24 weeks
Urinary Tract
Infections
Genital Infections
14
12.9
12.5
12
Patients (%)
10
7.8
8
5.7
6
4
4
1.3
2
0
PBO
5 mg
10 mg
75
64
70
N=
PBO
5 mg
75
10 mg
64
70
Diabetes Care. 2010;33(10):2217-2224.
Empagliflozin: Infections
78 Week Open Label Extension Study
Patients Affected (%)
Urinary Tract
Infections
Genital Infections
14
12
Men
Women
10
8
5.3
6
3.6
4
2
5.3
0
0
N=
7.1
5.8
7
7
5.8
4.1
0
Met
10 mg
Empa
25 mg
Empa
56
106
109
0
Met
10 mg
Empa
25 mg
Empa
106
109
56
Diabetes Care. 2013;36(12):4015-4021.
SGLT2 Inhibitors: Adverse Events
• Increased genital mycotic infection
– 2% to 8% excess over placebo
• Bacterial urinary tract infections
– 1% to 12% excess over placebo
– No observed episodes of pyelonephritis or urosepsis
• Infections were manageable and rarely led to
discontinuation of treatment
– Managed with standard antimycotic creams and
hygienic measures
Diabetes Obes Metab. 2013;15(8):721-728.
J Diabetes Complications. 2013;27:268-273.
Diabetes Care. 2011;34:2015-2022.
Diabetes Obes Metab. 2013;15:372-382.
Diabetes Obes Metab. 2013;15:403-409.
Page 11
SGLT2 Inhibition
• Efficacy
–
–
–
–
Reduction in HbA1C of 0.5% to 1.0%
Weight reduction of ~2-3 kg
Reduction in systolic BP of 3 to 5 mmHg
Effective as monotherapy and in combination
• Safety
– Little or no risk of hypoglycemia
– Increased risk of mycotic genital infections
– Uncommon hyperkalemia in select populations
 Elderly
 ACE inhibitors/ ARB
 Diuretic
• Side Effects
– Polyuria
– Transient mild hypotension
SGLT2 Inhibitor Summary



Efficacy independent of beta-cell function
Effective A1c reduction and weight loss
Safety Concerns
◦
◦
◦
◦
◦

Renal function
Hypoglycemia
Mycotic infections/UTIs
Concomitant use with blood pressure medications
Cardiovascular safety unknown
Potential therapy for T1DM?
Questions?
Page 12