Novel Diabetes Medications

Focus on Incretin Agents & SGLT2

Inhibitors and Cardiovascular
Outcomes/Safety

CSHP Spring Therapeutics Update

April 21, 2016
Anar Dossa BScPharm Pharm D CDE
Clinical Pharmacy Specialist Outpatient Diabetes and Kidney Clinics
Vancouver General Hospital
 Disclosures
I have no known or real conflicts of
interest to declare
 Objectives
By the end of the presentation, participants
will be able to:
Describe the benefits and risks of incretin agents
and SGLT2 inhibitors and know when to utilize
them in people with type 2 diabetes
Articulate the cardiovascular safety of incretin
agents and SGLT2 inhibitors and list the agents
that have been studied thus far
Type 2 diabetes is increasingly
prevalent

640

415

2040

This will rise to 640

million by 2040

www.idf.org/diabetesatlas
4
 So What if Blood Sugars are High?
Microvascular complications
Macrovascular complications
Death associated with this is concerning

Literature:Blood Glucose Lowering

Microvascular complications
Benefit
Macrovascular complications
Uncertain
N Eng J Med 2008;358:2545-59
Lancet 1998;352: 837-53
Safety Concerns About Rosiglitazone
2008 U.S. FDA Cardiovascular Safety Requirements for
New Antihyperglycemic Agents
Non-inferiority
Boundary
HR 1.3

Upper bound of
{
Superiority

the 95% CI for Approvable: no need for

Participants with
postmarketing study 2 years of
Non-inferiority
the estimated risk higher CV risk CV safety data
ratio of <1.3 Approvable: need for
postmarketing study { Non-inferiority

{
Inferior

Not approvable
Underpowered

Prospective,
Design
0.4 0.6and
0.8 1 1.2 1.4 1.6 1.8 2.0 2.2
independent and
conduct shouldHazard ratio
blinded
allow for future
adjudication of
meta-analysis
CV events

Diabetes Care 2011;34:S101-106

 Traditional CV Outcome Trials vs.
New CV Safety Trials
Traditional New
CV Outcome Trials CV Safety Trials
Demonstrate CV safety
Demonstrate CV benefit
(no increased CV risk vs. placebo
( CV risk vs. placebo or active comparator)
as part of standard care)
Initiation of blinded treatment Initiation of blinded treatment
or placebo or placebo
No adjustment Adjustment
to maintain to maintain
the same LDL-C levels the same A1C levels
in both groups in both groups

Difference in LDL-C Small or no difference in A1C

between treatment and placebo between treatment and placebo

CV benefit of treatment demonstrated by No increased CV risk ( CV safety) of

significant reduction in CV outcomes treatment demonstrated by non-inferiority

Diabetes Care 2011;34:S101-106

Lancet 2014;383:1068-83
 Incretin Agents
GLP-1R Agonists
Liraglutide-daily injectable
Exenatide-twice daily injectable, weekly injectable
Dulaglutide-weekly injectable
Lixisenatide-daily injectable-outcome trial published
DPP-4 Inhibitors-daily oral agents
Sitagliptin
Saxagliptin outcome trials published
Alogliptin
Linagliptin-outcome trial expected in 2018
rxfiles.ca
Mechanism of Action-Incretins
GLP-1& GIP: Secreted
upon the ingestion of
food
Promotes satiety and
reduces appetite

Alpha cells:
Postprandial
glucagon secretion

Liver:
Glucagon reduces
Beta cells: hepatic glucose output
Enhances glucose-dependent
insulin secretion
Stomach:
Helps regulate
gastric emptying

www.medscape.org
 SGLT2 Inhibitors

Canagliflozin
Dapagliflozin
Empagliflozin
Oral agents

rxfiles.ca
 The Kidneys and Glucose

How much glucose should you be peeing out?

www.medscape.org
 The Kidneys and SGLT2 Inhibitors

SGLT2
inhibitor
SGLT2 inhibitors
reduce glucose
re-absorption
in the proximal
tubule, leading to
X urinary glucose
excretion and
X osmotic diuresis

Loss of 80 g of glucose/day ( 240 cal/day).

www.medscape.org
 Benefits
Agent A1c reduction (%)
Sulfonylureas 1-1.5
Metformin 1-1.5
Acarbose 0.5-0.8
Meglitinides 1-1.5
TZDs 1-1.5
DPP-4 Inhibitors 0.4-1.0
GLP-1 Receptor Agonist 0.8-1.5
SGLT2 Inhibitors 0.4-0.8
Insulin Regimen Dependent
15
rxfiles.ca
 Incretin Agents-Benefits
GLP-1R Agonists
Liraglutide
Exenatide Weight loss
Dulaglutide Low risk of hypoglycemia
Lixisenatide
DPP-4 Inhibitors
Sitagliptin
Weight neutral
Saxagliptin Low risk of hypoglycemia
Alogliptin Oral
Linagliptin
rxfiles.ca
 SGLT2 Inhibitors-Benefits
Canagliflozin, Dapagliflozin, Empagliflozin
Low risk of hypoglycemia
Weight loss
Oral agents
Lower blood pressure
Cardiovascular benefit

rxfiles.ca
 Outcome Trials-Baseline Characteristics
DPP-4 Inhibitors GLP-1RA SGLT-2 Inhibitor
EXAMINE SAVOR-TIMI 53 TECOS ELIXA EMPA-REG

Study Drug Alogliptin Saxagliptin Sitagliptin Lixisenatide Empagliflozin

Sample size, N 5,380 16,492 14,671 6,068 7,020

Established CVD
ACS within 15 to Pre-existing ACS within 180
CV background and/or multiple risk Pre-existing CVD
90 days CVD days
factors

Females, % 32 33 29 31 29

61
Mean age, y 65 66 60 63
(median)

Duration of 57% had DM for

7 10 12 9
diabetes, y >10 years

Mean A1C, % 8.0 8.0 7.2 7.7 8.1

29
Mean BMI, kg/m2 31 30 30 31
(median)

N Engl J Med 2013; 369:1327-1335

Lancet 2015; 385:2067-2076
N Engl J Med 2015; 373:232-242
N Engl J Med 2015; 373:2247-2257
N Engl J Med 2015; 373:2117-2128
 Baseline Cardiovascular History

DPP-4 Inhibitors GLP-1RA SGLT-2 Inhibitor

% Incidence

EXAMINE SAVOR-TIMI 53 TECOS ELIXA EMPA-REG

Alogliptin Saxagliptin Sitagliptin Lixisenatide Empagliflozin

Hypertension 83 82 86 76 95
Established
100 78 100 100 99
CVD
MI 88 38 43 83 47

CABG 13 24 25 8 25

Stroke/TIA 7 13 21 7 23

CHF 28 13 18 22 10

N Engl J Med 2013; 369:1327-1335

Lancet 2015; 385:2067-2076
N Engl J Med 2015; 373:232-242
N Engl J Med 2015; 373:2247-2257
N Engl J Med 2015; 373:2117-2128
 SAVOR-TIMI 53
Primary Endpoint
Composite of CV death, MI, or ischemic stroke
Saxagliptin Placebo
14
Patients with endpoint (%)

12

10 HR (95% CI) = 1.00 (0.89-1.12)

8 P < 0.001 for non-inferiority
6
P = 0.99 for superiority
4

2 Saxagliptin met the primary endpoint of non-inferiority

0 but not superiority when compared to placebo
0 180 360 540 720 900
Days
No. at Risk
Placebo 8212 7983 7761 7267 4855 851
Saxagliptin 8280 8071 7836 7313 4920 847

N Engl J Med 2013; 369:1327-1335

 SAVOR-TIMI 53
Major Secondary Endpoints
Cardiovascular Endpoints Placebo Saxagliptin Hazard Ratio P
(N=8212) (N=8280) (95% CI) Value
no. (%)

Death from cardiovascular causes 260 (2.9) 269 (3.2) 1.03 (0.871.22) 0.72

Myocardial infarction 278 (3.4) 265 (3.2) 0.95 (0.801.12) 0.52

Ischemic stroke 141 (1.7) 157 (1.9) 1.11 (0.881.39) 0.38

Hospitalization for unstable angina 81 (1.0) 97 (1.2) 1.19 (0.891.60) 0.24

Hospitalization for heart failure 228 (2.8) 289 (3.5) 1.27 (1.071.51) 0.007

Hospitalization for coronary revascularization 459 (5.6) 423 (5.2) 0.91 (0.801.04) 0.18

N Engl J Med 2013; 369:1327-1335

 EXAMINE
Primary Endpoint
Composite of death from CV causes, non-fatal MI, or non-fatal stroke
24
Alogliptin Placebo
Cumulative Incidence of Primary

18
HR (95% CI) = 0.96 (1.16)
End-Point Events (%)

12
P < 0.001 for non-inferiority
P = 0.32 for superiority
6
Alogliptin was non-inferior but not superior to placebo
0
with respect to the primary endpoint
0 6 12 18 24 30

Months

No. at Risk
Placebo 2679 2299 1891 1375 805 286
Alogliptin 2701 2316 1899 1394 821 296

Lancet 2015; 385:2067-2076

 EXAMINE
Major Safety Endpoints
Placebo Alogliptin Hazard Ratio for P
(N=2679) (N=2701) Alogliptin Group Value
(95% CI)
no. (%)

Components of primary endpoint

Death from cardiovascular causes 111 (4.1) 89 (3.3) 0.79 (0.601.04) 0.10

Non-fatal myocardial infarction 173 (6.5) 187 (6.9) 1.08 (0.881.33) 0.47

Non-fatal stroke 32 (1.2) 29 (1.1) 0.91 (0.551.50) 0.71

Principal secondary end-point 359 (13.4) 344 (12.7) 0.95 (1.14) 0.26

Other end-points

Death from any cause 173 (6.5) 153 (5.7) 0.88 (0.711.09) 0.23

Death from cardiovascular causes 130 (4.9) 112 (4.1) 0.85 (0.661.10) 0.21

Hospital admission for heart failure 89 (3.3) 106 (3.9) 1.19 (0.901.58) 0.22

Hospital admission for heart failure was a post-hoc analysis due to SAVOR-TIMI 53 trial results

Lancet 2015; 385:2067-2076

 TECOS
Primary Endpoint
Time from randomization to the first confirmed CV-related death, non-fatal MI, non-
fatal stroke, or UA requiring hospitalization

15

10
Percent of patients with an event

100

5
80 HR (95% Cl): 0.98 (0.89, 1.08)
P =0.645
60 0
0 4 8 12 18 24 30 36 42 48
Sitagliptin
40
was non-inferior but not superior to placebo
with respect to the primary endpoint
20
Placebo
Sitagliptin
0
0 4 8 12 18 24 30 36 42 48

Patients at risk:
Month in the trial
Sitagliptin 7,332 7,131 6,937 6,777 6,579 6,386 4,525 3,346 2,058 1,248
Placebo 7,339 7,146 6,902 6,751 6,512 6,292 4,441 3,272 2,034 1,234

N Engl J Med 2015; 373:232-242

 TECOS
Major Secondary Endpoints
Placebo Sitagliptin Hazard Ratio
(N=7266) (N=7250) (95% CI) P Value
n (%)
Secondary end point
CV death 366 (5.0) 380 (5.2) 1.03 (0.891.19) 0.71
Hospitalization for unstable
129 (1.8) 116 (1.6) 0.90 (0.70-1.16) 0.42
angina
Fatal or non-fatal MI 316 (4.3) 300 (4.1) 0.95 (0.81-1.11) 0.49
Fatal or non-fatal stroke 183 (2.5) 178 (2.4) 0.97 (0.79-1.19) 0.76
Death from any cause 537 (7.3) 547 (7.5) 1.01 (0.90-1.14) 0.88
Hospitalization for heart failure 229 (3.1) 228 (3.1) 1.00 (0.83-1.20) 0.98

N Engl J Med 2015; 373:232-242

 ELIXA
Primary Endpoint
Time to the first occurrence of the primary CV event (CV death, non-fatal MI, non-fatal
stroke, hospitalization for UA)
20

15

HR = 1.02 (0.89, 1.17)

Percent

10

Lixisenatide: 406/3034 = 13.4%

Placebo:
5 Lixisenatide was non-inferior but 399/3034 = 13.2%
not superior
to placebo with respect to the primary end point
0
0 12 24 36
Months
No. at risk
Placebo 3034 2759 1566 476
Lixisenatide 3034 2785 1558 484

N Engl J Med 2015; 373:2247-2257

 ELIXA
Major Secondary Endpoints
Placebo Lixisenatide Hazard Ratio
(N=3034) (N=3034) (95% CI)
n (%)
Secondary end point
Primary* + HF Hospitalization 469 (15.5) 456 (15.0) 0.97 (0.85-1.10)
Primary* + HF Hospitalization
659 (21.7) 661 (21.8) 1.00 (0.90-1.11)
+ Coronary Revascularization
HF Hospitalization 127 (4.2) 122 (4.0) 0.96 (0.75-1.23)
CV Death + HF Hospitalization 253 (8.3) 248 (8.2) 0.97 (0.82-1.16)

N Engl J Med 2015; 373:2247-2257

 Potential reasons for differences in
heart failure signals
Differences in patients enrolled
Differences in background care provided
Variation in acquisition/definition of HF events
among trials
Intrinsic pharmacologic differences among the
DPP-4 inhibitors
Play of chance in prior trials

JAMA Cardiol. Published online April 13, 2016

doi:10.1001/jamacardio.2016.0184
Heart Failure and Diabetes Mellitus
8% increased
Each 1%
risk of heart
increase in A1C
failure
Diabetes
Accelerates the development of coronary atherosclerosis
Often associated with hypertension
Promotes the development of myocardial fibrosis
Associated with
Increased autonomic dysfunction (including insulin resistance)
Worsened renal and endothelial function
Neurohormal activation

Lancet Diabetes Endocrinol 2014;2:843-51

 Other Safety Endpoints of Interest
DPP-4 Inhibitors GLP-1RA

EXAMINE SAVOR-TIMI 53 TECOS ELIXA

Placebo Alogliptin Placebo Saxagliptin Placebo Sitagliptin Placebo Lixisenatide

Study Arms n=2,679 n= 2,701 n= 8,212 n= 8,220 n= 7,339 n= 7,332 n= 3,034 n= 3,034

Acute
pancreatitis 8 12 16 22 12 23 8 5
(n)
Chronic
pancreatitis 4 5 6 2 0 4 0 0
(n)

Malignancy
4.4 3.9 1.9 2.0 4.0 3.7 2.6 2.9
(%)

Pancreatic
0 0 12 5 14 9 9 3
cancer (n)
N Engl J Med 2013; 369:1327-1335
Lancet 2015; 385:2067-2076
N Engl J Med 2015; 373:232-242
N Engl J Med 2015; 373:2247-2257
N Engl J Med 2015; 373:2117-2128
 Baseline characteristics: CV medication
Placebo Empagliflozin Empagliflozin
(n=2333) 10 mg 25 mg
(n=2345) (n=2342)
Anti-hypertensive therapy 2221 (95.2%) 2227 (95.0%) 2219 (94.7%)
ACE inhibitors/ARBs 1868 (80.1%) 1896 (80.9%) 1902 (81.2%)
Beta-blockers 1498 (64.2%) 1530 (65.2%) 1526 (65.2%)
Diuretics 988 (42.3%) 1036 (44.2%) 1011 (43.2%)
Calcium channel blockers 788 (33.8%) 781 (33.3%) 748 (31.9%)
Mineralocorticoid receptor 136 (5.8%) 157 (6.7%) 148 (6.3%)
antagonists
Renin inhibitors 19 (0.8%) 16 (0.7%) 11 (0.5%)
Other 191 (8.2%) 193 (8.2%) 190 (8.1%)

N Engl J Med 2015; 373:2117-2128

32
 Baseline characteristics: CV medication
Placebo Empagliflozin Empagliflozin
(n=2333) 10 mg 25 mg
(n=2345) (n=2342)
Lipid-lowering drugs 1864 (79.9%) 1926 (82.1%) 1894 (80.9%)
Statins 1773 (76.0%) 1827 (77.9%) 1803 (77.0%)
Fibrates 199 (8.5%) 214 (9.1%) 217 (9.3%)
Ezetimibe 81 (3.5%) 95 (4.1%) 94 (4.0%)
Niacin 35 (1.5%) 56 (2.4%) 35 (1.5%)
Other 175 (7.5%) 172 (7.3%) 193 (8.2%)
Anti-coagulants and anti-platelets 2090 (89.6%) 2098 (89.5%) 2064 (88.1%)
Acetylsalicylic acid 1927 (82.6%) 1939 (82.7%) 1937 (82.7%)
Clopidogrel 249 (10.7%) 253 (10.8%) 241 (10.3%)
Vitamin K antagonists 156 (6.7%) 141 (6.0%) 125 (5.3%)

N Engl J Med 2015; 373:2117-2128

33
 EMPA-REG
Primary Endpoint
Time to the first occurrence of CV death, non-fatal MI or non-fatal stroke

HR 0.86 Placebo
(95.02% CI 0.74, 0.99)
P =0.04
Patients with event (%)

Empagliflozin

Empagliflozin was superior to placebo with respect to the

primary endpoint

Months
No. of patients
Empagliflozin 4687 4580 4455 4328 3851 2821 2359 1534 370
Placebo 2333 2256 2194 2112 1875 1380 1161 741 166

N Engl J Med 2015; 373:2117-2128

 EMPA-REG
Major Secondary Endpoints
Patients with event/analysed
Empagliflozin Placebo HR (95% CI) P value

Primary endpoint* 490/4687 282/2333 0.86 (0.74, 0.99) 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

CV death, non-fatal MI, non-fatal

599/4687 333/2333 0.89 (0.78, 1.01) 0.0795
stroke, or hospitalization for UA

Favours empagliflozin Favours placebo

N Engl J Med 2015; 373:2117-2128

Hospitalisation for heart failure
HR 0.65
(95% CI 0.50, 0.85)
p=0.0017

N Engl J Med 2015; 373:2117-2128 36

 All-cause mortality
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001

N Engl J Med 2015; 373:2117-2128 37

Number needed to treat (NNT) to prevent one death across
landmark trials in patients with high CV risk

Simvastatin Ramipril Empagliflozin

for 5.4 years for 5 years for 3 years

High CV risk High CV risk T2DM with high CV risk

5% diabetes, 26% hypertension 38% diabetes, 46% hypertension 92% hypertension

Pre-ACEi/ARB era >80% ACEi/ARB

Pre-statin era <29% statin >75% statin

1994 2000 2015

Lancet 1994; 344: 1383-89
N Engl J Med 2000;342:145-53
N Engl J Med 2015;373:2117-28 38
 SGLT2 Inhibitors-Warnings and
Precautions
Ketoacidosis
Webinar
Bladder cancer
Dapagliflozin
Bone fractures
Canagliflozin
Hyperkalemia
Canagliflozin
Renal impairment
Increased LDL
Drink plenty of fluids-hypotension, loop diuretics

rxfiles.ca
 CDA Guidelines-After Metformin
Add another agent best suited to the individual by prioritizing patient
characteristics:

PATIENT CHARACTERISTIC CHOICE OF AGENT

PRIORITY: SGLT2 inhibitor with demonstrated

Clinical Cardiovascular Disease CV outcome benefit

Degree of hyperglycemia Consider relative A1C lowering

Risk of hypoglycemia
Overweight or obesity
CV disease or multiple risk factors
Comorbidities (renal, CHF, hepatic)
Preferences & access to treatment
Rare hypoglycemia
Weight loss or weight neutral
Effect on cardiovascular outcome
See therapeutic considerations
See cost column; consider access

2016 diabetes.ca
 What About Other Guidelines?
CADTH
Canadian
NICE
UK
ADA
American
 Antihyperglycemic agents and Renal Function
CKD Stage: 5 4 3 2 1
eGFR (mL/min/1.73 m2): <15 1529 3059 6089 90
Alpha-glucosidase
Inhibitor Acarbose Not recommended 25
Biguanide Metformin 30 60
Alogliptin Not recommended
6.25 mg 30 12.5 mg 50
DPP-4 Linagliptin 15
inhibitors
Saxagliptin 15 2.5 mg 50
Sitagliptin 25 mg 30 50 mg 50
Albiglutide 50
GLP-1R Dulaglutide 50
agonists
Exenatide (BID/QW) 30 50
Liraglutide 30 50
Insulin
Gliclazide/Glimepiride 15 30
Secreta-
gogues Glyburide 30 50
Repaglinide
Canagliflozin 25 45 100 mg 60*
SGLT2
inhibitors Dapagliflozin 60
Empagliflozin 45 60*
Thiazolidinediones 30
Contraindicated Not recommended Caution and/or reduce dose Safe
Can J Diabetes 2015;39:440. * = do not initiate if eGFR <60 ml/min 2016
 Case
65 y.o. male with type 2 diabetes x 10 years
MI, hypertension
BMI=30
A1c=9%
eGFR=65 ml/min
Metformin 1g bid, gliclazide MR 120mg daily
Ramipril 10mg daily, ASA 81mg daily,
Atorvastatin 40mg daily
 Extra Slides
Summary from CDA
Cost
Sick Day management incorporating the new
agents
 diabetes.ca
Add another class of agent best suited to the individual (agents listed in alphabetical order):
Class Relative Hypo- Weight Effect in Other therapeutic considerations Cost
A1C glycemia Cardiovascular
Lowering Outcome Trial
-glucosidase Rare neutral to Improved postprandial control, GI side- $$
inhibitor (acarbose) effects
Incretin agents:
DPP-4 Inhibitors Rare Neutral to Neutral (alo, saxa, sita) Caution with saxagliptin in heart failure $$$
GLP-1R agonists to Rare Neutral (lixi) GI side-effects $$$$

Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-
$$$$
Insulin secretagogue:
Meglitinide Yes Less hypoglycemia in context of missed $$
meals but usually requires TID to QID
Sulfonylurea Yes dosing $
Gliclazide and glimepiride associated
with less hypoglycemia than glyburide
SGLT2 inhibitors to Rare Superiority Genital infections, UTI, hypotension, $$$
(empa in T2DM dose-related changes in LDL-C, caution
patients with clinical with renal dysfunction and loop
CVD) diuretics, dapagliflozin not to be used if
bladder cancer, rare diabetic
ketoacidosis (may occur with no
hyperglycemia)
Thiazolidinediones Rare Neutral CHF, edema, fractures, rare bladder $$
cancer (pioglitazone), cardiovascular
controversy (rosiglitazone), 6-12 weeks
required for maximal effect
Weight loss agent None GI side effects $$$
(orlistat)
alo=alogliptin; glar=glargine; saxa=saxagliptin; sita=sitagliptin; lixi=lixisenatide; empa=empagliflozin 2016
Pharmacare: Special Authority if insulin not an option and inadequate control with metformin+sulfonylurea
Sitagliptin, alogliptin not covered

diabetes.ca
Pharmacare: not covered diabetes.ca
Pharmacare: not covered diabetes.ca
Pharmacare: not covered diabetes.ca
diabetes.ca