Ferhan Siddiqi, MD FRCPC MScHQAssistant Professor
Division of Endocrinology & Metabolism, QEII HSC (Central Zone)April 19, 2018
This speaker has been asked to disclose to the audience any involvement with industry or other organizations that may potentially influence the presentation of any educational material.
Receiving evaluations is critical to the accreditation process. After the program, please provide feedback at: https://surveys.dal.ca/opinio/s?s=41441
– Grants/Research Support: AstraZeneca Canada
– Speakers Bureau/Honoraria: None
– Consulting Fees: None
– Advisory Boards: Novo-Nordisk, Sanofi, Janssen, Abbott
– Funded Conferences: None
At the end of this talk, participants will be able to:
◦ Describe the impact of early tight glycemic control in the development of complications in type 2 diabetes (DM2)
◦ Outline various new glucose-lowering agents developed for use in type 2 diabetes including knowledge of their mechanism, efficacy and safety in treatment
◦ Individualize the selection of pharmacotherapy in patients with type 2 diabetes based on patient and agent-specific characteristics including cardiovascular (CV) outcomes
58 year-old man, tour operator
DM2 x 8 yr, MI age 54
A1c 8.7%
On metformin 1 g bid, gliclazide MR 120 mg daily, ramipril 5 mg daily, rosuvastatin 5 mg daily
BMI 34.3, BP 128/78, LDL 1.9
What would you recommend for him?
Pe
rce
nta
ge d
ecr
eas
e in
ris
k co
rre
spo
nd
ing
to a
1%
de
cre
ase
in A
1c
**
Any diabetes-related
endpoint
21%
**
Diabetes-related death
21% **
All-cause
mortality
14%
*
Stroke
12%
**
Peripheral vascular disease†
43%
**
Myocardialinfarction
14%
**
Micro-vascular disease
37%
**
Cataract extraction
19%
Observational analysis from UKPDS
† Lower extremity amputation or fatalperipheral vascular disease
* p=0.035; **p<0.0001
Stratton IM et al. BMJ 2000;321:405-12.
Holman RR et al. N Engl J Med. 2008;359:1577-89.
7.9%
7.0%
~ 8%Intensive therapy
Holman RR et al. N Engl J Med. 2008;359:1577-89.
Early glycemic control reduces the risk of latermicrovascular and macrovascular complications
17%reduction
13%reduction
15%reduction
24%reduction
Diabetes-related mortality
All-cause mortality
Myocardial infarction
Microvascularendpoints
2013
which must be balanced against the risk of hypoglycemia
Consider 7.1-8.5% if:
Can J Diabetes 2013;37(Suppl 1):S1-S212.
Leiter et al. Can J Diabetes. 2013;37:82-89.
Proportions of patients at various A1C strata* (DM-SCAN)
A1C 7% to ≤8%
28.5%
A1C >9%
9%
A1C ≤7%
50%
*≤7.0% was the goal set by physicians for 81% of patients
A1C 8% to ≤9%
12.5%
DM-SCAN survey of 5103 Canadians
with type 2 diabetes (2012)
50%
Start metformin immediately
Consider a second concurrent
antihyperglycemic agent
Start healthy behaviour interventions
(nutritional therapy, weight management, physical activity) +/- metformin
A1C <1.5% above targetSymptomatic hyperglycemia
and/or metabolic decompensationA1C 1.5% above target
Initiate insulin +/-
metforminIf not at glycemic target
within 3 months,
start/increase metformin
If not at glycemic target
HE
AL
TH
Y B
EH
AV
IOU
R I
NT
ER
VE
NT
ION
S
Clinical CVD?
See next page
AT DIAGNOSIS OF TYPE 2 DIABETES
2018
If not at glycemic target
YES
Start antihyperglycemic agent with
demonstrated CV benefit
empagliflozin (Grade A, Level 1A)
liraglutide (Grade A, Level 1A)
canagliflozin* (Grade C, Level 2)
NO
If not at glycemic target
* Avoid in people with prior lower extremity amputation
Add additional antihyperglycemic agent best suited to the individual based
on the following
Other considerations:
Reduced eGFR and/or albuminuria
Clinical CVD or CV risk factors
Degree of hyperglycemia
Other comorbidities (CHF, hepatic
disease)
Planning pregnancy
Cost/coverage
Patient preference
see Renal Impairment Appendix
See Table Below
CLINICAL CONSIDERATIONS CHOICE OF AGENT
Avoidance of hypoglycemia and/or
weight gain with adequate glycemic
efficacy
DPP-4 inhibitor, GLP-1 receptor
agonist or SGLT2 inhibitor
Clinical CVD?
NO
2018
If not at glycemic targets
Add another antihyperglycemic agent from a different class and/or add/intensify insulin regimen
Make timely adjustments to attain target A1C within 3-6 months
2018
2018
Add additional antihyperglycemic agent best suited to the individual by prioritizing patient characteristics (agents listed in alphabetical order by CV outcome data):
Class Effect on CVD Outcomes
Hypo-glycemia
Weight RelativeA1C Lowering when added to metformin
Other therapeutic considerations Cost
GLP-1R agonists lira: Superiorityin T2DM with clinical CVD
exenatide LAR &lixi: Neutral
Rare to GI side-effects, Gallstone diseaseContraindicated with personal / family history of medullary thyroid cancer or MEN 2Requires subcutaneous injection
$$$$
SGLT2 inhibitors Cana & empa:Superiority in
T2DM patientswith clinical CVD
Rare to Genital infections, UTI, hypotension, dose-related changes in LDL-C. Caution with renal dysfunction, loop diuretics, in the elderly. Dapagliflozin not to be used if bladder cancer. Rare diabetic ketoacidosis (may occur with no hyperglycemia). Increased risk of fractures and amputations with canagliflozin. Reduced progression of nephropathy & CHF hospitalizations with empagliflozin and canagliflozin in those with clinical CVD
$$$
DPP-4 Inhibitors alo, saxa, sita: Neutral
Rare Neutral Caution with saxagliptin in heart failureRare joint pain
$$$
Insulin glar: Neutraldegludec:
noninferior to glar
Yes No dose ceiling, flexible regimensRequires subcutaneous injection
$-$$$$
Thiazolidinediones Neutral Rare CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks for maximal effect
$$
-glucosidase inhibitor (acarbose)
Rare Neutral GI side-effects commonRequires 3 times daily dosing
$$
Insulin secretagogue:Meglitinide
Sulfonylurea
Yes
Yes
More rapid BG-lowering responseReduced postprandial glycemia with meglitinides but usually requires 3 to 4 times daily dosing.Gliclazide and glimepiride associated with less hypoglycemia than glyburide. Poor durability
$$
$
Weight loss agent (orlistat)
None GI side effectsRequires 3 times daily dosing
$$$
2018
UKPDS-34, obese sub-group (n=753)
◦ Newly diagnosed DM2, mean age = 53 y
◦ Duration of Rx ~10 yr, compared to conventional Rx
*
Any diabetes-related
endpoint
21%
*
Diabetes-related death
30%
**
All-cause
mortality
27%
†
Stroke
20%
**
Myocardialinfarction
33%
*p<0.01**p<0.005
†p=NS
NNT=15
UKPDS-34 Lancet 1998; 352: 854-65.Holman RR et al. N Engl J Med. 2008;359:1577-89.
10 yr follow-up:
ARR 8% 5% 7% 6% -
Incretin-based agents
◦ DPP-4 inhibitors
◦ GLP-1 receptor agonists
SGLT-2 inhibitors
Newer insulins
Incretin-based agents
◦ DPP-4 inhibitors
◦ GLP-1 receptor agonists
SGLT-2 inhibitors
Newer insulins
Baggio LL, Drucker DJ. Gastroenterology. 2007;132(6):2131-2157.
Insulin secretion
Glucagon secretion
Hepatic glucose
production Insulin secretion
Glucagon secretion
Hepatic glucose production
GLP
-1 r
ecep
tor-d
ep
en
den
t acti
on
s
Progressive GLP-1 activity
Satiety
Energy intake
Gastric emptying
Baggio LL, Drucker DJ. Gastroenterology. 2007;132(6):2131-2157.
Inhibit dipeptidyl peptidase 4 enzyme
GLP-1 inactive
metabolites
DPP-4
GLP-1
Agent Dose Frequency
sitagliptin (Januvia®) 100 mg
50 mg (eGFR 30-50)
Once daily
saxagliptin (Onglyza®) 5 mg
2.5 mg (eGFR 30-50)
Once daily
linagliptin (Trajenta®) 5 mg Once daily
15Linagliptin
Sitagliptin 5030 50 mg25 mg
Saxagliptin 5015 2.5 mg
eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1
CKD=chronic kidney disease.Sitagliptin Product Monograph, Merck, 2017; saxagliptin Product Monograph, AstraZeneca Canada, 2014; linagliptin product monograph, Boehringer-Ingelheim Canada, 2015.
Decision characteristic Response
After metformin?
A1c 7-8%
With coverage
Pill vs. injection? Pill
Side effectsVirtually non-existent;
No hypoglycemia
Weight Neutral
once daily
◦ liraglutide (Victoza ®)
◦ exenatide (Byetta ®)
once weekly
◦ dulaglutide (Trulicity ®)
◦ exenatide once-weekly (Bydureon ®)
◦ semaglutide (Ozempic ®)
◦ albiglutide**Albiglutide not available in Canada as of April 2018
Mean difference in A1C from baseline
Baseline A1C
8.2%
8.3%
8.2%
8.3%
8.4%
8.4%
Mean difference in weight from baseline
1. Exenatide Product Monograph, AstraZeneca Canada, 2014; 2. DeFronzo R et al. Diabetes Care 2005;28(5):1092-100; 3. Liraglutide Product Monograph, Novo Nordisk Canada, 2014; 4. Nauck M et al. Diabetes Care 2009;32:84-90; 5. Pratley R et al. Lancet 2010;375:1447-56; 6. Pratley R et al. Int J Clin Pract. 2011;65(4):397-407.
5μgexenatide:
-0.5%10μg
exenatide:
-0.9%
p≤0.05 p≤0.0001
vs. placebo (0.0%)
vs. placebo (-0.2 kg)
vs. placebo (-1.2 kg)
vs. sitagliptin (-0.96 kg)
1.2 mg liraglutide
-1.0% to
-1.2%
P<0.0001
1.8 mg liraglutide
-1.0% to
-1.5%
vs. placebo (+0.1%)
vs. sitagliptin (-0.9%)
Exenatide1,2
(5 µg BID)
Exenatide1,2
(10 µg BID)
Placebo
Liraglutide3-6
(1.2 mg QD)
Liraglutide3-6
(1.8 mg QD)
Placebo
-1.3 kg to
-2.6 kg
-2.6 kg to
-3.7 kg
Hypoglycemia risk is elevated when combined with a
sulfonylurea
SU=sulfonylurea; MET=Metformin; EXE=exenatide; LIRA=liraglutide; PBO=placebo; GLAR=glargine. Liraglutide Product Monograph, Novo Nordisk Canada, 2014; Exenatide Product Monograph, AstraZeneca Canada, 2014.
Exenatide 5 μg BID
Exenatide 10 μg BID
Liraglutide 1.2 mg QD
Liraglutide 1.8 mg QD
Placebo
Proportion of patients with hypoglycemia on incretin therapies in combination with metformin (± sulfonylurea)
5.3
12.6
2.5
16.7
4.5
19.2
0.8
27.4
5.3
27.8
2.5
28.9
16.9
0
10
20
30
40
50
60
70
80
90
100
+ MET + MET + SU
Sulfonylurea
+ MET + MET + SU
Glargine
EXEN 5µg
EXEN 10µg
PBO EXEN 5µg
EXEN 10µg
PBO LIRA1.8mg
PBOLIRA1.2mg
LIRA1.8mg
GLARPBOSU
Pro
po
rti
on
of
pati
en
ts (
%)
Doses: 0.75 mg, 1.5 mg; convenient s.c. injection device
Modified from: Dungan K et al. Lancet 2014. 384: 1349-57.
A1c
lowering
A1c
lowering
Dose: 2 mg/pen
No titration, one pen per week
Modified from: Buse JB et al. Lancet 2013. 381:117-24.
SUSTAIN-2◦ vs. DPP-4 inhibitor
SUSTAIN-3◦ vs. exenatide QW
SUSTAIN-4◦ vs. insulin - 2nd line
SUSTAIN-5◦ vs. basal insulin
SUSTAIN-6◦ CV outcomes trial**
SUSTAIN-7◦ vs. dulaglutide
SUSTAIN trials program
Doses: 0.25 mg, 0.5 mg, 1 mg
Sorli C et al. Lancet Diabetes Endocrin 2017; 5(4):251-60.
1.5%
eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1
Liraglutide* 50
Albiglutide 50
30
Dulaglutide 50
Exenatide (BID/QW) 30 50
* May be acceptable
to continue use
down to eGFR 30-45
based on studies
(LIRA-RENAL,
LEADER)
Davies MJ et al. Diabetes Care 2016; 39:222-30.Marso SP et al. N Engl J Med 2016; 375:311-22.
BID=twice daily; QW=once weekly.Liraglutide Product Monograph, Novo Nordisk Canada, 2017; Exenatide Product Monograph, AstraZeneca Canada, 2014; Dulaglutide product monograph, Lilly Canada, 2016.
Possible side effects Counselling
Nausea and/or vomiting• Transient• Resolves over time in most cases
Local site reaction • Minor, rarely requires discontinuation
Pancreatitis• Current data do not support a causal association but still considered an ongoing rare complication/risk
Gallstone disease• In susceptible individuals, based on LEADER trial results (3.1% vs. 1.9%)
Risk of medullary thyroid cancer (rat studies)
• No evidence to support any increased risk of medullary thyroid cancer development in humans• Avoid if personal or family history of
MTC or MEN2
Liraglutide product monograph, Novo-Nordisk Canada, 2017; Marso SP et al. N Engl J Med 2016; 375:311-22.
MET=metformin. Ahmann A et al. American Diabetes Association 2014. Abst 331-OR.Morrow L et al. Diab Obes Metab 2010; 13:75-80.
Baseline body weight: 90.2 kg 91.8 kg
Change in body weight: -3.54 kg -0.42 kg
Baseline: 8.3%
Insulin detemir/glargine +
liraglutide 1.8 mg (±MET)
n=226
ETD 95% CI: -1.19 [-1.39; -0.99]; p<0.0001
Baseline: 8.3%
Insulin detemir/glargine +
placebo (±MET)
n=225
Change in A1C from baseline at week 26
ETD 95% CI: -3.11 [-3.85 ; -2.37]; p<0.0001
-1.30%
-0.11%
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Ch
an
ge in
A1
C f
ro
m b
aselin
e (
%)
>50% achieved
target with
liraglutide
add-on therapy
(vs. 14% placebo)
liraglutide 0.6 mg
s.c. daily x 1 week,
then 1.2 mg daily;
up to 1.8 mg od
Baseline Insulin
A1c change
>8.5% No ↓
7-8% ↓ 10%
<7.0% ↓ 20%
Decision characteristic Response
After metformin?
A1c 7-10%
With coverage
Pill vs. injection? Injection
Side effectsNausea/GI
No hypoglycemia
Weight Loss
Incretin-based agents
◦ DPP-4 inhibitors
◦ GLP-1 receptor agonists
SGLT-2 inhibitors
Newer insulins
↑ glucosuria
↑ natriuresis
SGLT-2=Sodium glucose co-transporter type 2
Matthaei S et al. Diabetes Care 2015; 38: 365-72.
Safety data available
for SGLT-2 inhibitors
out 3-4 years without
any unexpected AEs
Possible side effects Counselling
Urinary tract and genital mycotic (yeast) infections
• UTI 5.9 - 9.6% (women; mostly 1x)• Genital mycotic infections
Women 8.4 – 11.4%Men 4.2 – 5.4%
Volume depletion/hypotension• Patients should maintain adequate hydration; caution re: polypharmacy
Acute kidney injury• Hold medication during acute illness or dehydration (sick day management)
Diabetic ketoacidosis (DKA)• Reported cases observed in T2DM• Likely due to patient/insulin factors
eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1
Dapagliflozin 60
Empagliflozin 45
Canagliflozin 25 60*100 mg45
60*
• Reduced glycosuric effect at
lower eGFR (less effective!)
• May be renoprotective!!
(stay tuned…)
* = do not initiate if eGFR <60 ml/min
2016
CKD=chronic kidney disease.eGFR=estimated glomerular filtration rate.canagliflozin Product Monograph, Janssen Canada, 2015; dapagliflozin Product Monograph, AstraZeneca Canada, 2016; empagliflozin product monograph, Boehringer-Ingelheim Canada, 2016.
Decision characteristic Response
After metformin?
A1c 7-10%
With coverage
Pill vs. injection? Pill
Side effectsRisk of UTI/yeast infxn
No hypoglycemia
Weight Loss
DPP-4 INHIBITOR Date of Completion
sitagliptinTECOS Study:Trial Evaluating Cardiovascular Outcomes with Sitagliptin
CompletedNo differences in CV
outcomes
saxagliptinSAVOR-TIMI 53 Study:Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53
CompletedNo differences in CV
outcomes; possible increasein heart failure
linagliptinCARMELINA Study:Cardiovascular and Renal Microvascular OutcomE Study with LINAgliptin in Patients with Type 2 Diabetes Mellitus
January 2018Expected soon
alogliptin
EXAMINE Study:EXamination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome
CompletedNo differences in CV
outcomes
GLP-1 RECEPTOR AGONISTS Date of Completion
Dulaglutide
REWIND Study:The Effect of Dulaglutide on Major Cardiovascular Events in Patients with Type 2 Diabetes: Researching Cardiovascular Events with a Weekly INcretin in Diabetes
April 2019
Exenatide
EXSCEL Study:Exenatide Study of Cardiovascular Event Lowering Trial A Trial To Evaluate Cardiovascular Outcomes After Treatment With ExenatideOnce Weekly In Patients With Type 2 Diabetes Mellitus
CompletedNo differences in CV
outcomes
LiraglutideLEADER Study:Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation
CompletedSuperiority over placebo in
patients with CVD
Lixisenatide*
ELIXA Study:Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide
CompletedNo differences in CV
outcomes
*Lixisenatide is not approved in Canada as of March 2018
SGLT-2 INHIBITORS Date of Completion
EmpagliflozinEMPA-REG OUTCOME Study:Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
CompletedSuperiority over placebo in
patients with CVD
DapagliflozinDECLARE TIMI-58 Study:Dapagliflozin Effect on CardiovascuLAR Events
April 2019
CanagliflozinCANVAS Study:CANagliflozin cardioVascular Assessment Study
CompletedSuperiority over placebo in patients with CVD; possible
increase in amputations, fractures
7,028 DM2 patients with established CVD
A1c 7 – 10%
Randomized to either empagliflozin 10 mg, 25 mg, or placebo
Mean follow-up 3.1 yrs
Originally non-inferiority design hierarchical progression to superiority
Pooled empagliflozin vs. placebo for results
Zinman B et al. N Engl J Med. 2015
Zinman B et al. N Engl J Med. 2015
Months
Pati
ents
wit
hevent
(%)
HR 0.86 95.02% CI (0.74, 0.99)
P < 0.001 for non-inferiorityp=0.04 for superiority
Placebo
Empagliflozin
No. of patients
Empagliflozin 4687 4580 4455 4328 3851 2821 2359 1534 370
Placebo 2333 2256 2194 2112 1875 1380 1161 741 166
PBO EMPA HR P NNT3
CV death, MI, stroke (%) 12.1 10.5 0.86 0.04 63
CV death (%) 5.9 3.7 0.62 <0.001 46
Nonfatal MI (%) 5.2 4.5 0.87 0.22
Nonfatal stroke (%) 2.6 3.2 1.24 0.16
Hosp. heart failure (%) 4.1 2.7 0.65 0.002 72
All-cause mortality (%) 8.3 5.7 0.68 <0.001 39
Based on recent evidence:
◦ Established cardiovascular disease
◦ Not at target A1c
◦ Using an agent with “demonstrated CV benefit”
Effect across all SGLT-2 inhibitors likely exists◦ CANVAS, DECLARE
2016
No. of patients
Canagliflozin 5795 5566 4343 2555 2460 2363 1661
Placebo 4347 4153 2942 1240 1187 1120 789
HR 0.86 95% CI (0.75, 0.97)
P < 0.001 for non-inferiorityp=0.02 for superiority
Outcome (per 1000 pt-y)
PBO CANA HR P or 95% CI NNT3
CV death, MI, stroke 31.5 26.9 0.86 0.02 44
CV deaths 12.8 11.6 0.87 (0.72-1.06)
Nonfatal MI 11.6 9.7 0.85 (0.69-1.05)
Nonfatal stroke 8.4 7.1 0.90 (0.71-1.15)
Hosp. heart failure 8.7 5.5 0.67 (0.52-0.87) 63
All-cause mortality 19.5 17.3 0.87 (0.74-1.01)
Canagliflozin reduced CV eventsPrimary outcome: CV death, non-fatal MI, or non-fatal stroke
Canagliflozin
Placebo
Neal B et al. N Engl J Med 2017
9,340 DM2 patients with established CVD or CKD, or age>60 with high-risk CV factors (MAlb, LVH, low EF)
A1c>7%
Randomized to either liraglutide up to 1.8 mg or placebo
Mean follow-up 3.8 yrs
Originally non-inferiority design hierarchical progression to superiority
Subgroup analysis for results in high-risk pts
Marso SP et al. N Engl J Med 2016;375(4):311-22.
Patients at risk
Liraglutide 4668 4593 4496 4400 4280 4172 4072 3982 1562 424
Placebo 4672 4588 4473 4352 4237 4123 4010 3914 1543 407
Marso SP et al. N Engl J Med 2016;375(4):311-22.
Time from randomization (months)
Pati
ents
wit
hevent
(%)
HR 0.87 95% CI (0.78, 0.97)
P < 0.001 for non-inferiorityp=0.01 for superiority
Placebo
Liraglutide
PBO LIRA HR P NNT4
CV death, MI, stroke (%) 14.9 13.0 0.87 0.01 53
CV death (%) 6.0 4.7 0.78 0.007 77
Nonfatal MI (%) 6.8 6.0 0.88 0.11
Nonfatal stroke (%) 3.8 3.4 0.89 0.30
Hosp. heart failure (%) 5.3 4.7 0.87 0.14
All-cause mortality (%) 9.6 8.2 0.85 0.02 72
Liraglutide reduced CV eventsCV death, non-fatal MI, or non-fatal stroke
Marso SP et al. N Engl J Med 2016;375(4):311-22.
Subgroup analyses
Recommendation 7
7. In adults with type 2 diabetes with clinical CVD in
whom glycemic targets are not achieved with existing
antihyperglycemic medication(s) and with eGFR >30
mL/min/1.73m2, an antihyperglycemic agent with
demonstrated CV outcome benefit should be
added to reduce the risk of:
a) major CV events [Grade A, Level 1A for empagliflozin; Grade
A, Level 1A for liraglutide; Grade C, Level 2 for canagliflozin]
b) heart failure hospitalization [Grade B, Level 2 for
empagliflozin; Grade C, Level 2 for canagliflozin],
c) progression of nephropathy [Grade B, Level 2 for
empagliflozin; Grade C, Level 3 for canagliflozin]
2018
CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate
Recommendation 8
8. In adults with type 2 diabetes without clinical CVD in
whom glycemic targets are not achieved with existing
antihyperglycemic medication(s), incretin agents (DPP-
4 inhibitors or GLP-1 receptor agonists) and/or
SGLT2 inhibitors should be considered as add-on
medication over insulin secretagogues, insulin and
TZDs to improve glycemic control, if lower risk of
hypoglycemia and/or weight gain are priorities
[Grade A, Level 1A]
2018
HOLD the following medications:
Decision characteristic
DPP-4 inhibitor GLP-1 RASGLT-2inhibitor
After metformin?
A1c 7-8% 7-10%* 7-10%*
A1c reduction 0.5-1% 1-1.5% ~1%
With coverage
Pill vs. injection? Pill Injection Pill
Side effects None Nausea/GIRisk of UTI/
yeast infection
Hypoglycemia No No No
Weight Neutral Loss Loss
*esp. if prior clinical CVD
Incretin-based agents
◦ DPP-4 inhibitors
◦ GLP-1 receptor agonists
SGLT-2 inhibitors
Newer insulins◦ glargine-300 (Toujeo®)
◦ degludec (Tresiba®)
◦ Faster-acting aspart (Fiasp®)
3X concentrated
altered PK/PD profile
Less hypoglycemia
Smaller injection depots
Becker RHA et al. Diabetes Care 2015;38:637-643
Polymeric chain
Less hypoglycemia
Longer duration of action
~est. at 40 hours
Very flat profile
1. Owens DR, et al. Diabetes Metab Res Rev. 2014;30:104–19
2. Shah VN, et al. Diabetes Technol & Ther. 2013;15:727–32
3. Heise T , et al. Diabetes Obes Metab 2012;14:944–50
Upon
subcutaneous injection
forms soluble and
stable multihexamers,
that allow slow and
continuous absorption
of monomers into
the circulation1,2
0 4 8 12 16 20 24
0.8 U/kg
0.6 U/kg
0.4 U/kg
5
4
3
2
0
1G
luco
se
In
fusio
n R
ate
in
T1
DM
pa
tie
nts
at
Da
y 6
, m
g/k
g/m
in
Hours
▪ A half-life of ~25 hours, and is detectable
in serum for >120 hours post-injection2
degludec was noninferior to glargine with respect to
cardiovascular events; less hypoglycemia (DEVOTE)
“faster” NovoRapid Faster onset ~6 min
Shorter duration of action
Fiasp product monograph, Novo-Nordisk Canada, 2017;
Heise T et al. Diabetes, Obesity and Metabolism 2015; 17:682–688.
ThrLys
ThrTyr Phe Phe
GlyArg
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Glu
Val
Leu
His
Ser
Gly
CysLeuHisGlnAsnValPhe
Gly
Ile
Val
Glu
GlnCys Thr Ser Ile Cys
Ser
Leu
Tyr
Gln
Leu
Glu
Asn
TyrCysAsn
Cys
B30
B28
A21
A1
B1
Asp
Nicotinamide
O
NH2
N
L-arginine
NH
H2N
NH
NH2
O
OH
• Inject up to 2 minutes before the meal OR
up to 20 minutes after starting the meal
IAsp
Faster aspart
Basal insulin/GLP-1 RA fixed-ratio combination therapies
Insulin glargine 100 U/mL+
Lixisenatide
Insulin degludec+
Liraglutide
IDegLiraiGlarLixi
*iGlarLixi and IDegLira not available in Canada as of April 2018
58 year-old man, tour operator
DM2 x 8 yr, MI age 54
A1c 8.7%
On metformin 1 g bid, gliclazide MR 120 mg daily, ramipril 5 mg daily, rosuvastatin 5 mg daily
Private drug coverage
BMI 34.3, BP 128/78, LDL 1.9
What would you recommend for him?
Early glycemic control in DM2 by prompt intensive intervention reduces the risk of complications
An expanded “tool-kit” presents greater therapeutic choices to achieve glycemic target in patients with type 2 diabetes
Rigorous CV outcomes trials demonstrate the benefit of newer diabetes agents towards reducing cardiovascular events in pts with prior clinical CVD
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