Download Case 1

Development Committee
CHAIR
• Lawrence A. Leiter, Endocrinology & Metabolism, University of Toronto, Toronto
STEERING COMMITTEE
• Harpreet S. Bajaj, Endocrinology & Metabolism, LMC Diabetes & Endocrinology, Brampton
• C. Keith Bowering, Internal Medicine, University of Alberta, Edmonton
• Alice Y. Y. Cheng, Endocrinology & Metabolism, University of Toronto, Toronto
• Jean-Marie Ekoé, Endocrinology & Metabolism, Université de Montréal, Montreal
• Pierre Filteau, General Practice, Saint-Marc-Des-Carrières
• Stewart B. Harris, Family Medicine, Epidemiology & Biostatistics, Western University, London
• Ronald M. Goldenberg, Endocrinology & Metabolism, LMC Diabetes & Endocrinology, Thornhill
• Vincent C. Woo, Endocrinology & Metabolism, University of Manitoba, Winnipeg
• Jean-François Yale, Endocrinology & Metabolism, McGill University, Montreal
EDUCATIONAL COMMITTEE
• Carl Fournier, Family Physician, Montreal
• Theodore J. Jablonski, Family Physician, Calgary
• Kevin K. Saunders, Family Physician, Winnipeg
• Richard Ward, Family Physician, Calgary
Faculty/Presenter Disclosure
• Faculty: [Speaker’s name]
• Relationships with commercial interests:
–
–
–
–
Grants / research support:
Speakers Bureau / honoraria:
Consulting fees:
Other:
Disclosure of Commercial
Support
• This program has received financial support from Merck
Canada Inc. in the form of an educational grant.
• This program has received in-kind support from Merck Canada
Inc. in the form of logistical support.
• Potential for conflict(s) of interest:
– [Speaker name] has received [payment/funding, etc.] from Merck
Canada Inc.
– Merck Canada Inc. benefits from the sale of the products that will be
discussed in this program: Sitagliptin (Januvia®), Combination
Sitagliptin/Metformin (Janumet®).
Mitigating Potential Bias
• The information presented in this CME program is based
on recent information that is explicitly “evidence-based.”
• This CME Program and its material is peer-reviewed and
all the recommendations involving clinical medicine are
based on evidence that is accepted within the
profession. All scientific research referred to, reported or
used in the CME/CPD activity in support or justification
of patient care recommendations conforms to the
generally accepted standards.
Objectives
Following this program, participants will be able to:
1. Identify glycemic targets for patients with T2DM
2. Appropriately select a third antihyperglycemic
agent (AHA) for patients with inadequate glycemic
control on metformin + sulfonylurea (SU)
3. Identify strategies to improve adherence in patients
on polypharmacy
4. Recognize and manage side effects associated
with the different AHAs
Case 1
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55-year-old male full-time teacher
T2DM duration: 8 years with no known complications
BMI: 32 kg/m2 (gained 4 kg over last year)
BP: 135/85 mmHg
HR: 84 bpm
Sedentary lifestyle
Is unhappy “taking all these pills”
Medications
Labs
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•
•
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•
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•
Metformin 1,000 mg BID
SU prescribed as BID
Statin
ACEi
ASA
PPI
Antidepressant
A1C 7.9%
FPG 8.4 mmol/L
eGFR 75 mL/min/1.73m2
ACR normal
Lipids at target
Case 1
1. What would the target A1C be for this patient?
Individualizing A1C Targets
≤7%
>7%
7%
A target ≤ 6.5% may
be considered in
some patients with
type 2 diabetes to
further lower the risk
of nephropathy and
retinopathy which
must be balanced
against the risk of
hypoglycemia
Consider 7.1-8.5% if:
Most patients
with type 1
and type 2
diabetes
• Limited life expectancy
• High level of functional dependency
• Extensive coronary artery disease at high
risk of ischemic events
• Multiple co-morbidities
• History of recurrent severe hypoglycemia
• Hypoglycemia unawareness
• Longstanding diabetes patient for whom
it is difficult to achieve an A1C ≤ 7%,
despite effective doses of multiple
antihyperglycemic agents, including
intensified basal-bolus insulin therapy
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2013;37:S31-34.
Case 1
2. Before adding another antihyperglycemic
agent, what other interventions could you
consider?
Case 1 (continued)
Upon questioning, the patient reveals that he
works late and sometimes forgets his evening
dose of metformin and SU. A pharmacist, who is
also a diabetes educator, reviews his diet and
provides compliance packaging of his medications.
A kinesiologist working in your team suggests an
“exercise prescription.” He returns in 3 months and
his A1C has improved to 7.4%.
Case 1
3. Would you add a third antihyperglycemic
agent? If so, what would you add?
AT DIAGNOSIS OF TYPE 2 DIABETES
Start lifestyle intervention (nutrition therapy and physical activity) +/- metformin
L
I
F
E
S
T
Y
L
E
If not at glycemic
target (2-3 mos)
Start / increase
metformin
Symptomatic hyperglycemia with
metabolic decompensation
A1C  8.5%
A1C < 8.5%
Initiate
insulin +/metformin
Start metformin immediately
Consider initial combination with
another antihyperglycemic agent
If not at glycemic targets
Add another agent best suited to the individual by prioritizing patient characteristics:
PATIENT CHARACTERISTICS
CHOICE OF AGENT
SGLT2 inhibitor with demonstrated CV outcome benefit
Priority: Clinical Cardiovascular Disease
• Degree of hyperglycemia
• Risk of hypoglycemia
• Overweight or obesity
• Cardiovascular disease or multiple risk factors
• Comorbidities (renal, CHF, hepatic)
• Preferences & access to treatment
• Consider relative A1C lowering
• Rare hypoglycemia
• Weight loss or weight neutral
• Effect on cardiovascular outcome
• See therapeutic considerations, consider eGFR
• See cost column; consider access
See next page
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;40:193-195.
Add another class of agent best suited to the individual (classes listed in alphabetical order):
L
I
F
E
S
T
Y
L
E
Class
Relative A1C HypoLowering
glycemia
Weight
Alpha-glucosidase
inhibitor (acarbose)

Rare
Incretin agents:
DPP-4 Inhibitors
GLP-1R agonists

Rare
 to 
Insulin
Other Therapeutic considerations
Cost
Neutral to 
Improved postprandial control,
GI side-effects
$$
Caution with saxagliptin in
heart failure
GI side effects
$$$
Rare
Neutral to  Neutral
(alo,saxa, sita) Neutral

(lixi)

Yes

No dose ceiling, flexible regimens
$-$$$$
Insulin secretagogue:
Meglitinide

Yes

Sulfonylurea

Yes

SGLT2 inhibitors
 to 
Rare

Superiority
Genital infections, UTI,
$$$
(empa in T2DM patients hypotension, dose-related changes in
with clinical CVD)
LDL-C, caution with renal dysfunction
and loop diuretics, dapagliflozin not to
be used if bladder cancer, rare
diabetic ketoacidosis (may occur with
no hyperglycemia)
Thiazolidinediones

Rare

Neutral
None

Weight loss agent (orlistat) 
Effect in
Cardiovascular
Outcome Trial
Neutral (glar)
$$$$
Less hypoglycemia in context of
$$
missed meals but usually requires
TID to QID dosing
Gliclazide and glimepiride associated $
with less hypoglycemia than glyburide
CHF, edema, fractures, rare bladder
cancer (pioglitazone), cardiovascular
controversy (rosiglitazone), 6-12
weeks required for maximal effect
$$
GI side effects
$$$
alo=alogliptin; empa-empagiflozin; glar-glargine; lixi-lixisenatide; saxa-saxagliptin; sita-sitagliptin
If not at glycemic target
• Add another agent from a different class
• Add/intensify insulin regimen
Make timely adjustments to attain target A1C within 3-6 months
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;40:193-195.
Case 1
4. Discuss the advantages and disadvantages
of the various options for adjusting
antihyperglycemic agents in this case.
Fixed-dose Combination Therapy is Associated
with Improved Glycemic Control
Study
Mean difference
of A1C (95% CI)
Weight (%)
Baseline A1C
Blonde L et al, 2003
-0.53% (-0.80, -0.26)
28.0%
9.1–9.2%
Thayer S et al, 2010
-0.31% (-0.66, -0.04)
22.7%
8.0–8.1%
Thayer S et al, 2010
-0.45% (-0.77, -0.13)
24.7%
7.3–7.8%
Duckworth W et al, 2003
-0.60% (-0.97, -0.23)
21.4%
8.3%
Raptis AE et al, 1990
-2.30% (-3.65, -1.00)
3.2%
10.6%
Overall
-0.53% (-0.78, -0.28)
100%
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
Mean difference in HbA1C (FDC – CDT)
Favours FDC
CDT = coadministered dual therapy; FDC = fixed-dosed combination
Adapted from Han S et al. Curr Med Res Opin. 2012;28(6):969-77.
0
0.5
Network Meta-analysis Comparing
Antihyperglycemic Drugs as
Add-ons to Metformin Plus SU
Change in
A1C vs. PBO
(%)
Change in
wt vs. PBO
(kg)
Change in
SBP vs. PBO
(mm Hg)
Risk of
hypoglycemia vs.
PBO (OR)
DPP-4 inhibitors
-0.68*
NS
NS
2.99*
GLP-1R agonists
-1.07*
-1.14*
NS
3.26*
SGLT2 inhibitors
-0.86*
-1.71*
-3.73*
3.12*
TZDs
-0.93*
+3.62*
NS
2.64*
Insulin: basal
-1.08*
+2.63*
NS
5.61*
Insulin: premixed
-1.30*
+3.98*
NS
11.62*
Insulin: bolus
-1.54*
+5.69*
NS
38.90*
* Significant vs. PBO; NS= not significant vs placebo
Lozano-Ortega G, et al. Network Meta-analysis of Treatments for Type 2 Diabetes Mellitus following Failure with Metformin +
Sulfonylurea. Abstract 1266-P. Presented at the 75th Scientific Sessions of the American Diabetes Association, June 5 - 9, 2015, Boston,
Massachusetts.
Placebo-controlled Clinical Trials of
SGLT2 inhibitor as an Add-on to Metformin + SU
Canagliflozin (CANA)
Change in A1C from baseline (%)
MET + SU combination
26 weeks
BL A1C ~8.1%
Dapagliflozin (DAPA)
MET + SU combination
24 weeks
BL A1C ~8.2%
Empagliflozin (EMPA)
MET + SU combination
24 weeks
BL A1C~8.1%
0.4
0.2
0.0
CANA CANA
100 OD 300 OD PBO
-0.2
DAPA
10 OD
-0.13
PBO
EMPA
10 OD
EMPA
25 OD
-0.17
PBO
-0.17
-0.4
-0.6
-0.8
-1.0
-0.77*
-0.85*
-0.82*
-0.86*
-1.06*
-1.2
* Significant vs. comparator
-1.4
Δ wt (kg):
Hypos (%):
-2.1*
25.8
-2.6*
30.1
-0.7
15.4
-2.7*
12.8*
-0.6
3.7
-2.2*
16.1
-2.4*
11.5
-0.4
8.4
SGLT2: sodium-glucose cotransporter 2; MET: metformin; SU: sulfonylurea; BL: baseline; A1C: glycated hemoglobin;
PBO: placebo
Wilding J, et al. Int J Clin Pract 2013;67:1267–82. Wilding J, et al. ADA 2012. Abstract 1022-P. Matthaei S, et al. Diabetes Care 2015;38:365–72.
Haring HU, et al. Diabetes Care 2013;36:3396–404.
Case 1
5. What side effects could the patient experience
with the new therapy/therapies and how would
you and the patient co-manage them?
ACARBOSE
DPP-4 INHIBITORS
GASTROINTESTINAL SIDE EFFECTS
MAJOR ADVERSE CV EVENTS & HEART FAILURE (HF)
• Titrate slowly
• Reassure
- Alogliptin (EXAMINE), Saxagliptin (SAVOR) and Sitagliptin
(TECOS) neutral on major adverse CV events
- Alogliptin and sitagliptin neutral on HF
- Saxagliptin increased HF (SAVOR), so use with caution in
patients with HF
PANCREATIC ISSUES
•
Reassure
- EMA release and ADA/EASD/IDF position statement: Cases of
pancreatitis were uncommon and pancreatic cancers rare in the
SAVOR, EXAMINE and TECOS populations
- Avoid if the patient has a history of pancreatitis
GLP-1R AGONIST
METFORMIN
GASTROINTESTINAL SIDE EFFECTS
GASTROINTESTINAL SIDE EFFECTS
•
•
•
•
•
•
Reduce metformin
Slowly titrate the dose
Decrease meal portions and reduce fat content
Provide hand-holding reassurance – inform patients
that GI issues are transient
ENDOCRINE ISSUES
•
•
Thyroid medullary cancer occurred in rodents
- Not observed in monkeys and humans
- No other related thyroid issues
Avoid if patient has a personal or family history of
MTC or if patient has MEN2
PANCREATIC ISSUES
•
•
Reassure and discuss
- EMA release and ADA/EASD/IDF position
statement
- ELIXA reported numerically and percentagewise lower pancreatitis and pancreatic cancer
events in test group vs. placebo
Avoid if the patient has a history of pancreatitis
MAJOR CV EVENTS & HEART FAILURE (HF)
•
ELIXA reported neutral results for rates of MACE and
HHF
•
•
•
Take in the middle of the meal
Try different brand/formulation of metformin or switch
to a DPP-4 fixed-dose combination
Slowly down-titrate and continue to use if the patient is
able to tolerate a lower dose
Limit dose to 1,500 or 2,000 mg a day
Add a second agent before up-titrating to the maximum
dose
SGLT2 INHIBITORS
GENITAL MYCOTIC INFECTIONS (GMI)
• Reassure
- GMIs are infrequent, more common in women,
usually mild to moderate and easily treated,
plus, most with GMI have only 1 event
• Consider proactive prescription (cream or fluconazole)
• Encourage local hygiene
• Avoid if resistant GMIs recur
LIPID PROFILE
• Small increase in LDL-C of about 0.1 to 0.2 mmol/L on
average – dose-dependent
• Reassure that HDL-C also goes up
• Empagliflozin superior for MACE and CV mortality in
patients with established CVD in EMPA-REG OUTCOME
• Ongoing long-term trials will provide more information
POLYURIA/POLLAKIURIA
• Occurs in 3-6% of patients
• Provide reassurance as polyuria/pollakiuria may be
temporary
• Consider reducing diuretic dose or stopping entirely, as it
may not be necessary
• Avoid alcohol and coffee
DIABETIC KETOACIDOSIS (DKA)
• Rare (≤0.1%), usually associated with major illness,
dietary restriction (low carbohydrate or reduced intake),
inappropriate insulin reduction.
• May be euglycemic
• Most cases are in insulin-treated patients, some of whom
have had unrecognized T1D or LADA
HYPOTENSION
• Consider reducing the dose of the antihypertensive
agent(s) (start with the diuretic if taking) if blood
pressure is low-normal or volume-depleted
• Down-titrate, as the occurrence of hypotension may
be dose-dependent
• If patient has concomitant diseases, stop temporarily
(SADMANS)
MALIGNANCIES
• 10:1 imbalance in bladder cancer in dapagliflozin trials
• Not observed with other SGLT2 inhibitors
• Most of the cases of bladder cancer occurred in
patients who had hematuria at baseline
• Dapagliflozin should not be used in patients with a
history of bladder cancer
URINARY TRACT INFECTIONS (UTI)
• Reassure
- 20-30% higher rates than placebo in pooled
analyses
- More common in women, mild to moderate
- Most with UTI have 1 event
FRACTURES
• Rare fractures with canagliflozin
• Higher rates of fractures: may be in part related to
more falls related to hypotension
• Reduction in bone mineral density: may be in part
related to weight loss. Increased phosphate levels and
PTH levels may also contribute
• No increase in EMPA-REG OUTCOME trial
SULFONYLUREAS
HYPOGLYCEMIA
• If possible, switch to an incretin agent or a SGLT2
inhibitor
• Provide/refer for education on nutrition, physical
activity, alcohol
• If staying on sulfonylureas
- Decrease dose
- Use gliclazide or glimepiride in the morning
(discuss timing) rather than glyburide
- Use repaglinide if skipping meals
• Verify eGFR
• Reduce dose or discontinue if patient becomes ill
WEIGHT GAIN
• Lifestyle changes
• If possible, switch to
- Acarbose
- DPP-4 inhibitor
- GLP-1R agonist
- SGLT2 inhibitor
• To avoid hypoglycemia
- Use gliclazide rather than glyburide
- Use repaglinide if skipping meals
THIAZOLIDINEDIONES (TZD)
MYOCARDIAL INFARCT CONCERNS
FRACTURES
• Not an issue with pioglitazone
• Pioglitazone may reduce stroke and revascularization
• Controversial
- Not demonstrated by all meta-analyses
- Not demonstrated in RCTs
• Evidence that TZDs double the risk of fractures
after 3 years of usage (MOA is integral to this
class effect)
• Switch to a different class of AHA
• Note that BMD is not a predictor for fractures
HEART FAILURE
WEIGHT GAIN
• Use of rosiglitazone and pioglitazone has been
associated with a >2-fold increased risk of heart failure
EDEMA
• Switch to another class of AHA
• Avoid if patient has a history of CHF
• As edema is more evident with insulin, avoid combining
TZDs with insulin
• Initiate potassium-sparing diuretics
MALIGNANCIES (BLADDER CANCER)
• Rare
• Although a signal has been suggested by some
observational studies, an ADA position statement states
there is no causal relationship
• FDA has indicated that TZDs are safe except in those
with a (family) history of bladder cancer
• NOT an issue with rosiglitazone
• Encourage healthy lifestyle changes
• Reduce dose
• As weight gain is more evident with insulin,
avoid combining TZDs with insulin
• If possible, switch to acarbose, a DPP-4
inhibitor, a GLP-1R agonist, or a SGLT2
inhibitor
NEWER AGENTS + SU/INSULIN
SU, INSULIN & DRIVING
HYPOGLYCEMIA
HYPOGLYCEMIA
• Consider reducing SU/insulin dose when adding
DPP-4 inhibitor, GLP-1R agonist or SGLT2 inhibitor
if the A1C is not very high
• Recognize and educate on the variability in glucose
levels
• Consider switching to another class
• The patient should be advised to:
- Test glucose levels before driving and every 4
hours if s/he is on a long trip
- Keep a meter and source of carbohydrate handy
- NOT drive if blood glucose is under 5.0 mmol/L
- Pull over if experiencing symptoms of hypoglycemia
- NOT drive for an hour even after an occurrence of
mild hypoglycemia
Antihyperglycemic Agents and Renal Function
CKD Stage
eGFR
(mL/min/1.73m2)
Acarbose
Biguanide
Metformin
4
3
2
1
<15
15-29
30-59
60-89
≥90
25
Alogliptin
6.25 mg
30
30
Linagliptin
Saxagliptin
15
15
2.5 mg
Sitagliptin
25 mg
30
60
12.5 mg
50 mg
Albiglutide
Dulaglutide
Exenatide (BID/QW)
Liraglutide†
Gliclazide/glimepiride
15
Glyburide
30
30
30
30
50
50
50
50
50
50
50
50
Repaglinide
SGLT2
inhibitors
Insulin
secretagogues GLP-1 receptor
agonists
DPP-4
inhibitors
ɑ-Glucosidase
inhibitor
5
45
60*
60
4510 or 25 mg 60*
Canagliflozin
Dapagliflozin
Empagliflozin
30
Thiazolidinediones
• Do not initiate if
GFR < 60 mL/min/1.73m2
100 mg
Contraindicated
Not recommended
Caution and/or dose reduction
†Based on SaxendaTM Product Monograph November 2015
Adapted from: Product Monographs as of Nov. 2015; Harper W et al. Can J Diabetes 2015;39:250-252.
No dose adjustment but dose
monitoring of renal function
Safe
FEAR ABOUT INTENSIVE GLUCOSE CONTROL AND MORTALITY
• Intensive control has been proven to reduce microvascular complications, particularly
nephropathy
• Guidelines suggest intensive therapy to achieve
- A1C ≤ 6.5% when there is no risk of hypoglycemia to reduce microvascular
complications
- ≤ 7.0% in most patients
- 7.1% to 8.5% in people with short life expectancy, extensive CAD at high risk of
ischemic events or recurrent severe hypoglycemia
• One study (ACCORD) showed an increase in CV and total mortality in patients
randomized to intensive glycemic control, but this risk was confined to those not
achieving A1C ≤ 7% and was not demonstrated in a meta-analysis
- Reduced myocardial infarctions – also demonstrated in a meta-analysis
• Although there is a link between severe hypoglycemia and mortality, a causal
relationship has not been proven
KEY MESSAGES
•Medication side effects can affect adherence, quality of life and, ultimately, glycemic
control
• Ask about side effects and make therapeutic choices to maximize tolerability
Conclusions
• In most patients, strive for an A1C target of
≤7.0%
• For patients who are not at target, first consider
adherence and lifestyle modification prior to
altering medical therapy
• The choice of a “third agent” should be
individualized to the patient’s characteristics,
co-morbidities and values