2. 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, Diabetologist, 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

3. Faculty/Presenter Disclosure
Faculty: [Speaker’s name]
Relationships with commercial interests:
Grants / research support:
Speakers Bureau / honoraria:
Consulting fees:
Other:
Please fill in your disclosures on the following slides and take a moment to review them before beginning the presentation.

4. 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®).

5. 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.

6. Objectives Following this program, participants will be able to:
Identify glycemic targets for patients with T2DM
Appropriately select a third antihyperglycemic agent (AHA) for patients with inadequate glycemic control on metformin + sulfonylurea (SU)
Identify strategies to improve adherence in patients on polypharmacy
Recognize and manage side effects associated with the different AHAs

7. Case 1 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
Metformin 1,000 mg BID
SU prescribed as BID
Statin
ACEi
ASA
PPI
Antidepressant
Labs
A1C 7.9%
FPG 8.4 mmol/L
eGFR 75 mL/min/1.73m2
ACR normal
Lipids at target
Speaker’s notes
Review patient’s case history

8. Case 1
What would the target A1C be for this patient?

9. 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 % 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
Speaker’s notes
Intensive glucose control, lowering A1C values to 7%, provides strong benefits for microvascular complications and, if achieved early in the disease, might also provide a significant macrovascular benefit, especially as part of a multifactorial treatment approach.
More intensive glucose control, A1C 6.5%, may be sought in patients with a shorter duration of diabetes, no evidence of significant CVD and longer life expectancy, provided this does not result in a significant increase in hypoglycemia.
An A1C target of 8.5% may be more appropriate in patients with limited life expectancy, higher level of functional dependency, a history of severe hypoglycemia, advanced comorbidities, and a failure to attain established glucose targets despite treatment intensification.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2013;37:S31-34.

10. Case 1
Before adding another antihyperglycemic agent, what other interventions could you consider?

11. 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%.

12. Case 1
Would you add a third antihyperglycemic agent? If so, what would you add?

13. AT DIAGNOSIS OF TYPE 2 DIABETES PATIENT CHARACTERISTICSL I F E S T Y
Start lifestyle intervention (nutrition therapy and physical activity) +/- metformin
A1C < 8.5%
A1C  8.5%
Symptomatic hyperglycemia with metabolic decompensation
If not at glycemic target (2-3 mos)
Start metformin immediately
Consider initial combination with another antihyperglycemic agent
Initiate insulin +/-
metformin
Start / increase metformin
If not at glycemic targets
Add another agent best suited to the individual by prioritizing patient characteristics:
PATIENT CHARACTERISTICS
CHOICE OF AGENT
Priority: Clinical Cardiovascular Disease
Antihyperglycemic agent with demonstrated CV outcome benefit (empagliflozin, liraglutide)
• 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
Speaker’s notes
May start metformin at the time of diagnosis
Change to 8.5% as threshold
Start metformin immediately as an option
Concept of individualizing therapy based on patient and agent characteristics
With that in mind, the next figure shows the characteristics of the agents. . .
See next page
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Pharmacologic Management of Type 2 Diabetes: 2016 Interim Update. Can J Diabetes. 2016;40:

14. Make timely adjustments to attain target A1C within 3-6 months
Add another class of agent best suited to the individual (classes listed in alphabetical order):
Class
Relative A1C Lowering
Hypo-
glycemia
Weight
Effect in Cardiovascular Outcome Trial
Other Therapeutic considerations
Cost
Alpha-glucosidase inhibitor (acarbose) 
Rare
Neutral to 
Improved postprandial control, GI side-effects $$
DPP-4 inhibitors 
Alo, saxa, sita: neutral
Caution with saxagliptin in heart failure
$$$
GLP-1R agonists
 to 
Lira: superiority in T2DM patients with clinical CVD
Lixi: neutral
GI side effects
$$$$
Insulin

Yes 
Glar: neutral
No dose ceiling, flexible regimens
$-$$$$
Insulin secretagogue: Meglitinide
Sulfonylurea 
Less hypoglycemia in context of missed meals but usually requires TID to QID dosing
Gliclazide and glimepiride associated with less hypoglycemia than glyburide $
SGLT2 inhibitors
Empa: superiority in T2DM patients with clinical CVD
Genital infections, UTI,
hypotension, dose-related changes in 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
Neutral
CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect
Weight loss agent (orlistat)
None
alo=alogliptin; empa-empagiflozin; glar-glargine; lixi-lixisenatide; saxa-saxagliptin; sita-sitagliptin L I F E S T Y
Speaker’s notes
Concept of RELATIVE A1C lowering – not absolute
Concept of RELATIVE cost considerations
Change to achieve target within 3 to 6 months
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. Pharmacologic Management of Type 2 Diabetes: 2016 Interim Update. Can J Diabetes. 2016;40:

15. Case 1
Discuss the advantages and disadvantages of the various options for adjusting antihyperglycemic agents in this case.
Speaker’s notes
Given the multiple possibilities of modifying the patient’s diabetes medications, this question specifically allows the facilitator to adapt and drive the discussions based on the group’s interest and current practice patterns as well as take into consideration evolutionary changes in guideline recommendations, availability of newer antihyperglycemic agents and changes in indications.
A slide detailing the pros and cons of some of the potential options for adjusting the patient’s antihyperglycemic management plan is provided in the back-up section.

16. Mean difference in HbA1C (FDC – CDT)
Fixed-dose Combination Therapy is Associated with Improved Glycemic Control
Mean difference of A1C (95% CI)
Study
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%
Speaker’s notes
This was a systematic review and meta-analysis that compared the effects fixed-dosed combinations (FDCs) and coadministered dual therapy (CDT) had on A1C outcome and medication adherence in individuals with type 2 diabetes.
Ten articles met inclusion criteria. Total sample size was 70,573 patients
The forest plot shows the difference in A1C levels between patients with type 2 diabetes who were on FDCs vs. those on CDT.
A1C levels were significantly lower in individuals who were on FDCs.
Mean differences in A1C between the two groups were -0.53% [95% CI: -0.78, -0.28]; (p < 0.0001).
Note: A shortcoming of this analysis was that it included studies with very different patient characteristics, e.g. baseline A1C ranged from the low 7s to the mid 10s.
Not shown here but also reported in the same paper was the revelation that medication adherence (using medication possession ratio as a surrogate) was significantly higher among individuals who were on FDCs vs CDT.
Blonde L (2003) compared glyburide/metformin FDC to glyburide co-administered with metformin
Thayer S (2010) compared switch to rosiglitazone/glimepiride FDC from monotherapy or dual therapy with a TZD and/or a SU
Duckworth (2003) compared switch from sulfonylurea co-administered with metformin to glyburide-metformin FDC
Raptis (1990) compared glibenclamide or glibenclamide-phenformin FDC with those of gliclazide, chlorpropamide or biguanides
Overall
-0.53% (-0.78, -0.28)
100% -4
-3.5 -3
-2.5 -2
-1.5 -1
-0.5
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):

17. Risk of hypoglycemia vs. PBO (OR)
Network Meta-analysis Comparing Antihyperglycemic Drugs as Add-ons to Metformin Plus SU
Change in
A1C vs. PBO
(%)
wt vs. PBO
(kg)
Change in SBP vs. PBO
(mm Hg)
Risk of hypoglycemia vs. PBO (OR)
DPP-4 inhibitors
-0.68* NS
2.99*
GLP-1R agonists
-1.07*
-1.14*
3.26*
SGLT2 inhibitors
-0.86*
-1.71*
-3.73*
3.12*
TZDs
-0.93*
+3.62*
2.64*
Insulin: basal
-1.08*
+2.63*
5.61*
Insulin: premixed
-1.30*
+3.98*
11.62*
Insulin: bolus
-1.54*
+5.69*
38.90*
Speaker’s notes
The results from this network meta-analysis detail the efficacy and hypoglycemia outcomes following the addition of various classes of antihyperglycemic agents to a background of metformin and sulfonylurea. Insulin produced the best improvements in A1C levels but were also associated with the most weight gain and highest risk of hypoglycemia. DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors all effectively reduced A1C levels but with appreciably less risk of hypoglycemia. GLP-1 receptor agonists and SGLT2 receptor inhibitors produced significant weight benefits and blood pressure was significantly lowered by SGLT2 inhibitors.
* 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 plus sulfonylurea. Curr Med Res Opin May;32(5):

18. Change in A1C from baseline (%) * Significant vs. comparator
Placebo-controlled Clinical Trials of SGLT2 inhibitor as an Add-on to Metformin + SU
Canagliflozin (CANA)
Dapagliflozin (DAPA)
Empagliflozin (EMPA)
MET + SU combination
26 weeks
BL A1C ~8.1%
MET + SU combination
24 weeks
BL A1C ~8.2%
MET + SU combination
24 weeks
BL A1C~8.1%
0.4
0.2
PBO
CANA 100 OD
CANA 300 OD
DAPA 10 OD
EMPA 10 OD
EMPA 25 OD
PBO
PBO
0.0
-0.2
-0.13
-0.17
-0.17
-0.4
Change in A1C from baseline (%)
-0.6
-0.8
-0.77*
Speaker’s notes
This slide shows how A1C changed when an SGLT2 inhibitor was added to a background of
metformin+sulfonylurea.
These are not head-to-head comparisons so cross-trial comparisons cannot be made due to
differences in study designs, trial durations and patient populations.
Notes:
Canagliflozin trial: Patients with type 2 diabetes on metformin plus a sulfonylurea were randomized to receive canagliflozin 100 mg (n=157) or 300 mg (n=156) or placebo (n=156) once daily during a 26-week core period and a 26-week extension. The primary endpoint was change in A1C from baseline at 26 weeks. A1C was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (p<0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced body weight vs. placebo at week 26 (p<0.001) and week 52. More subjects treated with canagliflozin had ≥1 hypoglycemic episode compared with those who received placebo, but the number of subjects with severe hypoglycemic events was very low (≤1 per group) (note, no p-values for hypoglycemic episodes were provided).1,2
Dapagliflozin trial: In this trial, patients on metformin and a sulfonylurea were randomized to receive dapagliflozin 10 mg/day (n=109) or placebo (n=109) for 24 weeks. The primary endpoint was A1C change from baseline to week 24. At primary endpoint analysis, A1C significantly improved with dapagliflozin vs. placebo (p<0.0001). Body weight was also significantly reduced with dapagliflozin (p<0.0001). Significantly more patients on dapagliflozin experienced hypoglycemia vs. placebo (p=0.02).3
Empagliflozin trial: Patients inadequately controlled on metformin and a sulfonylurea were randomized and treated with once-daily empagliflozin 10 mg (n=225) or 25 mg (n=216), or placebo (n=225) for 24 weeks. The primary endpoint was A1C change from baseline at week 24. At endpoint analysis, adjusted mean A1C changes were significantly greater with empagliflozin vs. placebo (both p<0.001). Empagliflozin also significantly reduced weight vs. placebo.4
-0.82*
-1.0
-0.85*
-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 Abstract 1022-P. Matthaei S, et al. Diabetes Care 2015;38:365–72. Haring HU, et al. Diabetes Care 2013;36:3396–404. 18

19. Case 1
What side effects could the patient experience with the new therapy/therapies and how would you and the patient co-manage them?

20. ACARBOSE DPP-4 INHIBITORS GASTROINTESTINAL SIDE EFFECTS
Titrate slowly
DPP-4 INHIBITORS
MAJOR ADVERSE CV EVENTS & HEART FAILURE (HF)
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
FDA warning for both saxagliptin and alogliptine with respect to risk of hospitalization for HF
PANCREATIC ISSUES
Meta-analysis of SAVOR, EXAMINE and TECOS suggest a small increased risk of pancreatitis (1/1000-1/2000)
Avoid if the patient has a history of pancreatitis
Speaker’s notes
Heart failure
Although all three DPP-4 inhibitors were non-inferior to placebo with respect to the primary end point, there were some differences in hospitalization for heart failure (HHF). Concerns around HHF were first raised in the SAVOR-TIMI 53 study. However, a subsequent analysis indicated that even in patients at high risk of HHF, the risk of the primary and secondary end points were similar between the two treatment groups. The EXAMINE group conducted a post-hoc analysis with an exploratory extended MACE endpoint and found that alogliptin-treated individuals had numerically higher (but non-significant) HHF rates vs. placebo despite comparable primary endpoint rates. As yet unpublished data from the TECOS group has revealed no statistically significant differences in the placebo and sitagliptin arms after adjustment for baseline heart failure history. Below are the possible reasons for the different HHF signals:
Play of chance
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
Pancreas concerns
In June 2013, the ADA/EASD/IDF released a joint position statement that read “At this time, there is insufficient information to modify current treatment recommendations.”
In July 2013, the European Medicines Agency released a statement that read “. . . the results of the study by Butler et al. are not considered to constitute a new safety signal . . .” and “However, due to the mechanism of action, there are still some uncertainties with respect to long-term pancreatic safety associated with these products.”
It should be emphasized that pancreatitis events were uncommon and pancreatic cancers rare in the three DPP-4 inhibitor cardiovascular safety trials. Furthermore, although there were numerical imbalances in the frequency of pancreatitis and pancreatic cancers for placebo vs. drug, they moved in different directions.
Buse JB, et al. Pancreatic safety of sitagliptin in the TECOS study. Diabetes Care Sep 14. pii: dc [Epub ahead of print]

21. GLP-1R AGONIST METFORMIN 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
No signal of increased risk of pancreatitis in ELIXA and LEADER trials
Non-significant excess of pancreatic cancer vs. placebo in the LEADER trial
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
LEADER reported reduced risk for MACE
METFORMIN
GASTROINTESTINAL SIDE EFFECTS
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
Speaker’s notes
Pancreas concerns
In June 2013, the ADA/EASD/IDF released a joint position statement that read “At this time, there is insufficient information to modify current treatment recommendations.”
In July 2013, the European Medicines Agency released a statement that read “. . . the results of the study by Butler et al. are not considered to constitute a new safety signal . . .” and “However, due to the mechanism of action, there are still some uncertainties with respect to long-term pancreatic safety associated with these products.”
ELIXA reported numerically and percentage-wise lower pancreatitis and pancreatic cancer events with lixisenatide vs. placebo. With regards to pancreatitis: Placebo 8 (0.3%); Lixisenatide 5 (0.2%). With regards to pancreatic cancer: Placebo 9 (0.3%); Lixisenatide (<0.1%).

22. SGLT2 INHIBITORS HYPOTENSION 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

23. SULFONYLUREAS HYPOGLYCEMIA WEIGHT GAIN
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

24. THIAZOLIDINEDIONES (TZD)
MYOCARDIAL INFARCT CONCERNS
Not an issue with pioglitazone
Pioglitazone may reduce stroke and revascularization
Controversial
Not demonstrated by all meta-analyses
Not demonstrated in RCTs
HEART FAILURE
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
FRACTURES
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
WEIGHT GAIN
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

25. NEWER AGENTS + SU/INSULIN SU, INSULIN & DRIVING
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
SU, INSULIN & DRIVING
HYPOGLYCEMIA
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

26. Antihyperglycemic Agents and Renal Function
<15 5
15-29 4
30-59 3
≥90 1
60-89 2
CKD Stage
eGFR
(mL/min/1.73m2) 25
Acarbose 30 60
Metformin 50
6.25 mg
12.5 mg
Alogliptin 15
Linagliptin
2.5 mg
Saxagliptin
25 mg
50 mg
Sitagliptin
Exenatide (BID/QW)
Albiglutide
Dulaglutide
Liraglutide
Gliclazide/glimepiride
Glyburide
Repaglinide 45
60*
Canagliflozin
Dapagliflozin
Empagliflozin
Thiazolidinediones
Contraindicated
Not recommended
Caution and/or dose reduction
No dose adjustment but dose
monitoring of renal function
Safe
Do not initiate if
GFR < 60 mL/min/1.73m2
SGLT2
inhibitors
secretagogues
Insulin
GLP-1 receptor
agonists
DPP-4
Biguanide
ɑ-Glucosidase
inhibitor
100 mg
10 or 25 mg
Adapted from: Product Monographs as of Nov. 2016; Harper W et al. Can J Diabetes 2015;39:

27. 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

28. 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