DR Stafford DM Grand Rounds

1. Even more about
diabetes…
Dollars and sensible
therapeutics
Sara Stafford MDCM, FRCPC
26 February 2014
Abbotsford Regional Hospital

2. Outline
 Case
 Guidelines
 Hypoglycemia
 Driving and Diabetes
 Metformin & Combination Tablets: Side Effects &
Compliance
 CV Risk with Oral Agents
 Cost analysis & Pharmacare coverage
 CDA Toolkit

3. Case
 John is 47yo man with type 2 diabetes, diagnosed 5 years
ago. He is a truck driver, and has private insurance through
his work. He has hypertension and dyslipidemia, but no
microvascular or macrovascular complications. His work
schedule is irregular. He sometimes forgets to take his
medication, and find that his metformin bothers his stomach
a bit if he misses dinner on the road.
 Medications: Metformin 1g bid, perindopril 4mg, atorvastatin
20mg
 On examination: BMI 32.1 kg/m2, BP 127/76
 Labs: A1c 7.9%, eGFR 72, urine ACR negative

4. 2013
Individualizing A1C Targets
Consider 7.1-8.5% if:
which must be
balanced against
the risk of
hypoglycemia

5. AT DIAGNOSIS OF TYPE 2 DIABETES
Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin
L
I
F
E
S
T
Y
L
E
A1C <8.5%
If not at glycemic
target (2-3 mos)
Start / Increase
metformin
A1C 8.5%
Symptomatic hyperglycemia with
metabolic decompensation
Start metformin immediately
Consider initial combination with
another antihyperglycemic agent
Initiate
insulin +/metformin
If not at glycemic targets
Add an agent best suited to the individual:
Patient Characteristics
Degree of hyperglycemia
Risk of hypoglycemia
Overweight or obesity
Comorbidities (renal, cardiac, hepatic)
Preferences & access to treatment
Other
Agent Characteristics
BG lowering efficacy and durability
Risk of inducing hypoglycemia
Effect on weight
Contraindications & side-effects
Cost and coverage
Other
2013
See next page…

6. From prior page…
L
I
F
E
S
T
Y
L
E
If not at glycemic target
• Add another agent from a different class
• Add/Intensify insulin regimen
2013
Make timely adjustments to attain target A1C within 3-6 months

7. Hypoglycemia

8. RISK FACTORS FOR
HYPOGLYCEMIA
 Risk factors for hypoglycemia1,2,3,4










Older age
Renal Impairment
Long duration of diabetes treatment
Prior episode of severe hypoglycemia
Hypoglycemia unawareness, especially during sleep
Delayed, smaller, or missed meal
Alcohol
Recent moderate, or intensive exercise
Glucose lowering medications: Secretagogues & Insulin
Glycemic control – Inverse? Correlated?
1. CDA. Can J Diabetes 2008; 32:S29–S31. 2. Workgroup on Hypoglycemia, American Diabetes Association. Diabetes Care. 2005;28(5):1245-1249; 3. Frier BM.
Diabetes Metab Res Rev. 2008;24(2):87-92; 4. Cryer PE. Diabetes. 2008;57(12):3169-3176.

9. Hypoglycemia in the
Community
 Based upon US public health surveillance data,
adverse drug events account for 1 in 67 emergency
admissions
 100 000 emergency hospitalizations for ADE in adults
65+ each year
 48.1% of these admissions in adults 80+
 65.7% unintentional overdoses
Budnitz et al. 2011. Emergency Hospitalizations for Adverse Drug Events in Older
Americans. NEJM. 365(21): 2002-2012

10. Adverse Drug Events
 Four medications classes accounted for 67.0% of
hospitalizations:
 Warfarin 33.3%
 Insulin 13.9%
 Oral antiplatelet agents 13.3%
 Oral hypoglycemic agents 10.7%
Of hospitalizations related to diabetes medications, 94.6%
were for hypoglycemia and 66.6% of these were for severe
hypoglycemia (LOC, seizure, altered mental status)
Budnitz et al. 2011. Emergency Hospitalizations for Adverse Drug Events in Older
Americans. NEJM. 365(21): 2002-2012

11. RELATIONSHIP BETWEEN SEVERE
HYPOGLYCEMIA AND HbA1c
Severe hypoglycemia correlated to poor control in intensively
treated patients
6
Incidence per 100 person-years
5
4
3
2
1
0
6.0
7.0
Updated average HbA1c
8.0
9.0

12. HYPOGLYCEMIA UNAWARENESS IS ASSOCIATED
WITH A HIGHER RATE OF SEVERE
HYPOGLYCEMIA
9-fold higher rate of severe
hypoglycemia
2.5
Severe hypoglycemia*
(episodes/patient/year)
2.15
2.0
1.5
1.0
0.5
0.22
0
Normal
awareness
Impaired
awareness
(n=144)
(n=13)
Severe hypoglycemia was defined as an episode requiring external assistance for recovery. Subjective changes in hypoglycemia symptom intensity were
recorded by the participants based on a hypoglycemia awareness scale of 1 to 7, where 1 equals always aware and 7 equals never aware and a score of 4 or
more correlates with impaired awareness.
* Based on data from a retrospective survey of 215 patients with T2DM treated with ≥2 injections of insulin daily for ≥1 year.
Henderson et al. Diabetes Med. 2003;20(12):1016-21.
12

13. SEVERE HYPOGLYCEMIA INCREASES THE
RISK FOR ADVERSE OUTCOMES
Hazard ratios represent the risk of an adverse cardiovascular outcome or death
among patients reporting severe hypoglycemia (<2.8 mmol/L)* as compared with
those not reporting severe hypoglycemia
Clinical Outcome and
Interval After Hypoglycemia
Hazard Ratio
(95% CI)†
Microvascular events
Macrovascular events
3.45 (2.34-5.08)‡
Death from any cause
3.30 (2.31-4.72)‡
Death from non-CV cause
2.86 (1.67-4.90)‡
Death from CV cause
*Severe
2.07 (1.32-3.26)‡
3.78 (2.34-6.11)‡
hypoglycemia is defined as blood glucose <2.8 mmol per litre with transient dysfunction of the CNS, without other apparent cause, during which the patient
was unable to administer treatment (requiring help from another person).
†Adjusted for multiple covariates: sex, duration of diabetes, treatment assignment, presence or absence of a history of macrovascular disease, presence or absence of
a history of microvascular disease, and smoking status at baseline. Time-dependent covariates during follow-up included age; level of glycated hemoglobin; body
mass index; creatinine level; ratio of urinary albumin to creatinine; systolic blood pressure; use or nonuse of sulfonylurea, metformin, thiazolidinedione, insulin, or any
other diabetes drug; and use or nonuse of antihypertensive agents.
‡p<0.001.
CI=confidence interval.
Zoungas S. N Engl J Med. 2010;363(15):1410-18.

14. Hypoglycemia &
Sulphonylureas

15. Hypoglycemia in Patients with
Antihyperglycemic Therapy
Add-on to
metformin
Monotherapy
OR (95% CI)
Metformin
Sulfonylureas
Glucosidase inhibitors
Glinides
Thiazolidinediones
DPP-4 inhibitors
AHA monotherapy
AHA dual combination therapy
0.64 (0.50–0.82)
2.16 (1.75–2.67)
0.41 (0.17–1.02)
1.29 (0.82–2.02)
0.87 (0.56–1.36)
0.60 (0.34–1.07)
0.72 (0.58–0.89)
1.39 (1.13–1.72)
Sulfonylureas
Glucosidase inhibitors
Glinides
Thiazolidinediones
DPP-4 inhibitors
2.08 (1.44–2.99)
0.22 (0.03–1.60)
0.87 (0.46–1.63)
0.50 (0.28–0.89)
0.34 (0.16–0.72)
0.01
0.1
Less frequent
1.0
10.0
More frequent
AHA = antihyperglycemic agent; CI = confidence interval; DPP-4 = dipeptidyl peptidase 4; OR = odds ratio
Adapted from: Tschöpe D et al. Cardiovasc Diabetol 2011; 10:66.
15

16. Meta-analysis of Hypoglycemia:
Glyburide vs. Other
Secretagogues
RR, 95% CI
Baba 1983
Dills 1996
Draeger 1996
Haider 1976
Hamblin 1970
Harrower 1994
Landgraf 1999
Mafauzy 2002
Marbury 1999
Rosenstock 1993
UKPDS 13 1995
Wolffenbuttel 1999
Gliclazide
Glimipiride
Glimipiride
Chlorpropamide
Chlorpropamide
Gliclazide
Repaglinide
Repaglinide
Repaglinide
Glipizide
Chlorpropamide
Repaglinide
2.23
1.42
1.24
5.26
3.29
3.58
0.93
1.23
1.25
2.96
2.39
1.03
0.1 0.2 0.5 1 2
Secretogogue
more
CI = confidence interval; RR = relative risk
Adapted from: Gangji AS et al. Diabetes Care 2007; 30(2):389-94.
1.08–4.59
0.94–2.13
0.90–1.71
0.26–07.81
0.72–15.05
0.77–16.76
0.39–2.24
0.66–2.31
0.86–1.81
0.32–27.74
1.78–3.20
0.55–1.94
1.52
Total (95% CI)
Test for heterogeneity I2 = 42.1%
RR (95% CI)
1.21–1.92
5 10
Glyburide
more
16

17. Proportion of patients experiencing
minor hypoglycemia at study end
Saxagliptin 5 mg QD + MET
Sitagliptin 100 mg QD + MET
35%
Proportion of Patients (%)
Linagliptin 5 mg QD + MET
29.0%
30%
25%
Exenatide 5 μg BID + MET
Exenatide 10 μg BID + MET
Liraglutide 1.2 mg QD + MET
Liraglutide 1.8 mg QD + MET
Sulphonylurea + MET
Placebo + MET
16.9%
R
20%
15%
10%
8.9%
10.1%
5%
3.3%
4.5% 5.3% 5.3%
2.8%
0.6%
0.8%
2.5% 2.5%
0%
SAXA
PBO
n=191 n=179
SITA
SU
n=979 n=748
EXE 5 μg EXE 10 μg PBO
n=110
n=113 n=113
LINA
PBO
n=523 n=177
LIRA
1.2 mg
n=240
LIRA
PBO
SU
1.8 mg n=121 n=242
n=242
SU=sulphonylurea; MET=Metformin. Saxagliptin Canadian Product Monograph, Bristol Myers Squibb/Astra Zeneca, 2013; Sitagliptin Canadian Product Monograph, Merck
Frosst, 2013.; Liraglutide Canadian Product Monograph, Novo Nordisk Canada, 2013; Exenatide Canadian Product Monograph, Bristol Myers Squibb, 2013. Linagliptin
Canadian Product Monograph. Boehringher Ingelheim (Canada) Ltd. 2012. Pratley R et al. Lancet 2010;375:1447-56.

18. Proportion of patients achieving HbA1c
goal of <7% after 52 weeks
Sitagliptin 100 mg QD
Glipizide
% of patients to HbA1c goal
70.0
60.0
62.8%
50.0
58.9%
40.0
30.0
20.0
HbA1c <7% at 52 weeks
Nauck MA, et al. Diabetes Obes Metab. 2007;9:194–205.

19. Add on to metformin: Sitagliptin Was
Noninferior to Sulphonylureas in Reducing
HbA1c
Per-Protocol Population
LS mean change from baseline at 30 weeks
(for both groups): –0.5%
Difference in LS Mean HbA1c= -0.03
(95% CI: –0.13, 0.07)
7.8
Glipizide (up to 20 mg/d; mean 9.5 mg/d)+metformin (n=256)
Sitagliptin (100 mg/day)+metformin (n=248)
8.0
7.4
7.6
HbA1c (%)
7.0
HbA1c (%)
7.2
6.6
6.8
6.2
5.8
6.4
0
12
24
38
52 60
Weeks
78
CI=confidence interval; LS=least-squares; SD=standard deviation.
SE=standard error.
1. Seck T, et al; Sitagliptin Study 024 Group. Int J Clin Pract. 2010;64(5):562-576.
2. Arechavaleta R, et al. Diabetes Obes Metab. 2011;13(2):160-168.
91
104
6.0
Glimepiride (up to 6 mg/d; mean 2.1 mg/d)+metformin (n=436)
Sitagliptin (100 mg/d)+metformin (n=443)
0
6
12
18
Weeks
24
30

20. Despite Similar Glycemic Efficacy to
Sulphonylureas, Sitagliptin are Associated with
a Lower Risk of Hypoglycaemia
50
Hypoglycemia over 104 weeks
Between-groups difference = –28.8%
50
40
40
30
30
20
20
Hypoglycemia Over 30 Weeks
Between groups difference =
–15.0%
P<0.001
P<0.001
10
10
0
0
Sitagliptin (100 mg/d)+metformin
Glipizide (mean 9.5 mg/d)+metformin
APaT=all-patients-as-treated; CI=confidence interval; LS=least-squares.
1. Seck T, et al; Sitagliptin Study 024 Group. Int J Clin Pract. 2010;64(5):562-576.
2. Arechavaleta R, et al. Diabetes Obes Metab. 2011;13(2):160-168.
Sitagliptin (100 mg/d)+metformin
Glimepiride (mean 2.1mg/d)+metformin

21. A1C reductions with
antihyperglycemic agents
Network meta-analysis comparing antihyperglycemic drugs as
add-on to metformin
Mean difference from placebo
AGIs
DPP-4i
Meglitinides
SUs
TZDs
Basal
insulin
GLP-1 RA
Premixed
insulin
21
*All statistically significant vs. placebo. TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820.

22. Overall risk of hypoglycemia
Network meta-analysis comparing antihyperglycemic
drugs as add-on to metformin
Odds ratio vs. placebo
Premixed Meglitinides SUs
insulin
Basal
insulin
DPP-4i
Placebo GLP-1 RA
(Ref)
TZDs
AGIs
22
*Statistically significant vs. placebo. TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820.

23. Hypoglycemia & Driving in
BC: OSMV Regulations
 Drivers who have a medical condition that has the
potential to affect their fitness to drive may be required
to have their doctor complete a Driver’s Medical
Examination Report (DMER)
 The type and frequency of assessment varies by the
class of licence, as well as the type and control of
diabetes

24. Class 5-8 Licences

25. Type 2 Not Treated with
Insulin or Secretagogues
 DMER required
 Report to OSMV if beginning insulin
 Remain under medical supervision to monitor for
progression or complications
 Reassess q5y, or if starting insulin or secretagogues

26. Type 2 Treated with
Secretagogues
 DMER Required
 Fit to drive if:
 Good understanding of diabetes
 Follow medical care & supervision
 Report if: begin insulin, episode of severe hypoglycemia
 Stop driving if hypoglycemia suspected
 Not drive for at least 45min after treating BG 2.5-4.0mM
 Reassess q5y unless unstable or insulin initiated

27. Diabetes treated with insulin
(Type 1 or 2)
 DMER Required
 Fit to drive if:
 Understand diabetes, follow medical care and supervision
 Report if episode of severe hypoglycemia or hypoglycemia
unawareness
 On long drives:





check BG before driving and q4h
Carry carbohydrates
not drive if BG <4.0
prophylactically treat if BG 4.0-5.0
not drive for 45 min after treating BG 2.5-4.0
 Reassess q5y if stable

28. Drivers with an episode of
severe hypoglycemia
 DMER required
 Report to OSMV if episode of severe hypoglycemia
 For next 6m, test BG immediately before driving and
q1h
 For next 6m, not drive if BG <6.0mM
 Once no episodes of severe hypoglycemia for 6
months, regular guidelines

29. Class 1-4 Licences

30. Type 2 Diabetes – Not Treated
with insulin or secretagogues
 DMER required
 Report if beginning insulin
 Remain under medical supervision to monitor for
progression or complications
 Reassess q5y, or if insulin or secretagogue therapy
initiated

31. Type 2 treated with
secretagogues
 DMER required
 Fit to drive if good understanding of diabetes, and following
instructions, remain under medical supervision
 Report if beginning insulin, experience severe hypoglycemia
 Stop driving if hypoglycemia suspected
 Do not drive for at least 45 min after treating BG 2.5-4.0mM
 Reassess q1y or if initiating insulin

32. Diabetes treated with insulin
(type 1 or 2)
 Diabetic Package: DMER (MD), Diabetic Driver Report
(MD), Driver’s Diabetes Questionnaire (patient), Exam of Visual
Function (optho or opto)
 Log of BG performed at least twice daily
 Fit to drive if:
 Certificate of competence from DEC
 MD has approved work schedule as compatible with your insulin
regimen
 No uncontrolled diabetes (A1c >12% or >10% of BG < 4.0mM)
 No significant changes to insulin therapy
 No indication of lack of compliance
 Must carry supplies (monitor, CHO) when driving
 Test BG <1h before driving and q4h while driving, not drive if BG
falls below 6.0mM

33. Drivers who have had severe
hypoglycemia
 DMER Required
 Fit to drive if:
 Log of BG at least 4/d, less than 5% below 4.0mM
 Re-established stable glycemic control
 Report to OSMV if episode of severe hypoglycemia
 For the next 6m, test BG immediately before driving and q1h
while driving
 Not drive or stop if BG <6.0mM
 Reassess q1y

34. Side Effects & Compliance

35. Metformin
 Metformin remains first-line therapy for type 2 diabetes
 Standard dosing is 1g po bid
 Higher doses (e.g. 1g/500mg/1g) do not improve
glycemic control but are associated with more
gastrointestinal side effects and reduced compliance
(tid dosing)

36. Metformin Dose-Response
Decrease in FPG from
Placebo [mg/dl]
100
3
2.5
80
2
60
1.5
40
1
20
0.5
0
0
500
1000
1500
2000
2500
Dose [mg/d]
Garber et al. Am J Med 1997; 102:491

37. Metformin Dose-Response Curve
Reduction in A1C (%)
2,0
1,5
1,0
30
20
0,5
10
0
0
500
1000
1500
2000
2500
Dose
Riddle M. Am J Med. 2000;108(6A):15S-22S

38. Starting metformin
 Start with metformin 250mg once daily with largest
meal
 Ask patient to slowly increase dosing in 250mg
increments
 250mg bid
 500mg AC-B, 250mg AC-S
 500mg bid
…
 Target 1g bid

39. Metformin XR
 Standard, immediate release metformin is limited by:
 Bid or tid dosing leading to poor compliance
 Particularly problematic for patients on multiple different
medications
 GI symptoms affecting up to 25% of patients, leading to
cessation of drug in 5-10% of patients
Adapted from Levy J et al. Diabetol Metab Syndr 2010, 2:16
1- Garber AJ et al. Am J Med 1997; 103: 491.

40. Metformin XR – Equivalent Efficacy to
Standard Metformin
10
Metformin XR 1500 mg QD
Metformin XR 2000 mg QD
Metformin IR 1500 mg (AM/PM) †
HbA1c (%)
9
8
*
*
7
*
11.
1
Fasting Plasma Glucose
(mmol/L)
Metformin XR 1500 mg (AM/PM) †
12.
2
*
10
*
*
8.9
*
*
*
*
*
20
24
7.8
6
6.7
5
5.6
0
4
8
12
Treatment
Week
16
20
24
0
4
8
12
16
Treatment
Week
Randomized, double blind, active-controlled study.
*Significant change from baseline within each treatment group (P < 0.001), intent-to-treat population.
N = 706 T2DM, A1c ~8.4%, Age ~54years, ~54% Male, BMI~33, ~48% Drug Naïve, Diabetes Duration ~4.2 years
† 500 mg in the morning and 1,000 mg in the evening
Adapted from Schwartz S et al. Diabetes Care. 2006 Apr;29(4):759-64.

41. Metformin XR – Improved Tolerability
25
Incidence (%) during
dosing at 1000 mg o.d.
1500mg qd
20
15
1500mg bid
20.7
19.3
18.9
ExtendedRelease
Metformin
2000mg qd
IR 1500mg bid
15.5
10
*
10.5
8.3
8.9
8.2
6.9
5
2.9
3.9
2.4
0
Any gastrointestinal event
Diarrhea
Nausea
*p<0.050
Randomized, double blind, active-controlled study.
N = 706 T2DM, A1c ~8.4%, Age ~54years, ~54% Male, BMI~33, ~48% Drug Naïve, Diabetes Duration ~4.2
years, † 500 mg in the morning and 1,000 mg in the evening
Adapted from Schwartz S et al. Diabetes Care. 2006 Apr;29(4):759-64.

42. Metformin XR – Improved Tolerability in
Patients Switched from Standard Metformin
60
*
Metformin-IR
Metformin-XR
Incidence
(%)
50
Total of 77% of patients were free of
gastrointestinal side effects and 83% of
patients stated a preference for
metformin XR
40
30
*vs metformin IR p = 0.013
20
*
*
10
0
Diarrhea
Nausea
Epigastric
pain
Diarrhea
Nausea
Vomiting
Abdominal
pain
Open-label, prospective 24-week study conducted in hospital based outpatients (n=61) with type 2 diabetes
Incidence of Gastrointestinal side effects before and after switchover to extended release metformin XR in patients completing the 6
month study. The metformin daily dose at baseline and following titration of metformin XR was 1861 +/- 711 mg and 1500 +/- 402 mg
per day (p = 0.004) respectively
Adapted from Levy J et al. Diabetol Metab Syndr 2010, 2:16

43. Metformin XR – Improved Patient
Adherence When Switched from
Standard Metformin
Adherence (%) Before & After
Switch from Standard Metformin
Adherence (%), Overall
Population
*
82
90
80
80%
78
76
p = 0.0001
80
81%
75
70
74
65
72
70
*
p = 0.0026 85
72%
60
62%
55
68
Metformin IR (n=10
019)
Metformin XL (n=80)
50
Metformin IR (n=40)
Metformin XL (n=40)
Retrospective observational study, T2DM patients from a single diabetes clinic in Scotland
Adapted from Donnelly LA et al. Diabetes Obes Metab. 2009 Apr;11(4):338-42.

44. Effect of Medication Dosing Frequency
on Adherence in T2DM – Systematic
Review
100%
79% to 94%.
Differences in
adherence ranged
from 13% to 41%*
75%
Adherence
Range (%) 50%
38% to 67%.
25%
0%
QD dosing
BID or TID
*with all studies
reporting the
differences across
regimens to be
statistically
significant.
Study selection criteria included the use of MEMS to measure adherence
Adapted from Saini SD et al. Am J Manag Care. 2009 Jun 1;15(6):e22-33.

45. Adjusted Adherence to Oral Antidiabetic Therapy: A
Comparison of Monotherapy, Combination Therapy, and
Fixed-Dose Combination Therapy
Adherence Rate (%)
100
80
87
P<0.001
P<0.001
77
71
60
54
40
20
0
Metformin and
Glyburide
Metformin/Glyburide
Previously on Monotherapy
Retrospective database analysis of pharmacy claims
Metformin and
Glyburide
Metformin/Glyburide
Previously on both, then switch to FDC
Melikian C et al. Clin Ther 2002;24:460

46. % HbA1c (LS Mean± SE)
A1c >7.5%, drug naïve, mono- vs
combination therapy
10
Sitagliptin/Metformin FDC
Metformin monotherapy
9
Difference
in change
from baseline =
−0.6%; p<0.001
8
7
0
6
Week
12
18
At Week 18, the mean HbA1c change from baseline was -2.4% (95% CI: -2.5,-2.2) for
sitagliptin/metformin FDC and -1.8% (95% CI: -1.9,-1.6) for metformin monotherapy,
Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644

47. Change from baseline in HbA1c at Week 18
presented by baseline HbA1c subgroup
Change from baseline in HbA1c (%) at Week 18
(LS Mean ± SE)
HbA1c (%) at baseline
≤ median (9.70%)
0.0
N=288
N=291
HbA1c (%) at baseline
> median (9.70%)
N=271
N=273
-0.5
-1.0
-1.5
-2.0
**
-2.5
-3.0
-3.5
Sitagliptin/Metformin FDC
Metformin monotherapy
**
-4.0
**p<0.001
Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644

48. Initial Combination Therapy with Sitagliptin and Metformin
Summary of Adverse Events
Sita/Met FDC
(N = 625)
n (%)
Metformin
(N = 621)
n (%)
One or more AEs
271 (43.4)
303 (48.5)
Drug-related* AEs
109 (17.4)
118 (18.7)
Serious AEs (SAEs)
13 (2.1)
20 (3.2)
Drug related* Serious AEs
1 (0.2)
1 (0.2)
Deaths
1 (0.2)
1 (0.2)
Discontinued due to AEs
25 (4.0)
25 (4.0)
Discontinued due to drug-related* AEs
18 (2.9)
16 (2.6)
Discontinued due to SAEs
6 (1.0)
5 (0.8)
Discontinued due to serious drug-related*
AEs
1 (0.2)
1 (0.2)
*Drug-related, considered by the study investigator to be possibly, probably or
definitely drug-related.
Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644

49. Initial Combination Therapy with Sitagliptin and
Metformin
Incidence Rates for Gastrointestinal AEs of Interest
Sita/Met FDC (n=625)
Metformin (n=621)
P<0.05
P=0.021
16.6
Incidence Rates (%)
18.0
16.0
14.0
12.0
P=0.622
P=0.612
12.0
10.0
8.0
6.0
P<0.05
P=0.002
3.9
4.0
2.0
5.6
6.3
P=0.735
P=0.742
2.9
2.6
1.1
0.0
Abdominal
Pain*
Diarrhea
Nausea
Vomiting
*Includes abdominal pain lower, abdominal pain upper, abdominal pain, abdominal discomfort and epigastric pain.
Reasner C et al. Diabetes, Obesity and Metabolism2011;13: 644

50. Cumulative Percentage of Patients
Kaplan-Meier curves for the Addition of
AHAs over Time by Treatment Group
24
Metformin
Sita/Met FDC
20
16
12
8
4
0
0
Patients at Risk
6
12
18
31
Time to First Additional AHA (Weeks)
44
Sita/Met FDC
625
563
514
472
414
264
Metformin
621
562
509
458
374
238
Olansky L et al Diabetes, Obesity and Metabolism 2011;13: 841–9

51. CV Risk with Oral Agents?

52. Mortality and Cardiovascular Risk With
Different Secretagogues1
 Cardiovascular outcomes were assessed in Danish patients who
initiated an insulin secretagogue or metformin as monotherapy
between 1997 and 2006
– 75,354 patients were eligible for propensity score matching, including 6,448 with prior MI
No Prior MI
Prior MI
MI, Stroke, and Cardiovascular Death
Metformin
Glimepiride
Gliclazide
Glibenclamide
Glipizide
Tolbutamide
Repaglinide
MI, Stroke, and Cardiovascular Death
Metformin
1
Glimepiride
1.29 (1.20, 1.39)
Gliclazide
1.18 (1.02, 1.36)
1.16 (1.04, 1.29) Glibenclamide
1.24 (1.09, 1.40)
Glipizide
1.17 (1.03, 1.33) Tolbutamide
0.87 (0.49, 1.54)
0
1
2
Hazard Ratios (95% confidence intervals)
MI=myocardial infarction; SU=sulfonylurea.
1. Schramm TK et al. Eur Heart J. 2011; 32:1900–1908.
Repaglinide
1
1.22 (1.30, 1.46)
0.71 (0.52, 1.99)
1.10 (0.85, 1.41)
1.54 (1.12, 2.10)
1.44 (1.01, 2.05)
1.10 (0.67, 1.82)
0
1
2
Hazard Ratios (95% confidence intervals)

53. CV events: Met vs. SU
Composite CV events (ITT analysis)
**Glipizide:
14 deaths [11 CV, 3 sudden],
6 nonfatal MI,
15 nonfatal strokes,
25 revascularizations,
Composite CV events after 5 years
70
60
p = 0.026
50
60**
40
30
Events
43*
20
10
0
Metformin
Glipizide
* Metformin:
7 deaths [all CV],
5 nonfatal MI,
10 nonfatal strokes,
21 revascularizations
metformin composite CV event HR 0.54 (95%CI 0.30–0.90; P = 0.026
adjusted for baseline diabetes duration, CAD duration, age, sex, smoking hx
Hong J. et al. Diabetes Care 2013 36(5)

54. DPP-4 inhibitors and MACE
Meta-analysis of available RCTs
MACE
Events MH-OR
All
595 0.71 [0.59–0.86]
Sitagliptin
144 0.86 [0.60–1.24]
Vildagliptin
149 0.61 [0.43–0.86]
Saxagliptin
108 0.67 [0.45–0.99]
Linagliptin
78 0.72 [0.45–1.16]
Alogliptin
16 0.86 [0.25–2.93]
MH-OR, Mantel–Henzel odds ratio.
Monami M, et al. Diabetes Obes Metab 2013;15:112–20.

55. Ongoing Cardiovascular Outcome
Trials With DPP-4 Inhibitors
Sitagliptin
TECOS1
Start: Dec 2008
Estimated Proj.
Completion: Dec 2014
N = 14,000
Start: Sept 2009
Alogliptin
EXAMINE2,5 Estimated Proj.
Completion: Dec 2014
N = 5,400
Sitagliptin vs Placebo added to stable doses of either
monotherapy or dual combination therapy with metformin,
pioglitazone, or a sulphonylurea
5,400 men and women with type 2 diabetes and ACS (acute myocardial
infarction or unstable angina) randomized to alogliptin vs placebo
Saxagliptin
SAVOR3,6
Start: May 2010
Estimated Proj.
Completion: April 2014
N = 16,500
16,500 patients with T2DM either treatment naive or on any background
antidiabetic treatment (except incretin therapy) with history of established
cardiovascular (CV) disease or multiple risk factors randomized 1:1 to
saxagliptin vs. placebo
Linagliptin
CAROLINA
Start: Oct 2010
Estimated Proj.
Completion: Sept
2018
N = 6,000
head-to-head cardiovascular outcome study comparing linagliptin with
glimepiride
4
CV=cardiovascular; DPP-4=dipeptidyl peptidase-4; MI=myocardial infarction.
ClinicalTrials.gov NCT identifiers: 1. 00790205; 2. 00968708; 3. 01107886; 4. 01243424.
5. White W et al. Am Heart J. 2011;162:620-626; 6. Scirica B et al. Am Heart J. 2011;162:818-825.
55

56. Cost

57. BC Statistics
2013
2020 (estimated)
Prevalence
8.3%
10.3%
Number of people with
diabetes
400 253
548 000
Number of people with
type 1
31 356
35 522
Cost
$1.5B
$1.9B
Prevalence Increase
37%
Cost Increase
25%

58. Out-of Pocket Cost
 Type 1 Diabetes
 Income < $15K: $475 (3.3%)
 Income $43K:
$1925 (4.5%)
 Income $75K:
$2481 (3.3%)
 Type 2 Diabetes
 Income < $15K: $2033 (6.8%)
 Income $43K:
$2313 (5.4%)
 Income $75K:
$2880 (3.8%)

59. 90 d supply
 Metformin 1g bid
 Glyburide 10mg bid
$42
$37
 Diamicron MR 60mg tabs, 120mg qAM
$67
 Gliclazide MR 30mg tabs, 120mg qAM
$75
 Sitagliptin (Januvia) 100mg
$324
 Linagliptin (Trajenta) 5mg
 Liraglutide (Victoza) 1.2mg
$251
$546
 Janumet 50/1000mg bid or Janumet XR
 Jentadueto 2.5/1000mg bid
 Lantus 20 U qHS
 plus Needles $35
$350
$263
$123

60. Fair Pharmacare Assistance
Levels - Regular
Family Net
Income
Family
Deductible
Portion
Pharmacare
Pays after
Deductible
Family
Maximum
(Pharmacare
pays 100% once
maximum met)
< $15 000
0
70%
$300
$30 000
$900
70%
$1200
$60 000
$1800
70%
$2400
$90 000
$2750
70%
$3675
$120 000
$3500
70%
$4675

61. Fair Pharmacare Assistance
Levels – Enhanced (born
before 1939)
Family Net
Income
Family
Deductible
Portion
Pharmacare
Pays after
Deductible
Family
Maximum
(Pharmacare
pays 100% once
maximum met)
$15 000
0
70%
$200
$30 000
0
70%
$400
$60 000
$1200
70%
$1800
$90 000
$1800
70%
$2700
$120 000
$2500
70%
$3750

62. Pharmacare coverage
 Fully or partially covered:
 aspart, glulisine, lispro, regular
insulin, glyburide, tolbutamide, metformin (glucophage &
glumetza)
 Only if meeting eligibility criteria and preapproved by BC
drug formulary:
 sitagliptin, sitagliptin & metformin
(Janumet), linagliptin, NPH, detemir, glargine, gliclazide, pioglita
zone
 Not available through BC drug formulary:
 saxagliptin, liraglutide, exenatide, glimepiride, nateglindine, rep
aglinide, linagliptin & metformin (Jentadueto), rosiglitizone
 Removed from formulary: acarbose

63. Pharmacare eligbility
 Gliclazide: Treatment failure or intolerance with
glyburide
 Hypoglycemia)
 Sitagliptin, Sitagliptin/Metformin, Linagliptin:
 When insulin NPH is not an option
 AND
 After inadequate glycemic control on maximum tolerated
doses of dual therapy of metformin AND a sulphonylurea

64. Pharmacare Eligibility
 Glargine or Detemir:
 Type 1 (any age), Type 2 (age > 17y)
 Currently taking NPH and/or pre-mix at optimal dosing
AND
 Has experienced unexplained nocturnal hypoglycemia at
least once a month despite optimal management
Or
 Has experienced or continues to experience severe
systemic or local allergic reaction to existing insulin
treatment

65. Private Insurance?
 Don’t forget that many private insurance programs for
public employees (teachers, nurses, etc.) are now
based upon the BC drug formulary

66. CDA Toolkit

67. 67

68. What is important to your patient?
Comparing antihyperglycemic agents
kg
hypo
Relative A1C
lowering
Change in
body weight
Overall risk of
hypoglycemia
Cost

Neutral to 
Rare
$$

Neutral to 
Rare
$$$
 to 

Rare
$$$$


Yes
$-$$$$
Meglitinides


Yes
$$
Sulfonylureas


Yes
$
TZDs


Rare
$$


None
$$$
A1C
Alpha glucosidase
inhibitor (acarbose)
DPP-4 inhibitors
GLP-1 receptor agonists
Insulin
Weight loss agent
(orlistat)
68
TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.

69. What is important to your patient?
Comparing antihyperglycemic agents

kg
hypo
Relative A1C
lowering
Change in
body weight
Overall risk of
hypoglycemia
Cost


Yes
$-$$$$
 to 

Rare
$$$$
DPP-4 inhibitors

Neutral to 
Rare
$$$
Meglitinides


Yes
$$
Sulfonylureas


Yes
$
TZDs


Rare
$$
Alpha glucosidase
inhibitor (acarbose)

Neutral to 
Rare
$$
Weight loss agent
(orlistat)


None
$$$
A1C
Insulin
GLP-1 receptor agonists
69
TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.

70. What is important to your patient?
Comparing antihyperglycemic agents
A1C
kg

hypo
Relative A1C
lowering
Change in
body weight
Overall risk of
hypoglycemia
Cost
 to 

Rare
$$$$
Weight loss agent
(orlistat)


None
$$$
Alpha glucosidase
inhibitor (acarbose)

Neutral to 
Rare
$$
DPP-4 inhibitors

Neutral to 
Rare
$$$
Meglitinides


Yes
$$
Sulfonylureas


Yes
$


Yes
$-$$$$


Rare
$$
GLP-1 receptor agonists
TZDs
Insulin
70
TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.

71. What is important to your patient?
Comparing antihyperglycemic agents
kg
hypo
Relative A1C
lowering
Change in
body weight
Overall risk of
hypoglycemia
Cost
Weight loss agent
(orlistat)


None
$$$
Alpha glucosidase
inhibitor (acarbose)

Neutral to 
Rare
$$

Neutral to 
Rare
$$$
 to 

Rare
$$$$


Rare
$$


Yes
$-$$$$
Meglitinides


Yes
$$
Sulfonylureas


Yes
$
DPP-4 inhibitors
GLP-1 receptor agonists
TZDs
Insulin

A1C
71
TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.

72. What is important to your patient?
Comparing antihyperglycemic agents
kg
hypo
Relative A1C
lowering
Change in
body weight
Overall risk of
hypoglycemia
Cost


Yes
$

Neutral to 
Rare
$$
Meglitinides


Yes
$$
TZDs


Rare
$$
DPP-4 inhibitors

Neutral to 
Rare
$$$


None
$$$
 to 

Rare
$$$$


Yes
$-$$$$
Sulfonylureas
Alpha glucosidase
inhibitor (acarbose)
Weight loss agent
(orlistat)
GLP-1 receptor agonists
Insulin

A1C
72
TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.

73. What is important to your patient?
Comparing antihyperglycemic agents
Alpha glucosidase inhibitor
(acarbose)
• Improved postprandial control, GI side effects
DPP-4 inhibitors
GLP-1 receptor agonists
• GI side effects
Insulin
• No dose ceiling, flexible regimens
Meglitinides
• Less hypoglycemia in context of missed meals but usually
requires TID to QID dosing
Sulfonylureas
• Gliclazide and glimepiride associated with less
hypoglycemia than glyburide
TZDs
• CHF, edema, fractures, rare bladder cancer
(pioglitazone), cardiovascular controversy (rosiglitazone),
6-12 weeks required for maximal effect
Weight loss agent (orlistat)
• GI side effects
73
TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4.
1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.

74. Case
 John is 47yo man with type 2 diabetes, diagnosed 5 years
ago. He is a truck driver, and has private insurance through
his work. He has hypertension and dyslipidemia, but no
microvascular or macrovascular complications. His work
schedule is irregular. He sometimes forgets to take his
medication, and find that his metformin bothers his stomach
a bit if he misses dinner on the road.
 Medications: Metformin 1g bid, perindopril 4mg, atorvastatin
20mg
 On examination: BMI 32.1 kg/m2, BP 127/76
 Labs: A1c 7.9%, eGFR 72, urine ACR negative

75. What agent would you add?
 Sulphonylurea
 DPP4 inhibitor
 GLP-1
 TZD
 Acarbose
 Insulin

76. Questions
 Thank you to Rudy Sedlak for drug price list