As pharmacists, you are rarely faced with a consistent patient population with similar problems and questions. More likely, each patient you interact with has unique and varied concerns that you must be ready to address in an instant. This session reflects the diversity of patients a pharmacist will face in day-to-day practice and covers a range of topics in a quick and snappy format. This session will cover the evidence as it relates to concurrent probiotic and antibiotic use, second line treatment for patients with type 2 diabetes, and explore new utilization strategies of using drugs traditionally used in the treatment of type 2 diabetes for patients with type 1 diabetes.

1. A Little Bit of Everything:
Evidence for Probiotics &
the Advances in the Care of Patients with Diabetes
DEBBIE BUNKA
CONTRACTOR
13 MAY 2018

2. Introduction / Disclosure
Presentation author: Debbie Bunka, BSc. Pharmacy
Presentation is based primarily on:
• Concurrent Probiotic and Antibiotic Use for In-Patients: A Review of the
Clinical and Cost-Effectiveness – Rapid Response Report. Ottawa: CADTH,
2015 Nov.
• New Drugs for Type 2 Diabetes: Second-Line Therapy – Recommendations
Report. Ottawa: CADTH; 2017 May. (CADTH therapeutic review; vol.4,
no.1c).
• New Drugs for Type 2 Diabetes: Second-Line Therapy – Science Report.
Ottawa: CADTH; 2017 Sep. (CADTH therapeutic review; vol.4, no.1b).
Available at: www.cadth.ca/newdrugsT2DM
• Newer drugs for type 2 diabetes: an emerging adjunctive therapy to insulin
for type 1 diabetes? Ottawa: CADTH; 2018 Jan. (CADTH issues in emerging
health technologies; issue 166).
CADTH adheres to the authorship and contribution guidelines established
by the International Committee of Medical Journal Editors (ICMJE).

3. Objectives
• To reflect the diversity of patients a pharmacist may assist
in day-to-day practice.
1) Examine concurrent probiotic and antibiotic use for
hospitalized inpatients.
2) To discuss 2nd
line pharmacologic treatments for patients
with type 2 diabetes.
3) Discuss early results from clinical trials testing the use of
newer drug classes for type 2 diabetes as adjunctive
therapy to insulin for patients with type 1 diabetes.
3

4. Concurrent Probiotic and
Antibiotic Use in
Hospitalized
Adult Inpatients

5. 5

6. Why probiotics?
• A prophylactic / preventative treatment to maintain
normal bacteria in the GI tract of hospitalized patients
on antibiotics.
• Antibiotic Associatied Diarrhea (AAD) = changes to
normal stool frequency, with at least 3 loose or watery
stools daily for 3 days.
• Occurs between 5 to 39% of patients who take
antibiotics, with the higher percentages seen in
hospitalized patients.
• AAD develops within 12 weeks of exposure to
antibiotics, with early onset occurring with 2 to 7 days.
6

7. Inclusion Criteria
POPULATION Hospitalized patients requiring
antibiotic treatment for various
reasons
INTERVENTION Probiotics in combination with
antibiotic
COMPARATOR Antibiotics alone
OUTCOMES Clinical effectiveness
Safety
Cost effectiveness
7

8. Evidence Evaluated in the Report
• 3 SRs / MAs (only RCTs included)
• 2 RCTs
• 1 economic evaluation
8

9. Comparators / Interventions
• SRs / MAs
• Probiotics against placebo or no treatment
• Probiotics against placebo
• Probiotics against no treatment
• RCTs & Economic Evaluation
• Probiotics against placebo
9

10. Clinical Effectiveness
OUTCOME: Incidence of AAD
• MIXED findings
•2 SRs/MAs & 1 RCT – found protective effects
•1 SR/MA – protective effects were greater in
higher quality studies, shorter study duration &
certain strains (Lactobacillus)
•1 RCT – protective effects were greater with
higher doses of probiotics
•1 RCT – no significant effect in older patients
10

11. Clinical Effectiveness
OUTCOME: Incidence of CDAD
• MIXED findings
•1 RCT – protective effects, greater with higher
doses of probiotics
•1 RCT – no significant effect in older adults
•1 SR / MA - protective effects, greater in higher
quality studies & support from probiotic companies
11

12. Clinical Effectiveness
OUTCOME: Incidence of CDI
•1 SR/MA found protective effects
OUTCOME: Incidence of CDD
•1 SR/MA found protective effects
OUTCOME: Hospital Length of Stay
•1 RCT – older patients, no significant effects of
probiotics
12

13. Others
OUTCOME: Quality of Life
•1 RCT – older patients, QOL measures were
similar between the probiotic & placebo arms
OUTCOME: Liquid stools / Diarrhea Duration
•1 RCT – number of liquid stools per day and the
average duration of diarrhea decreased with
higher doses of probiotic
13

14. Economic Evaluation
• Evidence from one economic
evaluation, published in the UK and conducted
alongside the aforementioned RCT on adult inpatients aged
65 years or older, suggested that the
intervention was unlikely to be cost-
effective.
14

15. Safety
OUTCOME – Adverse Events
•1 RCT – protective effects
•1 RCT – older patients, no significant effects
• Considered to be probably harmless in
healthy adults & well tolerated
• Some caution in immunocompromised,
critically-ill patients
• Some suggest to separate probiotic by at
least two hours from antibiotic
15

16. 16

17. Products?
17
• EXAMPLE:
• DanActive (93 mL bottle)
• Lactobacillus bulgaricus
Streptococcus thermophilus
Lactobacillus casei
• 1 bottle 2x daily during antibiotic treatment and 1 week
afterward
• Possibly effective for prevention of AAD (including CDD)
in hospitalized inpatients.
Canadian Pharmacist’s Letter: Comparison of Common Probiotic Products

18. Products?
18
• EXAMPLE:
• Florajen
• Lactobacillus acidophilus
• 1 capsule 3x daily during treatment, and for 7-14 days
after the last dose
• Possibly effective for prevention of AAD in hospitalized
adults
Canadian Pharmacist’s Letter: Comparison of Common Probiotic Products

19. Second-Line Therapy
for Type 2 Diabetes

20. Key Message #1
• For adults with type 2 diabetes without established
cardiovascular disease, add a sulfonylurea drug to
metformin once metformin, diet, and exercise are not
enough to control blood glucose levels.
20
Pharmacist’s Letter Canada

21. Key Message #1
RESEARCH QUESTION
What is the comparative efficacy and safety of using a drug
from one of the following classes as second-line agent:
• Sulfonylurea
• Insulin
• DPP-4 inhibitor
• GLP-1 analogue
• SGLT-2 inhibitor
21

22. What evidence was reviewed?
1. Patient group input
2. Systematic review and network meta-analysis of drugs
used as a second-line agent after metformin
3. Systematic review and network meta-analysis of trials that
use major adverse cardiovascular events as a primary
outcome
4. Clinical expert (endocrinologist) engagement
5. Stakeholder feedback
22

23. Results – Research Question 1
23
• Systematic review identified 175 unique RCTs that each
evaluated the efficacy and/or safety of the antidiabetic
agents in participants on metformin monotherapy.
• Of these, 166 RCTs reported outcomes of interest.
• Evidence was available for sulfonylureas, SGLT-2
inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors,
thiazolidinediones (TZDs), GLP-1 analogues, basal insulin,
alpha-glucosidase inhibitors, meglitinides, and biphasic
insulin. No studies of bolus insulin reported outcomes of
interest.

24. Results – Research Question 1
(84 RCTs)
24
A1C
Treatment
∆ in A1C
(%)
Sulfonylureas
-0.70
(-0.83, -0.58)
DPP-4 inhibitors
-0.58
(-0.68, -0.48)
SGLT-2 inhibitors
-0.67
(-0.84, -0.49)
GLP-1 analogues
-0.88
(-1.05, -0.71)
Basal Insulin
-0.85
(-1.16, -0.53)
Biphasic Insulin
-0.94
(-1.41, -0.48)

25. 25
Sulfonylureas, basal insulin
+3 kg
+2 kg
+1 kg
0 kg
-1 kg
-2 kg
-3 kg
DPP-4 inhibitors
SGLT-2 inhibitors, GLP-1 agonists
Body Weight (70 RCTs)

26. 26
Sulfonylureas6
5
4
3
2
1
0
Insulins
GLP-1 analogues, DPP-4 inhibitors
Severe Hypoglycemia (48 RCTs)
7
SGLT-2 inhibitors

27. Quick Facts:
Metformin + Sulfonylurea
Estimated based on data from Home PD, et al. Diabet Med. 2007;24(6):626-34.

28. 28
Sulfonylureas, Biphasic insulin
6
5
4
3
2
1
0
Basal insulin
Non-Severe Hypoglycemia (67 RCTs)
7
SGLT-2 inhibitors, GLP-1 analogues, DPP-4
inhibitors
8

29. Summary of Economic Findings
• When metformin alone becomes insufficient for treating
type 2 diabetes, adding a sulfonylurea is the most cost-
effective second-line therapy.
• Threshold analyses indicated that the costs of DPP-4
inhibitors, GLP-1 analogues, and SGLT-2 inhibitors
would require significant price reductions to surpass
sulfonylureas as the most cost-effective second-line
treatment option.
29

30. Sensitivity Analyses
• The results of sensitivity analyses indicate that
sulfonylureas added to metformin remain the most
cost effective option under any scenario tested:
• Examples:
• Price adjusting SU analysis for more
expensive agent compared to less expensive
glyburide
• Quality of life adjustments for weight gain
30

31. 31

32. Diabetes Canada – 2018 CPG’s
• Choice of 2nd
line agents should be made based on:
• individual patient characteristics, patient preferences, any
contraindications to the drug, glucose-lowering efficacy, risk of
hypoglycemia, affordability/access, effect on body weight and other
factors.
• Patients may prefer a DPP-4 inhibitor or GLP-1 receptor agonist, and/or
SGLT2 inhibitor to other agents (if there are no contraindications and
affordability and access are not barriers, as they will improve glycemic
control with a low risk of hypoglycemia and weight gain).
• These agents should be considered before an insulin secretagogue
(sulfonylurea or meglitinide) or insulin as add-on therapy in people
with a high risk of hypoglycemia (such as elderly people or those
with impaired renal function) and/or obesity.
32

33. 33
Don’t Rule Out Sulfonylureas for Type 2 Diabetes, Pharmacist’s Letter Canada,
January 2018.

34. Key Message #2
• For adults with type 2 diabetes with established
cardiovascular disease, refer to the CADTH Common Drug
Review (CDR) recommendations on individual drugsa
that
have been reviewed for this indication.
a
As of today, the only drug reviewed by the CADTH CDR for this indication is
empagliflozin (Jardiance). The recommendation is to reimburse empagliflozin for
patients with type 2 diabetes as a second-line therapy after metformin if these
patients have established cardiovascular disease as defined by the EMPA-REG
OUTCOME trial:
• MI > 2 months prior
• Multi-vessel CAD
• Single vessel CAD with positive stress test or UA hospitalization in prior year
• UA >2 months prior and evidence of CAD
• Stroke >2 months prior
• Occlusive PAD.
MI = myocardial infarction; CAD = coronary artery disease; UA = unstable angina; PAD = peripheral artery disease.
34

35. Individual Trial Results
• LEADER
• EMPA-REG OUTCOME
• CANVAS (reported only biomarker data
or an interim analysis at the time of analysis)
35

36. EMPA-REG OUTCOMES
36
www.RxFiles.ca

37. Research Question
37
For adults with type 2 diabetes, what are the comparative
cardiovascular effects of drugs belonging to one of the
following classes:
• Insulin
• DPP-4 inhibitor
• GLP-1 analogue
• SGLT-2 inhibitor

38. Results – Research Question 2
38
• Systematic review identified 17 unique RCTs that
each evaluated the efficacy and/or safety of the
antidiabetic agents in participants on any
background therapy who were at high risk for
cardiovascular events.
• Of these, 11 RCTs reported outcomes of interest
(all industry-funded trials).
• Evidence was predominantly available for SGLT-2
inhibitors, DPP-4 inhibitors, TZDs, and GLP-1
analogues.

39. Results – Research Question 2
39
• Major adverse cardiovascular events MACE (5 RCTs,
n=50,410)
- composite endpoint : CV mortality, nonfatal MI, and
nonfatal stroke
- data were insufficient to conclude that any of the
selected classes lowered the risk of MACE when
compared to placebo or with each other

40. Results – Research Question 2
40
• Mortality (8 RCTs, n=66,311)
- SGLT-2 inhibitors reduced the risk of all-cause mortality
when compared with placebo (OR 0.67; 95% CI 0.47 to
0.95) or DPP-4 inhibitors (OR 0.66; CI 0.45 to 0.99)
- data were insufficient to conclude that any other
treatments reduced the risk of all-cause mortality
- none of the selected classes significantly lowered the risk
of CV mortality when compared with placebo or with each
other (6 RCTs, n= 30,439)

41. Results – Research Question 2
41
• Hospitalizations for Heart Failure (5 RCTs, n=51,246)
- data were insufficient to conclude that any of the
selected classes significantly lowered the risk of
hospitalizations for heart failure when compared with
placebo or each other.

42. Results – Research Question 2
42
Severe hypoglycemia (8 RCTs, n= 66,163)
•There was a significantly lower risk of severe hypoglycemia
with GLP-1 agonists relative to DPP-4 inhibitors and placebo.

43. Summary Results – Research Question 2
43
• In the opinion of CADTH’s expert committee:
• the gaps in the evidence at this time & the limitations of
the available data are too large to support a specific
drug-class recommendation.
• At this time they support the decision to continue to
look to individual agents, as they are reviewed by the
CDR.

44. Diabetes Canada – 2018 CPG’s
• In people with clinical CV disease in whom A1C targets are
not achieved with existing pharmacotherapy, an
antihyperglycemic agent with demonstrated CV outcome
benefit should be added to antihyperglycemic therapy to
reduce CV risk.
• 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]
44

45. 45

46. Newer Drugs for Type 2 Diabetes:
an emerging adjunctive therapy to
insulin for Type 1 diabetes

47. Some of the new drugs
for type 2 diabetes
are now approved
in Canada for the
treatment of people
with type 1 diabetes.
47

48. Which drug classes are
being studied?
• Glucagon-like peptide (GLP-1) agonists
• Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Sodium-glucose cotransporter-2 (SGLT-2)
inhibitors
and
• Dual sodium-glucose transporter-1 & -2 (SGLT-
1/SGLT-2) inhibitors
48

49. Research
• Peer-reviewed & grey literature search conducted
• RCTs and clinical studies
• End points of interest – the effects of adjunctive therapy on:
• A1c
• Total daily insulin dose
• Weight
• Limitations of the data: in general, short study durations and
small sample sizes, funding sources, heterogeneity
(regimens, populations), exclusion criteria limits the
applicability to larger T1D patient population.
49

50. Efficacy
• Preliminary results showed that adding these drugs may
reduce A1c by 0.1 to 0.6%.
• May reduce the amount of insulin patients used (a decrease
in the total daily insulin dose by 1 to 25 units).
• Results also showed that most of these drugs appeared to
reduce body weight by 0.3 to 6.8 kg (depending on the drug
and the dose used).
• Of note, combining some of the DPP-4 inhibitors or GLP-1
agonists with insulin did not provide additional benefits in
some studies.
50

51. Safety
• Adding an adjunctive therapy to insulin was associated with
an incidence of hypoglycemia that was generally similar
to the incidence reported with insulin monotherapy.
• In some of the studies investigating the addition of GLP-1
agonists, SGLT-2 inhibitors, and SGLT-1/SGLT-2 inhibitor, a
higher risk of diabetic ketoacidosis was observed.
• Higher incidences of GI adverse events with GLP-1
agonists and SGLT-1/SGLT-2 inhibitor.
• Higher incidences of urinary and genital infections with
SGLT-2 inhibitors were also reported.
51

52. Conclusion
• Most of these results are based on
preliminary data.
• Some suggestion that these newer
classes of drugs could enhance primary
treatment with insulin for adult patients
with type 1 diabetes.
• More research is warranted, including a
pharmacoeconomic analysis.
52

53. Authorship
Presentation authors:
Debbie Bunka
Presentation based on:
Aeng E, Boucher M, Severn M. Newer Drugs for Type 2 Diabetes: An Emerging
Adjunctive Therapy to Insulin for Type 1 Diabetes? [Internet]. Ottawa: CADTH;
2018 Jan. (CADTH Issues in Emerging Health Technologies; issue 166). [cited
2018-04-26]. Available from:
www.cadth.ca/dv/ieht/newer-drugs-type-2-diabetes-emerging-adjunctive-therapy-ins
CADTH adheres to the authorship and contribution guidelines established by the
International Committee of Medical Journal Editors (ICMJE).

54. Authorship
Presentation authors:
Debbie Bunka
Presentation based on:
Kim J, Argaez C. Concurrent Probiotic and Antibiotic Use for In-Patients:
Clinical Effectiveness and Cost-Effectiveness [Internet]. Ottawa: CADTH; 2015
Nov. (Rapid Response Report: Summary with Critical Appraisal). [cited 2018-
04-26]. Available from:
www.cadth.ca/concurrent-probiotic-and-antibiotic-use-patients-clinical-effectiveness-
CADTH adheres to the authorship and contribution guidelines established by the
International Committee of Medical Journal Editors (ICMJE).

55. Authorship
Presentation authors:
Debbie Bunka
Presentation based on:
New Drugs for Type 2 Diabetes: Second-Line Therapy – Recommendations
Report. Ottawa: CADTH; 2017 May. (CADTH therapeutic review; vol.4, no.1c).
New Drugs for Type 2 Diabetes: Second-Line Therapy – Science Report.
Ottawa: CADTH; 2017 Sep. (CADTH therapeutic review; vol.4, no.1b).
Available at: www.cadth.ca/newdrugsT2DM
CADTH adheres to the authorship and contribution guidelines established by the
International Committee of Medical Journal Editors (ICMJE).

56. Science Report Authorship
CADTH adheres to the authorship and contribution guidelines established by the
International Committee of Medical Journal Editors (ICMJE).

57. 57
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