facilitator guide · diabetes. this slide lists some of the patient and agent characteristics that...

Facilitator Guide

1

DEVELOPMENT COMMITTEE….......................................................................

LEARNING OBJECTIVES.................................................................................Page 3

ACCREDITATION…………………..........................................................................Page 3

PROGRAM CONTENT......................................................................................Page 4

TABLE OF CONTENT

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CHAIR

Lawrence A. Leiter, MD, FRCPC, FACP, FAHA Division of Endocrinology & Metabolism, St. Michael's Hospital Professor of Medicine and Nutritional Sciences, University of Toronto

STEERING COMMITTEE

C. Keith Bowering, MD, FRCPC, FACP Clinical Professor of Medicine Division of Endocrinology & Metabolism University of Alberta

Ronald M. Goldenberg, MD, FRCPC, FACE LMC Diabetes & Endocrinology, Thornhill

Shaun G. Goodman, MD, FRCPC, FACC, FESC, FAHA, FCCS Division of Cardiology, St. Michael's Hospital Professor of Medicine, University of Toronto

Jean-François Yale, MD, CSPQ, FRCPC Endocrinologist, McGill University Health Centre Professor of Medicine Division of Endocrinology & Metabolism, McGill University

EDUCATIONAL COMMITTEE

Kevin K. Saunders, MD, CCFP Family Physician, Winnipeg

Carl Fournier, MD, CCFP Family Physician, Montreal

Stewart B. Harris, MD, MPH, FCFP, FACPM Professor, CDA Chair in Diabetes Management Ian McWhinney Chair of Family Medicine Studies Centre for Studies in Family Medicine Schulich School of Medicine and Dentistry Western University

DEVELOPMENT COMMITTEE

3

Upon completion of this program, participants will be able to:

Differentiate between non-insulin options for patients not at A1C target

Appraise and interpret data emerging from large T2DM CV safety trials

Personalize glucose-lowering therapy according to patient characteristics and CV risk

profile

ACCREDITATION

This Group Learning program has been certified by the College of Family Physicians

of Canada and the National Chapter for up to 1 Mainpro+ credits.

For accreditation purposes, please ensure that all participants complete the

evaluation forms. The evaluation forms should be collected by the representative who

organized this scientific program.

DISCLOSURE

Each facilitator should include a disclosure slide at the beginning of the presentation.

A template slide has been provided. To use this template, double-click on the slide,

type pertinent disclosure information and save file to desktop prior to the event.

Finally, remember to show the disclosure slide to participants on the day of the event.

LEARNING OBJECTIVES

ACCREDITATION

Please fill in your disclosures on the following slides and take a moment to review them

before beginning the presentation.

6

Facilitator’s notes:

Please review the learning objectives of the program.

9


Please review Susan’s clinical profile.

10


Please poll the attendees on what they think Susan’s A1C target should be.

11


Please poll the attendees on whether they think Susan’s current glucose management

strategy could benefit from the addition of a second antihyperglycemic agent.

13

Reference:

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee.

Pharmacologic Management of Type 2 Diabetes: November 2016 Interim Update.

Available at: http://guidelines.diabetes.ca/browse/chapter13_nov-2016. Accessed: January

17, 2017.

14


This slide lists the potential benefits that patients with uncontrolled glycemia may reap if

they are prescribed combination therapy earlier on in the disease continuum.

References:

1. Zinman B. Initial combination therapy for type 2 diabetes mellitus: is it ready for prime

time? Am J Med. 2011;124:S19-34.

2. Schernthaner G. Fixed-dose combination therapies in the management of

hyperglycaemia in Type 2 diabetes: an opportunity to improve adherence and patient care.

Diabet Med. 2010;27:739-43.

15


Please poll the attendees on which antihyperglycemic agent or class they would prescribe

as a second-line agent. i.e. on top of metformin.

16


The Canadian Diabetes Association, in accord with many professional and health

organizations, emphasizes the importance of personalized treatment for individuals with

diabetes. This slide lists some of the patient and agent characteristics that would need to

be considered when selecting an antihyperglycemic therapy.

Reference:




17, 2017.

17


This slide lists the classes of antihyperglycemic agents currently approved for the management of type 2 diabetes in Canada. The following buttons are hyperlinked to 1-2 slides that provide summaries of the efficacy and safety profiles of the most commonly prescribed classes of antihyperglycemic agents:

a) DPP-4 inhibitors

b) GLP-1 receptor agonists

c) SGLT2 inhibitors

d) Sulfonylurea

Reference:




17, 2017.

18


This slide summarizes important clinical considerations when choosing to add a

sulfonylurea to a patient’s diabetes treatment strategy.

References:

1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee.



17, 2017.

2.Berne C; Orlistat Swedish Type 2 diabetes Study Group. A randomized study of orlistat in

combination with a weight management programme in obese patients with Type 2

diabetes treated with metformin. Diabet Med. 2005;22:612-8.

3.Liu SC, Tu YK, Chien MN et al. Effect of antidiabetic agents added to metformin on

glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a

network meta-analysis. Diabetes Obes Metab. 2012;14:810-20.

4. Miles JM, Leiter L, Hollander P et al. Effect of orlistat in overweight and obese patients

with type 2 diabetes treated with metformin. Diabetes Care. 2002;25:1123-8.

19


This slide summarizes important clinical considerations when choosing to add a DPP-4

inhibitor to a patient’s diabetes treatment strategy.

References:

1. Canadian Diabetes Association Clinical Practice Guidelines Expert

CommitteePharmacologic Management of Type 2 Diabetes: November 2016 Interim

Update.


17, 2017.

2. Berne C; Orlistat Swedish Type 2 diabetes Study Group. A randomized study of orlistat in



3. Liu SC, Tu YK, Chien MN et al. Effect of antidiabetic agents added to metformin on





20


This slide summarizes important clinical considerations when choosing to add a GLP-1

receptor agonist to a patient’s diabetes treatment strategy.

References:




17, 2017.









21


Cases of pancreatitis were uncommon and pancreatic cancers rare in the six incretin-focused cardiovascular safety trials conducted for

the 2008 mandate of the U.S. Food and Drug Administration for new type 2 diabetes therapies.

Although there were numerical imbalances in pancreatitis and pancreatic cancer events for placebo vs. drug, they moved in different

directions.

EXAMINE:1 The incidence of pancreatitis and cancer was similar with alogliptin and placebo. Acute pancreatitis: 0.4% for alogliptin and

0.3% for placebo; chronic pancreatitis: 0.2% for both arms.

SAVOR-TIMI 53:2,3 Rates of adjudicated cases of acute and chronic pancreatitis were similar in the saxagliptin and placebo groups (acute

pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% for saxagliptin and 0.1% for

placebo). Overall cancer events were less frequent in the saxagliptin group while the incidence of pancreatic cancer was similar in the

two study arms.

TECOS:4 Confirmed acute pancreatitis events were uncommon overall but numerically more frequent in the sitagliptin group (0.3%) than

in the placebo group (0.2%). Chronic pancreatitis: sitagliptin <0.1%; placebo 0%. Confirmed pancreatic cancers were also uncommon

overall but numerically less frequent in the sitagliptin group (0.1%) than in the placebo (0.2%) group.

ELIXA:5 Events of pancreatitis and pancreatic cancer were lower both numerically and percentage-wise with lixisenatide than with

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%)

LEADER:6 Events of pancreatitis were non-significantly lower with liraglutide than with placebo (0.4% vs. 0.5% and 0% vs. 0.1% for acute

and chronic pancreatitis, respectively), while pancreatic cancer was non-significantly more common with liraglutide than with placebo

(0.3% vs. 0.1%).

SUSTAIN-6:7 Events of pancreatitis and pancreatic cancer were both numerically lower with semaglutide than with placebo (1.1% vs.

1.5% for acute pancreatitis and 0.1% vs. 0.4% for pancreatic cancer).

References:

1. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med.

2013;369:1327-35.

2. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J

Med. 2013;369:1317-26.

3. Raz I, Bhatt DL, Hirshberg B et al. Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-

TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin. Diabetes Care. 2014;37:2435-41.

4. Green JB, Bethel MA, Armstrong PW et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med.

2015;373:232-42.

5. Pfeffer MA et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373:2247-57.

6. Marso SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375:311-22.

7. Marso SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375:1834-44.

22


This slide summarizes important clinical considerations when choosing to add an SGLT2

inhibitor to a patient’s diabetes treatment strategy.

References:

1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian

Diabetes Association 2013 clinical practice guidelines for the prevention and management

of diabetes in Canada. Can J Diabetes. 2013;37:S1-S213.

2. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Policies,

Guidelines and Consensus Statements: Pharmacologic Management of Type 2 Diabetes -

2015 Interim Update. Can J Diabetes. 2015;39:250-2.









23


Please poll the attendees on whether they would adjust Susan’s glucose-lowering strategy

in a stepwise fashion or if they would incorporate a fixed-dose combination.

24


This slide details the fixed-dose combinations currently available in Canada.

Reference:


Pharmacologic Management of Type 2 Diabetes: November 2016 Interim Update. Available

at: http://guidelines.diabetes.ca/browse/chapter13_nov-2016. Accessed: January 17, 2017.

2., 2015)

25


A few years have passed since we first met Susan. Please review Susan’s current clinical

profile.

26

Facilitator’s notes:While the microvascular benefits of earlier intensive glycemic control have been repeatedly demonstrated, there is less concordance on whether glycemic control with antihyperglycemic agents influences CV morbidity and mortality.1-5

The landmark ACCORD, ADVANCE, UKPDS and VADT studies were long-term diabetes trials that independently failed to demonstrate a reduction in overall CV events when tight glycemic control was achieved with conventional antihyperglycemic agents.1-4

However, the UKPDS post-trial monitoring program5 revealed that earlier glycemic control vs. conventional therapy was associated with significant relative risk reductions for myocardial infarction (15%, P=0.014) and all-cause mortality (12%, P=0.007).

This meta-analysis by Turnbull and colleagues6 suggests that intensive glycemic control affords a modest but significant CV benefit (specifically MACE and MI) in the short to medium term, although all-cause and cardiovascular mortality do not benefit.

Extension data from the VADT group demonstrating the long-term benefits of intensive glucose lowering7 are discussed in slide 10. The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1,000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years).

References:

1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with

conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-53.

2. The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011; 364:818-

28.

3. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J

Med. 2008; 358:2560-72.

4. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2

diabetes. N Engl J Med. 2009; 360:129-39.

5. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577-

89.

6. Control Group, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288-98.7. Hayward RA, Reaven PD, Wiitala WL, et al; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372(23):2197-206.

27


UKPDS1,2

The UK Prospective Diabetes Study (UKPDS) was a landmark randomized, multicentre trial of glycemic therapies in 5,102 patients with newly diagnosed type 2 diabetes. The study ran from 1977 to 1997 in 23 UK clinical sites. In 1998, the investigators reported that tight glycemic control (A1C 7.0% vs. 7.9% over a median of 10.0 years), with either a sulfonylurea or insulin, reduced the risk of “any diabetes-related end point” by 12% and microvascular disease (renal failure, death from renal failure, retinal photocoagulation and vitreous hemorrhage) by 25%, with a 16% trend to a reduced risk of myocardial infarction (P=0.052).

At the end of the study, all surviving UKPDS patients were entered into a ten-year, post-trial monitoring program. In 2008, the post-trial investigators reported that despite loss of within-trial blood glucose differences, there was a continuing benefit of earlier glycemic control, i.e. a legacy effect. The data on the left panel of this slide demonstrate that after a median follow-up of 8.5 years following completion of the UKPDS study, earlier intensive glycemic control with a sulfonylurea or insulin was associated with maintenance of the relative risk reductions for any diabetes-related end point, microvascular disease, myocardial infarction and all-cause mortality.

VADT3

The landmark Veterans Affairs Diabetes Trial (VADT) showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1,791 military veterans (median follow-up: 5.6 years).

The graph on the right shows that over a median follow-up of 9.8 years, the intensive-therapy group had 8.6 fewer major cardiovascular events per 1,000 person-years than those assigned to standard therapy (HR 0.83; 95% CI 0.70 to 0.99; P = 0.04). Cardiovascular and total mortality between the two study arms were similar.

References:

1. Holman RR et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-89.

2. UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment

and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-53

3. Hayward RA, Reaven PD, Wiitala WL, et al; VADT Investigators. Follow-up of glycemic control and cardiovascular

outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197-206.

28


Please remind the attendees about Susan’s current A1C and the CV protection medications

that she’s on. Please poll the attendees to find out how many would keep Susan on her

metformin + DPP-4i FDC.

29


EXAMINE, SAVOR-TIMI 53 and TECOS are three DPP-4 inhibitor CV safety trials that have

been reported on.

This slide summarizes the A1C and CV inclusion criteria, study arms, follow-up duration,

primary end point investigated and primary end point HR for all three trials.

References:

1. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in

patients with type 2 diabetes. N Engl J Med. 2013;369:1327-35.

2. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in

patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-26.

3. Green JB, Bethel MA, Armstrong PW, et al. TECOS Study Group. Effect of Sitagliptin on

Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373:232-42.

30


Please poll the attendees on how many would replace Susan’s DPP-4i with a GLP-1

receptor agonist.

31


The 52-week study (26 weeks + 26 weeks extension) compared the efficacy and safety of

the GLP-1 receptor agonist liraglutide (QD) with the DPP-4 inhibitor sitagliptin as add-ons to

metformin in individuals with type 2 diabetes.

Both liraglutide and sitagliptin were effective at producing sustained decreases in A1C and

weight over the 52-week observation period. Both doses of liraglutide, however, were

associated with greater sustained A1C and weight benefits relative to sitagliptin.

Reference:

1. Pratley R, Nauck M, Bailey T et al. One year of liraglutide treatment offers sustained and

more effective glycaemic control and weight reduction compared with sitagliptin, both in

combination with metformin, in patients with type 2 diabetes: a randomised, parallel-

group, open-label trial. Int J Clin Pract. 2011;65:397-407.

32


LEADER was a Phase III study investigating the safety of liraglutide vs. placebo in patients

with type 2 diabetes mellitus, an A1C ≥ 7.0%, and at high CV risk. 9,340 participants were

randomized to placebo or liraglutide (1.8 mg QD or maximum tolerated dose) and followed

for a median of 3.8 years.

The primary outcome (a composite of death from CV causes, non-fatal MI and non-fatal

stroke) occurred in a significantly lower percentage of patients in the liraglutide group than

in the placebo group (P = 0.01 for superiority). While liraglutide was associated with

significantly lower risk for CV mortality and all-causes mortality, there were no significant

between-group differences in the occurrence of non-fatal MI, non-fatal stroke and

hospitalization for HF.

Reference:

1. Marso SP et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New Engl J Med

2016;375:311-22.

33


This slide summarizes some of the safety end points of interest that were documented in

the LEADER trial.

The proportions of patients who had adverse events and serious adverse events were

similar in the two study arms, while adverse events leading to permament discontinuation

of the trial regiment were more common in the liraglutide arm than the placebo arm (9.5%

vs. 7.3%, P <0.001). Severe hypoglycemia, acute gallstone disease, and severe injection-site

reactions were reported in a higher percentage of patients in the liraglutide arm than the

placebo arm. The proportions of patients with confirmed hypoglycemia, pancreatitis,

neoplasm, pancreatic carcinoma and medullary thyroid carcinoma were similar in the two

study groups.

Reference:

1. Marso SP et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New Engl J Med

2016;375:311-22.

34


This slide summarizes the A1C and CV inclusion criteria, study arms, follow-up duration, primary end point investigated and primary end point HR for all six incretin-based CV safety trials.

References:

1. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in

patients with type 2 diabetes. N Engl J Med. 2013;369:1327-35.

2. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in

patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-26.

3. Green JB, Bethel MA, Armstrong PW, et al. TECOS Study Group. Effect of Sitagliptin on

Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373:232-42.

4.Bentley-Lewis R, Aguilar D, Riddle MC et al. Rationale, design, and baseline characteristics

in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end

point trial of lixisenatide versus placebo. Am Heart J. 2015;169:631-638.

5. Pfeffer MA et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary

Syndrome. N Engl J Med. 2015;373:2247-57.

6. Marso SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J

Med. 2016;375:311-22.

7. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J

Med. 2016;375:1834-44.

35


Please poll the attendees on how many would replace the DPP-4i with an SGLT2 inhibitor.

36


This slide summarizes three non-head-to-head studies that compared the efficacy and

safety of a DPP-4 inhibitor with an SGLT2 inhibitor in individuals with type 2 diabetes

inadequately controlled with metformin monotherapy. Addition of either DPP-4 inhibitor or

an SGLT2 inhibitor to background metformin improved glycemic control. Additionally,

SGLT2 inhibitors were associated with greater weight losses and generally greater incidence

of hypoglycemia.

References:

1. Lavalle-González FJ, Januszewicz A, Davidson J et al. Efficacy and safety of canagliflozin

compared with placebo and sitagliptin in patients with type 2 diabetes on background

metformin monotherapy: a randomised trial. Diabetologia. 2013 Dec;56(12):2582-92.

2. Rosenstock J, Hansen L, Zee P et al. Dual add-on therapy in type 2 diabetes poorly

controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin

plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to

metformin. Diabetes Care. 2015;38:376-83.

3. DeFronzo RA, Lewin A, Patel S et al. Combination of empagliflozin and linagliptin as

second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin.

Diabetes Care. 2015;38:384-93.

37


EMPA-REG OUTCOME was a Phase III study investigating the safety of empagliflozin vs.

placebo in patients with type 2 diabetes mellitus, an A1C ≥ 7.0% and ≤ 10.0% for patients

on background therapy or an A1C ≥ 7.0% and ≤ 9.0% for drug-naive patients, and at high CV

risk. 7,020 participants were randomized to placebo or empagliflozin (10 mg or 25 mg QD)

and followed for a median of 3.1 years.

The primary outcome (3-point MACE) occurred in a significantly lower percentage of

patients in the empagliflozin group than in the placebo group (P = 0.04 for superiority). The

key secondary outcome (4-point MACE) occurred in 12.8% of the empagliflozin group and

14.3% of the placebo group (P = 0.08 for superiority). While empagliflozin was associated

with significantly lower risk for CV mortality, there were no significant between-group

differences in the occurrence of non-fatal MI, non-fatal stroke and hospitalization for UA.

Reference:

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and

Mortality in Type 2 Diabetes. N Engl J Med. 2015;373:2117-28.

38


EMPA-REG OUTCOME was a Phase III study investigating the safety of empagliflozin vs.

placebo in patients with type 2 diabetes mellitus, an A1C ≥ 7.0% and ≤ 10.0% for patients

on background therapy or an A1C ≥ 7.0% and ≤ 9.0% for drug-naive patients, and at high CV

risk. 7,020 participants were randomized to placebo or empagliflozin (10 mg or 25 mg QD)

and followed for a median of 3.1 years.

This slide summarizes the incidence rates, hazard ratios and absolute risk reductions for CV

outcomes with empagliflozin vs placebo.

Reference:



39


This slide summarizes some of the safety end points of interest that were documented in

the EMPA-REG OUTCOME trial.

The proportions of patients who had adverse events, serious adverse events, and adverse

events leading to the discontinuation of a study drug were similar in the two study arms.

Genital infection was reported in a higher percentage of patients in the pooled

empagliflozin group. The proportions of patients with confirmed hypoglycemic adverse

events, diabetic ketoacidosis, bone fracture, and events consistent with volume depletion

were similar in the two study groups.

Reference:



40


This slide summarizes the A1C and CV inclusion criteria, study arms, follow-up duration, primary end point investigated and primary end point HR for the EXAMINE, SAVOR, TECOS, ELIXA, LEADER, SUSTAIN-6 and EMPA-REG CV safety trials.

References:

1. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-35.2. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-26. 3. Green JB, Bethel MA, Armstrong PW, et al. TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373:232-42.4.Bentley-Lewis R, Aguilar D, Riddle MC et al. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J. 2015;169:631-638.5. Pfeffer MA et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373:2247-57.


Med. 2016;375:311-22.


Med. 2016;375:1834-44.

8. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and


41


Please poll the attendees on how many would consider adding an SGLT2 inhibitor on top of

the metformin-DPP-4i FDC, i.e. triple therapy.

42


This slide shows the data from four studies that evaluated the glycemic and safety outcomes associated with adding an SGLT2 inhibitor to metformin + a DPP-4 inhibitor in individuals with inadequately controlled type 2 diabetes. Compared to dual therapy with metformin + DPP-inhibitor, triple therapy resulted in significantly reduced A1C and weight.

Please note that triple therapy combining metformin with a DPP-4 inhibitor and an SGLT2 inhibitor is not currently approved in Canada.

References:

1. Jabbour SA, Hardy E, Sugg J et al. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37:740-50.2. Mathieu C, Ranetti AE, Li D, Ekholm E et al. Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes. Diabetes Care. 2015;38:2009-2017.3. Rodbard HW et al. Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin. Diab Obes Metab

2016;18:812-9.4. Søfteland E et al. Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately controlled with linagliptin and metformin: a 24-week randomized, double-blind, parallel-group trial. Diabetes Care 2016; [Epub ahead of print].

43


A few more years have passed and Susan has been diagnosed with congestive heart failure.

Please review Susan’s current clinical profile.

44


Diabetes is a risk factor for a multitude of chronic diseases, e.g. hypertension and atherothrombosis. The diabetic milieu tends to be permissive toward a dysregulatedmolecular and cellular environment that eventually translates to morphological and physiological changes with ensuing pathological outcomes.

Diabetes itself increases the risk of developing heart failure 2.5-fold. It also promotes the advancement of atherosclerosis and elevates the risk of hospitalization for heart failure by approximately 30%. Heart failure-associated mortality in those with diabetes is approximately double that of those without diabetes. A1C increases have been directly associated with elevations in risk of heart failure.

References:

1. Gilbert RE & Krum RE. Heart failure in diabetes: effects of anti-hyperglycaemic drug

therapy. Lancet. 2015;385:2107-17

2. Udell JA, Cavender MA, Bhatt DL et al. Glucose-lowering drugs or strategies and

cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of

randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3:356–366.

3. McMurray JV, Gerstein HXC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular

outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol.

2014;2:843-51.

4. Iribarren C, Karter AJ, Go AS et al. Glycemic control and heart failure among adult

patients with diabetes. Circulation. 2001;103:2668-73.

45


This forest plot provides a summary of hospitalization for heart failure signals for the three reported large DPP-4 inhibitor cardiovascular safety trials. While EXAMINE, SAVOR-TIMI 53 and TECOS all found composite CV outcomes similar among those on treatment vs. placebo, there were some differences in the hospitalization for heart failure signals.

EXAMINE1,2

Due to concerns around increased hospitalizations due to heart failure observed with saxagliptin in the SAVOR-TIMI 53 trial, the EXAMINE investigators conducted a post hoc analysis to assess hospital admission for heart failure in the EXAMINE trial. The prespecified exploratory extended major adverse cardiac event (MACE) end point was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularization due to unstable angina, and hospital admission for heart failure. The exploratory extended MACE end point was seen in 433 (16.0%) of patients assigned to alogliptin and in 441 (16.5%) assigned to placebo (HR 0.98, 95% CI 0.86–1.12). This post hoc analysis indicated that alogliptin-treated individuals had numerically higher (but non-significant) rates of hospitalization for heart failure vs. placebo (85 [3.1%] vs. 79 [2·9%]; HR 1·07, 95% CI 0·79–1·46) despite comparable primary end point rates.

SAVOR-TIMI 533,4

Hospitalization for heart failure was a predefined component of the secondary end point. The primary analysis revealed that despite comparable primary end point rates, saxagliptin was associated with an unexpected 27% increased relative risk (and 0.7% absolute risk over 2 years) of hospitalization for heart failure. Following publication of the primary paper, the subsequent analysis reported that individuals with a history of previous heart failure, estimated glomerular filtration rate <60 mL/min, and an elevated level of N-terminal pro B-type natriuretic peptide appeared to be at greatest risk of hospitalization for heart failure. Notably, even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between the two treatment groups.

TECOS5,6

TECOS investigators found that there was no significant difference in the rate of hospitalization for heart failure (sitagliptin group: 3.1%; 1.07 per 100 person-years; placebo group: 3.1%; 1.09 per 100 person-years; hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98) for the two study arms. Subsequent analysis (and as yet unpublished data) revealed no statistically significant differences in the placebo and sitagliptin arms after adjustment for baseline heart failure history.

References:

1. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-35.

2. Zannad F, Cannon CP, Cushman WC et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in

EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-76.

3.Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-

26.

4. Scirica BM, Braunwald E, Raz I et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation.

2014;130:1579-88.

5. Green JB, Bethel MA, Armstrong PW, et al. TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med.

2015;373:232-42.

6. Armstrong PW, Van de Werf F. Trial Evaluating Cardiovascular Outcomes with Sitagliptin in patients with type-2 Diabetes: TECOS. European Society of

Cardiology 2015, August 29-September 2, 2015, London, United Kingdom.

46


This slide summarizes hospitalization for heart failure signals from the three reported large DPP-4

inhibitor cardiovascular safety trials stratified according to the absence or presence of a prior heart

failure history. It is important to note that the three DPP-4 inhibitor studies were conducted in different

study populations and that the EXAMINE numbers presented were derived from a post hoc analysis with

an expanded exploratory end point. Also, note that the y-axes for the three trials are different, i.e. % of

events vs 2-year Kaplan-Meier. Accordingly, the data shown should not be used for direct comparisons.

Generally, individuals with a prior heart failure history were more likely to experience heart failure-

related hospitalizations during the observation windows of EXAMINE, SAVOR-TIMI 53 and TECOS. Within

this sub-population of individuals with a prior heart failure history, the differences between

hospitalization rates for heart failure signals between the DPP-4 inhibitor arms and their respective

placebo arms were non-significant in all three studies.

In EXAMINE and TECOS, the differences in hospitalization rates for heart failure signals between the

DPP-4 inhibitor arms and their respective placebo arms were not statistically significant. In contrast, the

difference was statistically significant in SAVOR-TIMI 53.

References:

1. Zannad F, Cannon CP, Cushman WC et al. Heart failure and mortality outcomes in patients with type 2

diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.

Lancet. 2015;385:2067-76.

2. Scirica BM, Braunwald E, Raz I et al. Heart failure, saxagliptin, and diabetes mellitus: observations

from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579-88.

3. Armstrong PW, Van de Werf F. Trial Evaluating Cardiovascular Outcomes with Sitagliptin in patients

with type-2 Diabetes: TECOS. European Society of Cardiology 2015, August 29-September 2, 2015,

London, United Kingdom.

47


This slide provides some of the potential reasons underlying the differential hospitalization rates for heart failure signals in the three DPP-4 inhibitor CV safety trials.

48


The Kaplan-Meier curves generated from the ELIXA data demonstrate no significant

differences in the rates of hospitalization for heart failure between the placebo and

lixisenatide study arms.

References:

1. Pfeffer MA et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary

Syndrome. N Engl J Med. 2015;373:2247-57.


Med. 2016;375:311-22.


Med. 2016;375:1834-44.

49


Compared with placebo, empagliflozin therapy resulted in a significantly lower risk of

hospitalization for heart failure (HR, 0.65; 95% CI, 0.50-0.85; P=0.002).

Reference:

1. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and


50


Susan is now almost 70. Please review Susan’s current clinical profile.

52


Given Susan’s current clinical (renal) profile, please poll the attendees on how many would

consider adjusting Susan’s diabetes treatment.

53


Individuals with T2DM are at high risk of developing chronic kidney disease.

References:

1. Canadian Institute for Health Information. Canadian Organ Replacement Register Annual

Report: Treatment of End-Stage Organ Failure in Canada, 2003 to 2012.Ottawa, ON: CIHI;

2014.

2. https://www.kidney.org/atoz/content/diabetes

54


Renal impairment becomes more prevalent with increasing age. Individuals with diabetes

are more likely to have diminished renal function compared with age-matched individuals

without diabetes.

References:

1. Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use and prevalence of chronic kidney

disease among patients with type 2 diabetes mellitus in the United States. Clin Ther.

2009;31:2608-17.

2. Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance

System—United States. Web site. http://nccd.cdc.gov/CKD. Accessed July 1, 2014.

55

This program was supported in part by an educational grant from Merck Canada Inc.

facilitator guide · diabetes. this slide lists some of the patient and agent characteristics that...

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