1. CV safety & Outcome trials of Oral Antidiabetics

2. Adverse CV events led the FDA to require demonstration of CV safety for new glucose-lowering drugs
1961
UGDP study: tolbutamide discontinued due to increased CV mortality vs other treatment groups1
Sponsor withdrew application1
2005
Muraglitazar found to potentially increase CV risk during FDA assessment2
Withdrawn in the EU1
Use restricted in US1*
2007
Rosiglitazone associated with increased risk for MI and CV-related death3
2008
ACCORD study: intensive glucose lowering was associated with increased all-cause mortality4
HR 1.22 (95% CI: 1.01‒1.46); p = 0.04
*In 2013, FDA panel voted to reduce safety restrictions on rosiglitazone7
Notes
Beginning with the UGDP study in the 1960s, there have been several safety signals that have caused concern over the CV safety of glucose-lowering therapies.
The evidence is inconclusive in most cases and therefore the FDA formulated guidance around the need to prove the CV safety of all new glucose-lowering agents for T2D.
Abbreviations
ACCORD, Action to Control Cardiovascular Risk in Diabetes; CI, confidence interval; CV, cardiovascular; CVOT, Cardiovascular outcomes trial; EMA, European Medicines Agency; FDA, Food and Drug Administration; HR, hazard ratio; MI, myocardial infarction; T2D, Type 2 Diabetes; UGDP, University Group Diabetes Program.
References
5. FDA Guidance for Industry. guidancecomplianceregulatoryinformation/ guidances/ucm pdf. Accessed March 2015.
6. EMA Guidelines. docs/en_GB/ document_library /Scientific_guideline/2012/06/WC pdf. Accessed March 2015.
7. FDA Safety Information. medium= &utm_source=govdelivery. Accessed March 2015.
2008
New FDA requirements5
New EMA requirements6
New diabetes drugs should demonstrate CV safety with meta-analysis and a CVOT
2012 2
1. Nissen. Ann Intern Med 2012;157:671–2. 2. Nissen et al. JAMA 2005;294:2581–6. 3. Nissen et al. N Engl J Med 2007;356:2457– ACCORD Study Group. N Engl J Med 2008;358:2545– FDA Guidance for Industry. 6. EMA Guidelines. 7. FDA Safety Information.

3. Regulatory requirements for drug-specific CV outcome data in T2DM
FDA 2008 Guidance for Industry1
‘To establish the safety of a new anti-diabetes drug to treat T2D, sponsors should demonstrate that the therapy will not result in an unacceptable increase in CV risk.’
Important CV events should be analysed
High-risk population to be included
Long-term data required (≥ 2 years)
Prospective adjudication of CV events by an independent committee
Phase II and III trials designed and conducted to permit meta-analysis to be performed at completion
EMA 2012 Guideline2
‘A fully powered CV safety assessment, e.g., based on a dedicated CV outcome study, should be submitted before marketing authorisation whenever a safety concern is intrinsic in the molecule/MOA or has emerged from pre-clinical/clinical registration studies.’
Two approaches are recommended:
Meta-analysis of safety events
Specific long-term controlled outcome study with at least 18–24 months’ follow-up
Notes
Both the FDA and EMA guidance recommend that specific long-term data on CV outcomes be gathered for every glucose-lowering agent for use in T2D.
Abbreviations
CV, cardiovascular; EMA, European Medicines Agency; FDA, Food and Drug Administration; MOA, mechanism of action; T2D, Type 2 diabetes. 1. 2.

4. RR of incidence of CV events with investigational agent vs control
FDA guidance for CV outcome data: meta-analysis limits and outcome trial requirements
Upper bound of 2-sided 95% CI
Post-marketing CV trial(s) generally not necessary if < 1.3
If overall risk–benefit analysis supports approval, post-marketing CV trial(s) needed to prove < 1.3
Inadequate data to support approval
0.5
Notes
According to the FDA guidance, the sponsor should plan for early integration of proper CV event handling with independent adjudication in the clinical development program (phase II and III trials).
All events occurring in the program should be analysed (meta-analysis) to rule out an increase in CV risk greater than 1.8-fold, which is the requirement at time of submission/pre-approval.
This should typically be followed post-approval by a dedicated CVOT to rule out an increase in CV risk > 1.3-fold.
If premarketing clinical data show that the upper bound of the two-sided 95% CI for the estimated RR is < 1.3, and the overall risk-benefit analysis supports approval, a post-marketing CV trial generally may not be necessary.
Abbreviations
CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; RR, risk ratio.
Reference
FDA 2008 Guidance for Industry:
1.0
1.3
1.8
2.0
RR of incidence of CV events with investigational agent vs control
s/ucm pdf.

5. Evolution of T2D agents
DPP4 inhibitors
SGLT2 inhibitors
 Older T2D agents
Newer T2D agents 
1950
1960
1970
1980
1990
2000
2010
2012
2013
GLP1 receptor agonists
Lente class of insulins produced
Recombinant human insulin produced
Glimepiride: 3rd generation SU
Insulin degludec
SUs first used
2nd generation SUs available
Not sure why Lantus reference?
Notes
Metformin was one of the earliest oral therapies introduced for T2D (in 1958 for the UK, in 1995 for the US).
The timings of DPP4i and GLP-1 agonists are adapted slightly from the paper, as in fact, they emerged at roughly the same time (e.g. saxagliptin approved in 2009; liraglutide approved 2009):
Abbreviations
DPP4, dipeptidyl peptidase-4; GLP, glucagon-like peptide; SGLT, sodium glucose cotransporter; SU, sulphonylurea; TZD, thiazolidinedione; T2D, Type 2 diabetes.
Reference
Lantus® Summary of Product Characteristics:
Insulin glargine available2
Metformin introduced
Metformin introduced in the UK
Three new classes introduced: -glucosidase inhibitors, meglitinides and TZDs
Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315– Lantus® SPC.

6. Metformin
Metformin is indicated for the treatment of T2D, and generally recommended as first-line therapy1,2
Evidence for effect on CV risk cited in international prescribing information differs for US vs EU
US prescribing information3
States that there are no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin (or any other anti-diabetes drug)
EU prescribing information1
Cites UKPDS analysis from 342 overweight patients treated with metformin after failure of diet alone1
Metformin significantly reduced any diabetes-related complication, mortality and risk of MI vs diet alone after 10.7 years
Notes
Metformin is indicated for the treatment of T2D, when dietary management and exercise alone does not result in adequate glycaemic control1,2 and generally recommend as first line therapy2
In UKPDS 34, in overweight patients, metformin reduced the risk for any diabetes-related endpoint, diabetes-related death and all-cause mortality. However, when metformin was added to an SU in non-overweight and overweight patients there was an increased risk for diabetes-related deaths and all-cause mortality (these latter data are not mentioned in the metformin SPC, however).
During 10 years of post-trial follow-up, risk reduction for MI and death from any cause emerged with intensive vs conventional treatment.
Analysis of the results for overweight patients treated with metformin hydrochloride after failure of diet alone showed:
a significant reduction of the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/ 1000 patient-years) versus diet alone (43.3 events/ 1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/ 1000 patient-years), p=0.0034;
a significant reduction of the absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;
a significant reduction of the absolute risk of overall mortality: metformin hydrochloride 13.5 events/ 1000 patient-years versus diet alone 20.6 events/ 1000 patient –years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/ 1000 patient-years (p=0.021);
a significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride 11 events/ 1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)
Benefit regarding clinical outcome has not been shown for metformin hydrochloride used as second-line therapy, in combination with a sulfonylurea.
Abbreviations
CV, cardiovascular; FPG, fasting plasma glucose; MI, myocardial infarction; SU, sulphonylurea; UKPDS, United Kingdom Prospective Diabetes Study.
American Diabetes Association. Diabetes Care 2015;38(suppl. 1):S1–S

7. Significant reduction in MI maintained over 10 years’ follow-up3
UKPDS 34 provides some evidence for beneficial CV effects of metformin in overweight patients
Risk of MI is 39% lower with metformin vs conventional therapy in obese patients1,2
Significant reduction in MI maintained over 10 years’ follow-up3
Myocardial infarction
Metformin vs conventional p = 0.01
Time from randomisation (years) 3 6 9 12 15
0.0 10 20 30
Proportion of patients with events (%)
Intensive (n = 951; events = 139)
Conventional (n = 411; events = 73)
Metformin (n = 342; events = 89)
1.4
1.2
1.0
0.8
0.6
0.4
HR (95% CI)
RR 0.611
p = 0.01
RR 0.67
p = 0.005
Overall values at study end in 1997
Annual values during 10-year post-trial monitoring period
Added refs to match citations. Pls check
Notes
UKPDS provides evidence for the beneficial CV effects of metformin.
In UKPDS 34, the metformin group had a 39% lower risk of MI than the conventional treatment group (p = 0.01).1
The significant reduction in MI risk was maintained over 10 years,2 as shown in the right-hand figure where all the upper CI limits are below the HR = 1.0 line.
Metformin added to SU vs SU alone was associated with increased risk of diabetes-related death (RR of 1.96, p=0.039) and all-cause mortality (RR of 1.60 p=0.041).1
Abbreviations
CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; RR, relative risk (in original study1); risk ratio (in follow-up study2); SU, sulphonylurea; UKPDS, United Kingdom Prospective Diabetes Study.
References
Metformin 500 mg tablets. Summary of Product Characteristics. Aurobindo Pharma Milpharm Ltd. Available at: Accessed 26 Jun 2015
1997
1999
2001
2003
2005
2007
No. of events:
Conventional therapy 73 83 92
106
118
126
Metformin 39 45 55 64 68 81
1. UKPDS 34. Lancet 1998;352:854– Holman et al. N Engl J Med 2008;359:1577–89.

8. UKPDS 34: CV effects of metformin added to SU
Metformin added to SU vs SU alone was associated with increased risk of diabetes-related death and all-cause mortality
Relative risk (95% CI)
Median follow up 6.6 years RR
p-value
Any diabetes related endpoint
1.04
0.78
Diabetes-related deaths*
1.96
0.039
All-cause mortality*
1.60
0.041
Myocardial infarction*
1.09
0.73
Stroke*
1.21
0.61
Microvascular*
0.84
0.62
Notes
In UKPDS 34, in overweight patients, metformin reduced the risk for any diabetes-related endpoint, diabetes-related death and all-cause mortality.
537 non-overweight and overweight patients who were treated with maximum doses of sulphonylurea, and had FPG of 6.1–15.0 mmol/L without symptoms of hyperglycaemia, were randomly assigned in equal proportions early addition of metformin to the sulphonylurea (n=269) or continued sulphonylurea alone (n=268).
When metformin was added to an SU in these patients there was an 96% increased risk for diabetes-related deaths and 60% increased risk for all-cause mortality.
SU-treated patients were on average 5 years older; more hyperglycaemic (baseline median FPG 9·1 vs 8·1 mmol/L); less overweight; and followed up on average for 5 years less
Authors concluded that the addition of metformin in patients already treated with SUs required further study.
Abbreviations
CI, confidence interval; CV, cardiovascular; FPG, fasting plasma glucose; MI, myocardial infarction; RR, relative risk; SU, sulphonylurea; UKPDS, United Kingdom Prospective Diabetes Study.
1.0
Favours added metformin
Favours SU alone
CV safety of Metformin remains questionable
*Interpret with caution in view of small event numbers. UKPDS 34. Lancet 1998;352:854–65.

9. Sulfonylureas Meta-analysis of SU CV safety trials (≥ 6 months) found no consistent association with MACE risk
0.01
0.1 1 10
100
Favours SUs
Favours comparators
MH-OR (95% CI)
First author (year)
Birkeland 1996
Chou 2008
Perriello 2006
Gerstein 2010
UKPDS
Hanefeld 2007
Seino 2010
Charbonnel 2005
Matthews 2005
Rubin 2008
Home 2009
Arechavaleta 2011
va der Laar 2004
Mazzone 2006
Riddle 1998
Giles 2010
Tolman 2009
Kahn 2006
Goke 2010
Garber 2009
Nissen 2008
Ristic 2007
Ferrannini 2009
Bakris 2006
Gallwitz 2012
Jain 2006
Johnston 1998
Nauck 2011
Seck 2010
Overall
Total # patients*
Total # events* 36 1
452 3
283 9
672 55
3041
610
587 4
400
630 14
1250 15
1805 46
2222
312
1035 96 2
458
145
300 26
2097 61
4351 72
858 13
495
543 24
262 5
2789 34
374 11
1551 38
502
272
801
1172
29,783
1495
Notes
A meta-analysis was conducted of trials of duration ≥ 6 months that compared an SU with a non-SU agent in patients with T2D.
MH-ORs were calculated for MACE.
There was variability among trials, but overall the risk of MACE was not increased in patients treated with SUs vs other agents (p = 0.52).
However, the authors concluded that the CV safety of SUs cannot be considered established unless evaluated in long-term CVOTs.
Abbreviations
CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial;
MACE, major adverse cardiovascular events; MH-OR, Mantel-Haenszel odds ratio; SU, sulphonylurea; T2D, Type 2 Diabetes.
Overall MACE risk estimate for SU vs comparators was not increased: MH-OR 1.08 (95% CI: 0.86–1.36); p = 0.52
*SU + comparator groups combined.
Monami et al. Diabetes Obes Metab 2013;15:938–53.

10. CV safety of SUs
The UGDP study raised safety concerns with tolbutamide (excess of cardiac deaths vs placebo)1
UKPDS 33 demonstrated no deleterious effect of SUs on CV safety compared with insulin or conventional management2
In a meta-analysis of 115 trials, overall MACE risk estimate for SUs vs comparators was not increased (OR 1.08)3
Abbreviations
CV, cardiovascular; CVOT, cardiovascular outcomes trial; MACE, major adverse cardiovascular events; OR, odds ratio; SU, sulphonylurea; UGDP, University Group Diabetes Program; UKPDS, UK Prospective Diabetes Study.
‘CV safety of SUs cannot be considered established unless evaluated in long-term CVOTs’4
1. Meinert et al. Diabetes 1970;19(suppl):789– UGDP. Diabetes 1970;19(suppl 2):747– UKPDS Group. Lancet 1998;352:837– Monami et al. Diabetes Obes Metab 2013;15:938–53.

11. Thiazolidinediones In 2007, separate meta-analyses suggested differing CV effects of drugs within the TZD class
Rosiglitazone meta-analysis1
1.0
2.0
Favours rosiglitazone
Favours control
MI OR 1.43 (95% CI: 1.03‒1.98) p = 0.03
CV death OR 1.64 (95% CI: 0.98‒2.74) p = 0.06
Pioglitazone meta-analysis2
1.0
2.0
Favours pioglitazone
Favours control
MI HR 0.81 (95% CI: 0.64‒1.02) p = 0.08
Death HR 0.92 (95% CI: 0.76‒1.11) p = 0.38
Notes
Examination of similar endpoints within two separate meta-analyses for rosiglitazone and pioglitazone (compared with placebo or active comparator) suggests differing CV effects of the 2 agents, despite being of the same class.
Compared with controls, rosiglitazone was associated with a significantly increased risk of MI and an increased risk of CV-related death that was of borderline significance.1
By contrast, there was a tendency for fewer incidences of MI (HR 0.81) or death (HR 0.92) with pioglitazone:
Pioglitazone was also associated with a significantly lower risk of death, MI or stroke (the composite primary endpoint; HR 0.82; 95% CI: 0.72–0.94; p = 0.005), but a significantly increased risk of serious HF (HR 1.41; 95% CI: 1.14–1.76; p = 0.002).2
Rosiglitazone meta-analysis
Included 42 trials (inclusion criteria were study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for MI and death from CV causes).
Pioglitazone meta-analysis
Included 19 trials (inclusion criteria were that studies be randomized, double-blinded, and controlled with placebo or active comparator).
The primary objective of most of the trials was to determine the efficacy of pioglitazone (with or vs insulin, metformin, SUs or rosiglitazone) in improving glycaemic control.
Six trials had other primary endpoints: hepatic toxicity (OPI-506 study), triglyceride levels (GLAI study), changes in carotid intima-medial thickness (CHICAGO trial), CV outcomes among patients with established vascular disease (PROactive), walking distance among patients with mild cardiac disease (OPI-520 study), or heart failure progression among patients with advanced CHF (OPI-504).
Of the total 16,390 patients included in the meta-analysis; PROactive was the largest single trial (n = 5,238).
Abbreviations
CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; OR, odds ratio.
References
1. Nissen & Wolski. N Engl J Med 2007;356:2457– Lincoff et al. JAMA 2007;298:1180–8.
No clinical trial directly compares the CV effects of pioglitazone and rosiglitazone
1. Nissen & Wolski. N Engl J Med 2007;356:2457– Lincoff et al. JAMA 2007;298:1180–8.

12. CV safety of TZDs
TZDs cause or exacerbate congestive heart failure in some patients1
CV meta-analyses in 2007 suggested differing effects on CV outcomes
Pioglitazone was associated with a significant 16% reduction in 3P-MACE (as a secondary endpoint) vs placebo in PROactive2
Rosiglitazone open-label RECORD data showed no increase in CV death1
FDA reduced the safety restrictions on rosiglitazone imposed following 2007 meta-analysis3 but controversy over CV safety remains
Notes
Whereas Rosenson et al. maintained that there is no class effect within the PPAR family, the available data are not strong enough to exclude a class effect for TZDs. TZDs have a consistent effect on HF and bone fracture.1
Abbreviations
CV, cardiovascular; FDA, Food and Drug Administration; PPAR, peroxisome proliferator-activated receptor; PROactive, PROspective pioglitAzone Clinical Trial in macroVascular Events; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Re
References
1. Rosenson et al. Am Heart J. 2012;164:672–80.
‘Within the PPAR family, there is no “class effect” and each agent must be considered unique. The FDA has mandated that each agent within this class be evaluated individually in a variety of ways including clinical outcome studies’4
1. AVANDIA US Prescribing information. 2. Dormandy et al. Lancet 2005;366:1279– FDA Safety Information. 4. Rosenson et al. Am Heart J. 2012;164:672–80.

13. CVOTs (Placebo-controlled) trials 3 Possible results
CV outcome trials PRIMARY ENDPOINT
3P-MACE: CV death, nonfatal MI, nonfatal stroke
4P-MACE: CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalisation
CV PROTECTION
Superiority to placebo
CV SAFETY
Non-inferiority to placebo +
In CV outcome trials with new antidiabetic drugs, the study drug is compared vs placebo, on the top of standard of care therapy in each treatment arm. The CV outcome is evaluated based on 3-4 cardiac endpoints, like CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalization. There can be three outcomes. 1) CV protection, if drug shows superiority to placebo. 2) CV safety: it shows non-inferiority to placebo. 3) Increase CV risk: it is inferior to placebo.
INCREASES CV RISK
Inferiority to placebo -
All patients receive standard-of-care treatment in addition to the study drug or placebo
MACE: major adverse cardiac events

14. Ongoing CVOTs Ongoing CVOTs GLP1 agonists SGLT2 inhibitors
DPP4 inhibitors
Notes
This slide provides a visual summary of this module.
Abbreviations
CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

15. CV safety trials within the newer classes
CANVAS-R8
(n = 5700)
Albuminuria
2013
2014
2015
2016
2017
2018
2019
SAVOR-TIMI 531
(n = 16,492)
1,222 3P-MACE
EXAMINE2
(n = 5380)
621 3P-MACE
TECOS4
(n = 14,724)
≥ P-MACE
LEADER6
(n = 9340) ≥ 611 3P-MACE
SUSTAIN-67
(n = 3297)
3P-MACE
DECLARE-TIMI 5815
(n = 17,150)
≥ P-MACE
EMPA-REG OUTCOME™5
(n = 7034)
≥ 691 3P-MACE
CANVAS10
(n = 4365)
≥ 420 3P-MACE
CREDENCE17
(n = 3700)
Renal + 5P-MACE
CAROLINA®11
(n = 6000)
≥ 631 4P-MACE
ITCA CVOT9
(n = 4000)
4P-MACE
EXSCEL14
(n = 14,000)
≥ P-MACE
DPP4 inhibitor CVOTs
SGLT2 inhibitor CVOTs
GLP1 CVOTs
Ertugliflozin CVOT18
(n = 3900)
OMNEON13
CARMELINA12
(n = 8300)
4P-MACE + renal
REWIND16
(n = 9622)
≥ P-MACE
2021
ELIXA3
(n = 6068)
≥ 844 4P-MACE
Notes
This overview indicates all of the ongoing and completed CVOTs for the newer T2D agents.
The trial name, the estimated recruitment and the primary outcome are indicated
The timings indicate the estimated completion dates of the trial
Planned or actual event rates are indicated in some cases (e.g. EXAMINE, ELIXA etc)
Abbreviations
CANVAS, Canagliflozin Cardiovascular Assessment Study
CANVAS-R, Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM
CARMELINA®, Cardiovascular Safety & Renal Microvascular Outcome Study with Linagliptin
CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes
CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy
CVOT, cardiovascular outcomes trial
DPP4, dipeptidyl peptidase 4
DECLARE-TIMI, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events
ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome
EMPA-REG OUTCOME™ [cardiovascular outcomes trial of empagliflozin: EMPA-REG OUTCOME™ is full title]
EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus usual care
EXSCEL, The EXenatide Study of Cardiovascular Event Lowering
GLP1, glucagon-like peptide 1
LEADER®, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
OMNEON™ [randomised, double-blind, placebo-controlled, multicenter study to assess cardiovascular outcomes following treatment OMNEON™ is full title]
REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes
SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction
SGLT2, sodium glucose cotransporter 2
SUSTAIN, Trial to Evaluate Cardiovascular and Other Longterm Outcomes With Semaglutide in Subjects With Type 2 Diabetes
T2D, Type 2 diabetes
TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin
3P-MACE, 3-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction or non-fatal stroke)
4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation)
References
1. Scirica et al. N Engl J Med 2013;369:1317–26.
2. White et al. N Engl J Med 2013;369:1327–35
3. Bentley-Lewis et al. Am Heart J 2015;0:1–8.e7.
4. Bethel et al. Diabetes Obes Metab 2015;17:1395–402
5. Zinman et al. Cardiovasc Diabetol 2014;13:102
6. NCT
7. NCT
8. NCT
9. NCT
10. NCT
11. NCT
12. NCT
13. NCT
14. NCT
15. NCT
16. NCT
17. NCT
18. NCT
Timings represent estimated completion dates as per ClinicalTrials.gov
Adapted from Johansen. World J Diabetes 2015

16. Ongoing CVOTs GLP1 agonists DPP4 inhibitors SGLT2 inhibitors Notes
This slide provides a visual summary of this module.
Abbreviations
CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

17. CV outcomes trials with GLP1 agonists
ELIXA1,2
LEADER®3
SUSTAIN-6™4
EXSCEL5
REWIND6
Intervention
Lixisenatide/ placebo
Liraglutide/ placebo
Semaglutide/ placebo
Exenatide ER*/ placebo
Dulaglutide/ placebo
Main inclusion criteria
History of acute coronary syndrome
Vascular disease, or risk factors, or CRF, or CHF
Evidence of CV disease
No CV criteria specified
Pre-existing vascular disease or ≥2 CV risk factors
No. of patients
6068
9340
3297
14,000
9622
Primary outcome
4P-MACE
3P-MACE
Key secondary outcome (s)
Expanded MACE
All-cause mortality; HHF
Microvascular composite
Target no. of events
844
> 611
Not specified
Estimated follow-up
2.1 years median
Up to ~5 years
Up to ~3 years
Up to ~7.5 years
Up to ~6.5 years
Estimated completion
Completed
(Safety proved)
Nov 2015
Jan 2016
Apr 2018
Apr 2019
Notes
This table provides a summary of the key features of the ongoing CVOTs of GLP1 agonists.
ELIXA: expanded MACE secondary endpoints examined are 4P-MACE + HHF and 4P-MACE + HHF + coronary revascularisation procedure.
LEADER: expanded MACE secondary endpoint examined is 3P-MACE + revascularisation + hospitalisation for unstable angina + hospitalisation for chronic heart failure.
SUSTAIN: the details of the expanded MACE to be performed as a secondary endpoint are not provided.
REWIND: a key secondary endpoint was a composite of diabetic retinopathy requiring laser therapy, vitrectomy or anti-vascular endothelial growth factor therapy (VEGF), clinical proteinuria, a 30% decline in estimated glomerular filtration rate, or need for chronic renal replacement therapy.
Abbreviations
CHF, chronic heart failure; CRF, chronic renal failure; CV, cardiovascular; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; ER, extended release; EXSCEL, The EXenatide Study of Cardiovascular Event Lowering; GLP1, glucagon-like peptide 1; HHF, hospitalisation for heart failure; LEADER®, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation; MACE, major cardiovascular events; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SUSTAIN, Study of Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration.
References
1. Accessed March 2015.
2. Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7. Accessed June 2015.
3. Marso SP et al. Am Heart J 2013;166:823–30.e5. Accessed March 2015.
4. Accessed March Accessed March 2015.
6. Accessed March 2015.
*Once weekly. 1. NCT Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7. 3. Marso et al. Am Heart J 2013;166:823–30.e NCT NCT NCT
I deleted comma after ‘vitrectomy’; can you check this hasn’t changed sense.
I also added ER, extended release to the Abbs list; please check this is correct.
AND, swapped the order of Bentely and Marso to match main slide; please confirm which is correct order.

18. Ongoing CVOTs GLP1 agonists DPP4 inhibitors SGLT2 inhibitors Notes
This slide provides a visual summary of this module.
Abbreviations
CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

19. CV outcome trials with SGLT2 inhibitors
EMPA-REG OUTCOME™1
CANVAS2
CANVAS-R3
CREDENCE4
DECLARE- TIMI 585
Ertugliflozin CVOT6
Interventions
Empagliflozin/ placebo
Canagliflozin/ placebo
Dapagliflozin/ placebo
Ertugliflozin/ placebo
Main inclusion criteria
Est. vascular complications
Est. vascular complications or ≥ 2 CV risk factors
Stage 2 or 3 CKD + macroalbuminuria
High risk for CV events
No. of patients
7034
4339
5700
3627
17,150
3900
Primary outcome
3P-MACE
Progression of albuminuria
ESKD, S-creatinine doubling, renal/CV death
Key secondary outcome
4P-MACE
Fasting insulin secretion, progression of albuminuria
Regression of albuminuria, change in eGFR
4P-MACE + HHF
4P-MACE + HHF + revascularisation
Target no. of events
691
≥ 420
TBD
1390
Estimated median FU
~3 years
6–7 years
3 years
~4 years
4–5 years
5–7 years
Estimated completion
2015
Apr 2017
2017
2019
2021
Notes
This table provides an overview of the ongoing CVOTs in SGLT2 inhibitors, including EMPA-REG OUTCOME™ with empagliflozin; CANVAS, CANVAS-R and CREDENCE with canagliflozin; DECLARE-TIMI 58 with dapagliflozin; and a CVOT on ertugliflozin.
All of these CVOTs take place in patients with established CVD or CV risk, and 3P-MACE is the primary outcome for most.
Abbreviations
BMI, body mass index; CANVAS, CANagliflozin cardioVascular Assessment Study; CANVAS-R, study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, NCT ; CHF, congestive heart failure; CKD, chronic kidney disease; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events; EASD, European Association for the Study of Diabetes; eGFR, estimated glomerular filtration rate; EMPA-REG OUTCOME™, cardiovascular outcomes trial of empagliflozin; ESKD, end-stage kidney disease; Est., established; FPI, first patient in; FU, follow-up; HbA1C, glycosylated haemoglobin; HHF, hospitalisation for heart failure; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; RRR, relative risk ratio; SGLT2, sodium glucose cotransporter; TBD, to be determined.
References
1. Zinman et al. Cardiovasc Diabetol 2014;13:102.
Accessed March 2015.
3. Accessed March 2015.
4. Accessed March 2015.
5. Accessed May 2015.
6. Accessed May 2015.
Results EASD 2015
Adapted from Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90‒100.

20. Ongoing CVOTs GLP1 agonists DPP4 inhibitors SGLT2 inhibitors Notes
This slide provides a visual summary of this module.
Abbreviations
CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

21. CV outcomes trials with DPP4 inhibitors
SAVOR-TIMI 531
EXAMINE2
TECOS3
CAROLINA®4
CARMELINA®5
Intervention
Saxagliptin/ placebo
Alogliptin/
placebo
Sitagliptin/ placebo
Linagliptin/
glimepiride
Linagliptin/ placebo
Main inclusion criteria
History of or multiple risk factors for CVD
ACS within 15–90 days before randomisation
CVD
≥ 2 specified traditional CV risk factors or manifest CVD
High risk of CV events (e.g. albuminuria, prior CVD)
No. of patients
16,492
5380
14,671
6041
8300
Primary outcome
3P-MACE
4P-MACE
Key secondary outcome
Expanded MACE
3P-MACE; renal composite
Target no. of events
10406
650
1300
631
6257
Estimated median follow-up (y)
2.1
1.5
3.0
6–7*
4*7
Estimated completion
Completed
20188
2018
Notes
This table provides a summary of the key features of the ongoing CVOTs of DPP4 inhibitors, and of those already completed (SAVOR-TIMI 53 and EXAMINE).
Links to study design slides (in backup) are provided for ease of reference.
SAVOR-TIMI 53: major secondary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, coronary revascularisation or heart failure.
CARMELINA®:
Inclusion: high risk of CV events is defined by: 1) albuminuria (micro or macro) and previous macrovascular disease and/or 2) impaired renal function with predefined UACR.
Secondary: composite renal endpoint is renal death, end stage renal disease and a sustained decrease of 50% or more in estimated glomerular filtration rate.
Abbreviations
ACS, acute coronary syndrome; CARMELINA®, Cardiovascular Safety & Renal Microvascular Outcome Study with Linagliptin; CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; HbA1c, glycosylated haemoglobin; HF, heart failure; MACE, major cardiovascular events; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UACR, urine albumin-to-creatinine ratio. 21
*Ongoing.
1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Marx et al. Diabetes Vasc Dis Res 2015;12:164– NCT Scirica et al. Am Heart J 2011;162:818–25.e Data on file (BI trial no trial protocol). 8. NCT

22. Number of events (event rate, % per 100 person-years)
For the primary outcome, all completed CVOTs fall within the FDA mandated upper 95% CI limit of 1.3
Number of events (event rate, % per 100 person-years)
Placebo
+ usual care
Comparator
DPP4 inhibitor trials
SAVOR-TIMI 531
609 (3.7%)
613 (3.7%)
FDA mandated upper 95% CI for CV safety
HR (95% CI)
EXAMINE2
316 (11.8%†)
305 (11.3%†) *
TECOS3
851 (4.17%)
839 (4.06%)
GLP1 agonist trials
ELIXA4
406 (13.4†%)
399 (13.2†%)
Notes
SAVOR-TIMI 53 – hazard ratio 1.00 (95% CI: 0.89, 1.12).
EXAMINE – HR 0.96 (upper boundary of 1-sided repeated CI: 1.16).
TECOS – HR 0.98 (95% CI: 0.89, 1.17).
ELIXA – HR 1.02 (95% CI: 0.89, 1.17).
Abbreviations
CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; FDA, US Food and Drug Administration; GLP1, glucagon-like peptide 1; HR, hazard ratio; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
0.6
0.8
1.0
1.3
2.0
Favours comparator
Favours placebo
*Upper boundary of 1-sided repeated CI.
†Total event rate, %.
1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

23. Hospitalisation for heart failure (HHF) data for all completed CVOTs
Number of events (event rate, %)
Placebo
+ usual care
Comparator
FDA mandated upper 95% CI for CV safety
HR (95% CI)
SAVOR-TIMI 53 (HHF)1
EXAMINE (HHF analysis 1)2
EXAMINE (HHF analysis 2)2
TECOS (HHF)3
TECOS (HHF + CV death)3
ELIXA (HHF)4
ELIXA (HHF + CV death)4
228 (2.8)
79 (2.9)
89 (3.3)
229 (3.1)
525 (7.2)
127 (4.2)
253 (8.3)
289 (3.5)
85 (3.1)
106 (3.9)
228 (3.1)
538 (7.3)
122 (4.0)
248 (8.2)
Notes
SAVOR-TIMI 53 – hazard ratio for HHF 1.27 (1.07, 1.51).
EXAMINE – Analysis 1 = Risk of HHF occurring as the first event in pre-specified exploratory extended MACE endpoint: HR 1.07 (0.79, 1.46).
EXAMINE – Analysis 2 = Risk of events assessed as component of post-hoc composite endpoint of CV death and HHF: HR 1.19 (0.90, 1.58).
TECOS – HHF: HR 1.00 (0.83, 1.20).
TECOS – HHF + CV death: HR 1.02 (0.90, 1.15).
ELIXA – HHF: HR 0.96 (0.75, 1.23).
ELIXA – HHF + CV death: HR 0.97 (0.82, 1.16).
Abbreviations
CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; FDA, US Food and Drug Administration; GLP1, glucagon-like peptide 1; HHF, hospitalisation for heart failure; HR, hazard ratio; MACE, major cardiovascular events; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
0.6
0.8
1.0
1.3
2.0
Favours comparator
Favours placebo
Analysis 1 = as component of expanded MACE.
Analysis 2 = as component of post-hoc composite of CV death and HHF.
1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

24. Gliptins - CVOTs SAVOR-TIMI 53 EXAMINE TECOS DPP4 inhibitor
Saxagliptin
Alogliptin
Sitagliptin
CV safety endpoint
Achieved
(non-inferior to placebo)
CV benefit endpoint
Not achieved
HHF*
Statistically significant increase in saxagliptin arm
Non-statistically significant increase in alogliptin arm
No increase in HHF sitagliptin arm vs placebo
*HHF : hospitalization for heart failure
Scirica BM et al. N Engl J Med 2013;369: White WB et al. N Engl J Med 2013;369: White WB. Zannad et al. Correspondence. NEJM. 370;5:

25. Linagliptin: No increased Cardiac risk
2015
Pooled analysis of 19 Linagliptin trials ~9400 patients
Arm
No. of patients
Incidence rate of
CV events*
(per 1000 patient years)
Hazard ratio
Linagliptin
5847
13.4
0.78
(95% CI: )
(Non-significant)
Comparator (Total)
Placebo
Glimepiride
Voglibose
3612
2675
775
162
18.9
*composite of CV death, non-fatal stroke, non-fatal myocardial infarction,
and hospitalization for unstable angina pectoris
Rosentock J et al. Cardiovascular Diabetology. 2015;14:57. doi: /s

26. Linagliptin: Data on HHF
Hospitalisation for heart failure (HHF)1
Hospitalisation for heart failure was added into the adjudication process after the initial regulatory submission and has been assessed for the available studies
Pooled-analysis with, adjudicated events
8 trials including 3314 patients
Combined comparator
Linagliptin
No of patients, n
1275
2039
No of pts with events, n (%)
9 (0.7)
12 (0.6)
Placebo*
Linagliptin
No of patients, n
1275
2039
No of pts with events, n (%)
5 (0.4)
9 (0.4)
Given the small number of reported cases of CHF, this data should be interpreted with caution
* The placebo-controlled dataset also includes 2,039 patients in the linagliptin group and 1,275 patients in the placebo group, as in one of the 8 studies all patients in the placebo group were switched to glimepiride. After switching to glimepiride, 5 patients on glimepiride and 3 patients on linagliptin were hospitalised for HF.
Rosentock J et al. Cardiovascular Diabetology. 2015;14:57. doi: /s

27. CAROLINA & CARMELINA: Linagliptin CV Safety studies
(CArdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes)
CARMELINA
(CArdiovascular Safety & Renal Microvascular outcomE study with LINAgliptin)

28. Questions unanswered even with the various CVOTs
Q1: Can we modify CV outcome by early intervention with gliptins in T2DM?
Q2: Which is an ideal drug of choice after metformin considering CV safety?
Will CAROLINA have the answer?

29. CAROLINA: Key Features
Will define an ideal choice after metformin considering CV safety: a DPP4i or SU? 1,2
Largest study vs. active comparator with patient profile closer to UKPDS3,4
CV Outcome trial with a gliptin with longest follow-up.2
Abdelmoneim AS et al. Diabetes Obes Metab Jun;17(6):
Marx N et al. Diab Vasc Dis Res May;12(3):
Johansen O-E, et al. 49th Ann Mtg of the European Association for the Study of Diabetes (EASD), Barcelona, Sep 2013, OP 3
Rosenstock et al. Diabetes & Vascular Disease Research 10(4) 289–301.Barcelona, Sep 2013, OP

30. Type of patients in CV Outcome trials: 3 D’s
Duration of trial Degree of CV risk Duration of diabetes
UKPDS showed CV benefit with metformin ONLY when started early
H2H comparison Linagliptin vs Glimepiride
Closest to UKPDS in terms of patient profile.
Interim results: 2016
Sitagliptin/Saxagliptin/ Alogliptin CV Neutral
Saxagliptin showed increase in HF Hospitalization
Linagliptin
If we map the CV outcome trials for all gliptins vs UKPDS, with respect to 3D’s. ie. Duration of trial, degree of CV risk of patients enrolled and duration of diabetes, it was seen that UKPDS was of longest duration and included mostly newly diagnosed patients. In this trial, metformin was the only OAD which showed CV benefit when started early in the disease. If we see, SAVOR TIMI with saxagliptin and EXAMINE with alogliptin, whose results r out, both trials have met the CV endpoints and are shown CV safe, but did not show any CV benefit. Saxagliptin showed some increase in heart failure hospitalization cases. TECOS (sitagliptin) and CARMELINA(linagliptin – results expected in 2018) trials are ongoing. (TECOS results are being expected this year), they will show if these drugs show CV safety and/or CV benefit, and it may confirm whether HF hospitalization seen with sitagliptin is a chance finding or class effect.
CAROLINA trial (with linagliptin) is the only trial with active comparator (glimepiride). It is the closest trial to UKPDS. It is not just being conducted to fulfil the FDA requirement but also to define an ideal choice of antidiabetic after metformin with respect to a drug’s CV risk profile. It has included parameters like cognitive dysfunction and also a CGMS analysis with linagliptin vs glimepiride to see the long term effect of hypoglycemia and glycemic fluctuation, respectively on the CV safety profile of both drugs.
Linagliptin vs. Placebo
Cardiac-Renal endpoints
Results Awaited
2018
Johansen O-E, et al. 49th Ann Mtg of the European Association for the Study of Diabetes (EASD), Barcelona, Sep 2013, OP 3

31. Thank you