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ACROSS T2D educational slide modules

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1 EDUCATIONAL SLIDE MODULES Module C: Evidence for effects of older glucose-lowering agents on CV risk

2 ACROSS T2D educational slide modules
Module A CV disease and T2D Module B Approaches to managing CV risk in patients with T2D Module C Evidence for effects of older glucose-lowering agents on CV risk Module D Evaluating CV safety and potential for CV risk reduction with newer T2D agents Module E EMPA-REG OUTCOME® results Abbreviations CV, cardiovascular; T2D, Type 2 diabetes. .

3 CV safety Metformin SU CVOT interpretation FDA mandate TZD Notes
This slide provides a visual summary of this module. Abbreviations CV, cardiovascular; CVOT, cardiovascular outcome trial; FDA, Food and Drug Administration; SU, sulphonylurea; TZD, thiazolidinedione.

4 CV safety Metformin SU TZD FDA mandate CVOT interpretation
Abbreviations CV, cardiovascular; CVOT, cardiovascular outcome trial; FDA, Food and Drug Administration; SU, sulphonylurea; TZD, thiazolidinedione.

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 Insulin glargine available2 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: Copyright Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. Figure 1. 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: MOA Metformin1  Hyperglycaemia Intestine Liver
Skeletal muscle  Glucose utilisation  Gluconeogenesis  Glycogenolysis  Fatty acid oxidation  Insulin-mediated glucose uptake  Glycogenesis  Fatty acid oxidation  Hyperglycaemia Notes Metformin is a first-line glucose-lowering agent and is most widely used to treat T2D. Metformin decreases hyperglycaemia primarily by suppressing glucose production (inhibition of gluconeogenesis) by the liver. In addition to its glucose-lowering effect, metformin has been found to provide various benefits, e.g., improving plasma lipid profile, as shown in large clinical trials.1 The effects of metformin on CV risk factors require further assessment, but may include improved lipid profiles, anti-atherogenic effects, decreased ischaemic injury and amelioration of oxidative stress.1 Recent research at the gut level reveals new pharmacological actions of metformin including alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion (particularly GLP1)2 Abbreviations CV, cardiovascular; MOA, mechanism of action; T2D, Type 2 diabetes. Reference 1. Batchuluun et al. J Endocrinol Diabetes Obes 2014;2:1035 2. Napolitano A et al. PLoS ONE 2014; 9(7): e100778 Copyright Bailey & Feher. Therapies for Diabetes Figure 6.5 In addition to its glucose-lowering effects, metformin may have potential effects on the CV system, e.g., improving plasma lipid profile2 Adapted from 1. Bailey & Feher. Therapies for Diabetes Batchuluun et al. J Endocrinol Diabetes Obes 2014;2:1035.

7 Metformin is recommended as first-line therapy in T2D
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 alone1,4 Metformin significantly reduced any diabetes-related complication, diabetes-related and overall mortality, and absolute risk of MI vs diet alone after 10.7 years Notes 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 UKPDS 34. Lancet 1998;352:854–65.

8 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 = 39) 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 1997 1999 2001 2003 2005 2007 No. of events: Conventional therapy 73 83 92 106 118 126 Metformin 39 45 55 64 68 81 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 Copyright Holman et al. N Engl J Med 2008;359:1577–89. Figure 3D. Page 1585 UKPDS 34. Lancet 1998;352:854–65. Figure7. Page 847. 1. UKPDS 34. Lancet 1998;352:854– Holman et al. N Engl J Med 2008;359:1577–89.

9 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 1.0 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. Copyright UKPDS 34. Lancet 1998;352:854–65. Figure 10. Page 863 Favours added metformin Favours SU alone *Interpret with caution in view of small event numbers. UKPDS 34. Lancet 1998;352:854–65.

10 Section recap CV safety of metformin Metformin is generally recommended as first-line therapy1,2 Some evidence to suggest a CV benefit in overweight patients1 There remains a paucity of evidence from large, long-term, placebo-controlled CV outcome trials3 Abbreviations CV, cardiovascular. American Diabetes Association. Diabetes Care 2015;38(suppl. 1):S1–S Boussageaon et al. PLoS Med. 2012; 9:e

11 CV safety Metformin SU TZD FDA mandate CVOT interpretation
Abbreviations CV, cardiovascular; CVOT, cardiovascular outcome trial; FDA, Food and Drug Administration; SU, sulphonylurea; TZD, thiazolidinedione.

12 Sulphonylureas: MOA Notes
SUs are a common second-line therapy for T2D (after metformin). SUs lower glucose by stimulating insulin secretion from the pancreas. Normally, the metabolism of an influx of glucose causes the ATP/ADP ratio to rise, leading to closure of the KATP channel, depolarisation of the β-cell membrane, influx of calcium ions and, finally, the release of insulin from storage granules. SUs bind to a specific receptor on the KATP channel, causing it to close and triggering the same series of events, and also causing impaired ischaemic pre-conditioning in cardiac myocytes. Abbreviations ADP, adenosine diphosphate; ATP, adenosine triphosphate; KATP, adenosine triphosphate-dependent potassium channel; MOA, mechanism of action; SU, sulphonylurea; SUR, SU receptor; T2D, Type 2 diabetes. Reference The figure was produced using Servier Medical Art: Copyright Gore and McGuire. Eur Heart J 2011;32:1832–4. Figure 1 Reproduced from 1. Gore and McGuire. Eur Heart J 2011;32:1832–4.

13 Sulphonylureas and CV safety
In the US, SUs carry a special warning around increased risk of CV mortality1–3 The warning is based on findings from the UGDP trial that reported an excess of cardiac deaths in patients receiving tolbutamide versus placebo4 In the EU, the same SUs do not carry safety warnings around increased CV mortality with SUs5–7 Notes The US label (but not the EU label, for example) carries a safety warning around CV mortality that is based on findings from the UGDP study. Abbreviations CV, cardiovascular; PI, prescribing information; UGDP, University Group Diabetes Program; SU, sulphonylurea; T2D, Type 2 Diabetes. 1. Glimepiride PI at Tolbutamide PI at Glipizide PI at Meinert et al. Diabetes 1970;19 (suppl):789– Glimepiride EU SmPC at Tolbutamide EU SmPC at Glipizide EU SmPC at

14 No deleterious CV effect of SUs vs insulin or conventional therapy observed in UKPDS 331
Patients with MI (%) 0.4 0.3 0.2 0.1 0.0 3 6 9 15 12 Years from randomisation Conventional (896) Chlorpropamide (619) Glibenclamide (615) Insulin (911) Conventional vs glibenclamide vs insulin p = 0.66 Notes In UKPDS 33, SUs were found to have no deleterious CV effect compared with insulin or conventional therapy, as illustrated here with data for MI. The risk of any diabetes-related endpoint was 12% lower with SUs or insulin versus conventional therapy (95% CI: 1–21, p = 0.029); there was no significant difference between the intensive therapy groups (p = 0.36). In ADVANCE, 11,140 patients with T2D were randomised to undergo either standard or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less This strategy lowered the glycated hemoglobin value to 6.5% and yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. Footnotes Note that glibenclamide is "glyburide" in the US Abbreviations CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; SU, sulphonylurea; UKPDS, UK Prospective Diabetes Study. Copyright UKPDS33. Lancet 1998;352:837–53. Figure 7. Page 847 In addition, in the ADVANCE study, intensive glucose control involving gliclazide was not associated with deleterious CV effects2 1. UKPDS33. Lancet 1998;352:837– Patel et al. N Engl J Med 2008;358:2560–72.

15 Meta-analysis of SU CV safety trials (≥ 6 months) found no consistent association with MACE risk1
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 including all randomized controlled trials with a duration ≥24 weeks of SU vs 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. Copyright Monami et al. Diabetes Obes Metab 2013;15:938–53. Figure 3. Overall MACE risk estimate: MH-OR 1.08 (95% CI: 0.86–1.36); p = 0.521 Mortality was significantly increased with sulphonylureas (MH-OR: 1.22 [1.01–1.49], p=0.047) 1. Monami et al. Diabetes Obes Metab 2013;15:938–53. *SU + comparator groups combined.

16 Section recap 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 ADVANCE, intensive glucose-lowering including gliclazide was not associated with negative CV outcomes vs standard treatment3 In a meta-analysis of 115 RCTs, overall MACE risk estimate for SUs vs comparators was not statistically increased (OR 1.08, p = 0.52)4 ‘CV safety of SUs cannot be considered established unless evaluated in long-term CVOTs’4 Abbreviations CV, cardiovascular; CVOT, cardiovascular outcomes trial; MACE, major adverse cardiovascular events; OR, odds ratio; RCT, randomised controlled trials; SU, sulphonylurea; UGDP, University Group Diabetes Program; UKPDS, UK Prospective Diabetes Study. 1. Meinert et al. Diabetes 1970;19(suppl):789– UKPDS Group. Lancet 1998;352:837– Patel et al. N Engl J Med 2008;358:2560– Monami et al. Diabetes Obes Metab 2013;15:938–53.

17 CV safety Metformin SU TZD FDA mandate CVOT interpretation
Abbreviations CV, cardiovascular; CVOT, cardiovascular outcome trial; FDA, Food and Drug Administration; SU, sulphonylurea; TZD, thiazolidinedione.

18 Thiazolidinediones (TZD; PPAR-γ agonists): MOA
Skeletal muscle Adipose Liver  Glucose uptake PPAR activation  Gluconeogenesis Adipogenesis  Fatty acid uptake  Lipogenesis  Glucose uptake  Plasma FFA Notes PPAR activation regulates the expression of multiple target genes involved in glucose homeostasis, fatty acid oxidation and lipid metabolism. In addition to improving glucose control and insulin sensitivity, TZDs reduce concentrations of atherogenic lipoproteins and decrease inflammatory mediators. Abbreviations FFA, free fatty acid; PPAR, peroxisome proliferator-activated receptor; TZD, thiazolidinedione. Copyright Bailey & Feher. Therapies for Diabetes Figure 7.5  Hyperglycaemia Adapted from Bailey & Feher. Therapies for Diabetes 2004.

19 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.

20 Pioglitazone: PROactive trial design
Aim Drug-specific trial to determine the impact of pioglitazone on macrovascular morbidity and mortality in high-risk patients with T2D Main inclusion criteria 1. Patients with T2D and evidence of macrovascular disease 2. Age 35–75 years 3. HbA1c > 6.5% With or without background therapy Pioglitazone versus Placebo N = 5238; average follow-up 34.5 months Primary endpoint: time to first occurrence of all-cause mortality, non-fatal MI, stroke, ACS, endovascular/surgical intervention in coronary/leg arteries, amputation above ankle Notes Data is available from CV outcome trials on pioglitazone (PROactive) and rosiglitazone (RECORD) to provide more robust evidence around the CV effects of the TZDs. The PROactive trial examined CV outcomes in patients with T2D and existing macrovascular disease, following treatment with pioglitazone or placebo. Abbreviations ACS, acute coronary syndrome; HbA1C, glycosylated haemoglobin; MI, myocardial infarction; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes; T2D, Type 2 diabetes. Secondary endpoint: time to first occurrence of all-cause mortality, non-fatal MI, stroke Statistical analysis ≥ 760 patients with ≥ 1 endpoint event Last patient recruited followed up for 30 months Dormandy et al. Lancet 2005;366:1279–89.

21 PROactive: Pioglitazone was superior to placebo for main secondary endpoint, but not for primary endpoint Time to primary endpoint* Pioglitazone (514 events) Placebo (572 events) HR 0.90 (95% CI: 0.80–1.02) p = 0.095 Proportion of events (%) Time from randomisation (months) 25 20 15 10 5 6 12 18 24 30 36 Time to all-cause mortality, non-fatal MI, stroke Proportion of events (%) Time from randomisation (months) 25 20 15 10 5 6 12 18 24 30 36 Pioglitazone (301 events) Placebo (358 events) HR 0.84 (95% CI: 0.72–0.98) p = 0.027 Notes The PROactive study demonstrated that pioglitazone was not significantly superior to placebo for the primary endpoint, which was the composite of all-cause mortality, non-fatal MI (including silent MI), stroke, ACS, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. However, pioglitazone was significantly superior to placebo for the key secondary endpoint, which was the composite of all-cause mortality, non-fatal MI and stroke. 6% (149 of 2605) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. Baseline characteristics: 43% on statins; HbA1c 7.8% pioglitazone and 7.9% placebo; BP 144/83 mmHg pioglitazone and 143/83 for placebo The effects of pioglitazone vs placebo on HbA1c and lipids are shown below: Pioglitazone Placebo HbA1c (% absolute change) (-1.6 to -0.1) (-1.1 to 0.4) Triglycerides (% change) (-34.4 to 18.3) (-23.7 to 33.9) LDL cholesterol (% change) (-11.2 to 27.6) 4.9 (-13.9 to 23.8) HDL cholesterol (% change) (6.6 to 33.3) (-1.7 to 21.4) LDL/HDL (% change) (-27.3 to 10.1) (-21.7 to 15.8) Abbreviations ACS, acute coronary syndrome; BP, blood pressure; CI, confidence interval; HbA1c, glycosylated haemoglobin; HDL, high-density lipoprotein; HR, hazard ratio; LDL, low-density lipoprotein; MI, myocardial infarction; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events. Copyright Dormandy et al. Lancet 2005;366:1279–89. Figure 2 and 3. Page 1283 Hospitalisation for Heart Failure: 6% (149 of 2605) in pioglitazone vs 4% (108 of 2633) in placebo; p = 0.007 *Death from any cause, non-fatal MI (including silent MI), stroke, acute coronary syndrome, leg amputation, coronary revascularisation or revascularisation of the leg. Dormandy et al. Lancet 2005;366:1279–89.

22 Rosiglitazone: RECORD trial design
Aim Drug-specific trial to compare macrovascular morbidity and mortality in patients with T2D treated with rosiglitazone + metformin / SU Main inclusion criteria 1. Patients with T2D on maximum tolerated doses of metformin or SU monotherapy 2. Age 40–75 years 3. BMI ≥ 25.0 kg/m2 N = 4447; follow-up 5–7 years OPEN-LABEL Metformin + SU OPEN-LABEL Rosiglitazone + metformin or Rosiglitazone + SU versus Primary endpoint: Statistical analysis Non-inferiority margin of 1.20 for HR 4000 participants followed for a median of 6 years to give 99% power Time to first occurrence of cardiovascular hospitalisation or cardiovascular death Time to first occurrence of CV hospitalisation or CV death Notes The design of the RECORD trial is shown here.1 The rosiglitazone group comprised patients initially on metformin or SU monotherapy randomised to receive rosiglitazone on a background of metformin or SU. The active control group comprised patients initially on metformin monotherapy who were randomised to receive add-on SU and also patients initially on SU monotherapy who were randomised to receive add-on metformin. It is important to note that a meta-analysis2 of rosiglitazone trials was published in 2007, approximately half-way through the RECORD study, reporting an increased risk of MI and of CV death. Since RECORD was open-label, it is conceivable that this information compromised the integrity of RECORD’s finding. It was noted that discontinuations from rosiglitazone therapy increased slightly (an excess of 32 people, 1.4% of the randomised population) compared with those in the active control group, in the 12 months following publication of the meta-analysis.1 The meta-analysis demonstrated that rosiglitazone was associated with a significant increase in the risk of MI and with an increase in the risk of death from CV causes that had borderline significance.2 Baseline characteristics:1 Statin use: 18% rosiglitazone; 19.2% active control. SBP was 138–140 mmHg and DBP 82–84 mmHg across the arms. HbA1c 7.8% in background metformin arms, 8.0% in background SU arms. Prior ischaemic heart disease (stable angina, MI): 14.8–20.1% across the arms. Abbreviations BMI, body mass index; CV, cardiovascular; DBP, diastolic blood pressure; HR, hazard ratio; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes; SBP, systolic blood pressure; SU, sulphonylurea; T2D, Type 2 diabetes. References Home et al. Lancet 2009;373:2125–35. Nissen & Wolski. N Engl J Med 2007;356:2457–71. Home et al. Lancet 2009;373:2125–35.

23 Rosiglitazone: RECORD trial results showed no increase in CV death
Rosiglitazone N = 2220 Active control N = 2227 HR 95% CI Primary endpoint CV death or CV hospitalisation 321 323 0.99 0.85–1.16 Secondary endpoint All-cause death 136 157 0.86 0.68–1.08 CV death 60 71 0.84 0.59–1.18 MI 64 56 1.14 0.80–1.63 Stroke 46 63 0.72 0.49–1.06 CV death, MI or stroke 154 165 0.93 0.74–1.15 Heart failure 61 29 2.10 1.35–3.27 CV outcomes for RECORD trial (original data)1,2 In 2013, FDA panel voted to reduce safety restrictions on rosiglitazone3 However, there are no long-term prospective data on CV safety, so controversy remains4 Notes The RECORD trial showed no increase in CV death with rosiglitazone.1 In 2013, the FDA reduced safety restrictions on rosiglitazone.2 However, controversy still remains, as there are no long-term prospective CV safety data for this agent.3 Abbreviations CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; HR, hazard ratio; MI, myocardial infarction; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes. References AVANDIA US prescribing Information: FDA safety information: Rosenson et al. Am Heart J 2012;164:672–80. 1. AVANDIA US Prescribing information. 2. Home et al. Lancet 2009;373:2125– FDA Safety Information. 4. Rosenson et al. Am Heart J 2012;164:672–80.

24 Section recap CV safety of TZDs TZDs cause or exacerbate 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 ‘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 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 Regulation of Glycaemia in Diabetes References 1. Rosenson et al. Am Heart J. 2012;164:672–80. 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.

25 CV safety Metformin SU TZD FDA mandate CVOT interpretation
Abbreviations CV, cardiovascular; CVOT, cardiovascular outcome trial; FDA, Food and Drug Administration; SU, sulphonylurea; TZD, thiazolidinedione.

26 Adverse CV events led the FDA to require demonstration of CV safety for new glucose-lowering drugs
1961 UGDP trial: 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* Rosiglitazone associated with increased risk for MI and CV-related death3 2007 2008 ACCORD trial: 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 2008 New FDA requirements5 New EMA requirements6 New diabetes drugs should demonstrate CV safety with meta-analysis and a CV outcome trial (CVOT) 2012 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. 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–

27 Regulatory requirements for drug-specific CV outcome data in T2D
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.

28 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) may not be 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 1.0 1.3 1.8 2.0 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: RR of incidence of CV events with investigational agent vs control

29 Satisfying FDA requirements for CV safety
Number of CV events needed to satisfy 1.3 non-inferiority margin 0.8 0.65 0.7 0.75 0.85 0.9 0.95 1 1.05 1.15 1.1 200 400 600 800 1000 1200 1400 1600 Number of events Assumed true relative risk 80% power 90% power 110 139 179 233 311 428 611 1507 922 1126 689 457 320 134 174 104 82 Notes This graph shows the number of CV events needed to satisfy the 1.3 non-inferiority margin according to different RRs, using a 1-sided alpha of If it is assumed that a new antidiabetic therapy is neutral in terms of CV safety (i.e., the true RR is 1.0), approximately 122 and 611 adjudicated CV events are needed to provide 90% power to discharge the 1.8 and 1.3 risk margins, respectively. Abbreviations CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; RR, relative risk. Copyright Geiger et al. Ther Innovation Reg Science 2014;1–15. Figure 1. Assuming relative risk of 1.0 and 90% power, adjudicated CV events needed to satisfy the CI upper limits for non-inferiority: 122 events for the 1.8 risk margin – 611 events for the 1.3 risk margin Geiger et al. Ther Innovation Reg Science 2014;1–15.

30 CV safety Metformin SU TZD FDA mandate CVOT interpretation
Abbreviations CV, cardiovascular; CVOT, cardiovascular outcome trial; FDA, Food and Drug Administration; SU, sulphonylurea; TZD, thiazolidinedione.

31 Contemporary CVOT trial design for T2D
Aim Determine effect of Drug X compared with placebo/comparator on CV outcomes, on top of glucose-lowering and CV therapies adjusted according to local guidelines, in patients with T2D Usual care – glucose lowering, BP lowering, lipid lowering etc. Placebo Compositeprimary endpoint High CV risk patients R Run-in Statistics Drug X Events FDA mandates that CV safety be demonstrated in high CV risk population1 Run-in helps to establish patient adherence to long-term treatment and FU All patients are on a usual care background (to control diabetes and CV risk factors); investigators encouraged to adjust therapy following local guidelines As adjustment of background therapy is encouraged, CVOTs not designed to assess impact of a difference in HbA1c between study arms FDA recommends 3P-MACE as primary CV endpoint or expanded 4P-MACE (e.g., including hospitalisation for unstable angina pectoris)1 Sequential statistical testing (superiority tested only if non-inferiority established) Trials are event driven, rather than of fixed duration Notes The CVOTs that are ongoing in T2D are designed to assess drug-specific CV effects of T2D agents beyond glucose-lowering; they also satisfy FDA requirements to establish CV safety of new glucose-lowering therapies. This slide details some of the considerations intrinsic to CVOT study design. Abbreviations BP, blood pressure; CV, cardiovascular; CVOT, cardiovascular outcome trial; FU, follow-up; T2D, type 2 diabetes; 3P-MACE, 3-point major adverse cardiovascular events; 4P-MACE, 4-point major adverse cardiovascular events. Adapted from Geiger et al. Ther Innovation Reg Science 2014;1–15. 1.

32 CVOTs designed to assess effects of a specific drug or of a treatment strategy (e.g. glucose lowering) Treatment strategy trials (intensive vs standard glucose lowering) Compound-specific trials UKPDS1,2 FPG < 6 vs < 15 mmol/L Also assessed metformin vs SU + insulin2 VADT3 HbA1c ≤ 6% vs 8–9% ACCORD4 HbA1c < 6% vs 7–7.9% ADVANCE5 HbA1c < 6.5% vs SOC Also assessed gliclazide + other drugs in intensive arm vs standard care arm PROactive6 Pioglitazone vs placebo RECORD7 Rosiglitazone + metformin or SU vs metformin + SU SAVOR-TIMI 538 Saxagliptin vs placebo EXAMINE9 Alogliptin vs placebo ELIXA10 Lixisenatide vs placebo TECOS11 Sitagliptin vs placebo EMPA-REG OUTCOME®12 Empagliflozin vs placebo Notes Compound-specific trials refers to those that assess drug-specific effects beyond glucose-lowering (e.g., EMPA-REG OUTCOME®), while treatment strategy trials refers to those that assess the effects of glucose lowering (e.g., ACCORD – intensive vs conventional glucose lowering). In some cases, trials fall into both categories. Abbreviations ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE - Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CVOT, cardiovascular outcomes trial; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE; FPG, fasting plasma glucose; HBA1c, glycosylated haemoglobin; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus-Thrombolysis In Myocardial Infarction; SU, sulphonylurea; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial. 1. UKPDS 33. Lancet 1998;352:837– UKPDS 34. Lancet 1998;352:854– Duckworth et al. N Engl J Med 2009;360:129– ACCORD. N Engl J Med 2008;358:2545– ADVANCE. N Engl J Med 2008;358:2560– Dormandy et al. Lancet 2005;366:1279– Mahaffey et al. Am Heart J 2013;166:240–9.e Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Bentley-Lewis et al. Am Heart J 2015;0:1–8.e Bethel et al. Diabetes Obes Metab 2015;17:1395– Zinman et al. Cardiovasc Diabetol 2014;13:102.

33 Considerations for interpretation of contemporary compound-specific CVOTs
Design features Demonstration of CV safety is required by regulators for newer anti-hyperglycaemic drugs as ‘class effects’ cannot be assumed based on drug-specific trials Most CVOTs employ hierarchical testing to test for superiority following establishment of non-inferiority CVOTs are typically event-driven; study duration can only be estimated1 Power and duration Inclusion characteristics vary across trials (e.g., degree of pre-existing CV risk or prior CVD, duration of T2D) This necessitates caution in comparing results across trials1 Population Background therapy Trials performed on a usual care background (e.g., high antihypertensive and statin use) so CV risk factors (e.g. BP, LDL-C) are generally well controlled Investigators should adjust background therapy according to local guidelines1 Notes This slide details some of the considerations necessary for interpretation of ongoing CVOTs. Abbreviations BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcome trial; LDL-C, low-density lipoprotein cholesterol; 3P-MACE, 3-point major adverse cardiovascular events; 4P-MACE, 4-point major adverse cardiovascular events. Primary and secondary outcomes vary across trials (3P-MACE and 4P-MACE are common primary outcomes)2 Outcomes 1. Hirshberg & Katz. Diabetes Care 2013;36(suppl 2):S253–8. 2.

34 Statistical considerations in CVOT interpretation
Power is the probability that the effect, if it exists, will be detected Power is usually set to 80% or 90% (i.e. the chance of demonstrating statistical significance if the true effect is at least as pronounced as specified)1 Sample size must be pre-planned Variables needed to calculate1,2: Assumed effect size (and accepted non- inferiority margin) Expected event rate in control group Desired power Significance level (incl. interim analyses) Event rate 2008 FDA guidance highlights the need to conduct T2D trials that obtain sufficient end points Event rate varies according to baseline CV risk of study population3 Hierarchical testing for non-inferiority and then superiority is common among CVOTs, e.g., in a recent protocol:4 Primary analysis is non-inferiority for 3P-MACE If achieved, non-inferiority testing of 4P-MACE (key secondary outcome) will be conducted If achieved, superiority testing will follow of first 3P-MACE and, if positive, 4P-MACE Event rate (events / 1000 patient-years) Baseline characteristics CV death CVD 16.7 No CVD 3.6 Notes Power calculations are essential for all scientific and clinical trials, to ensure that clinically useful conclusions can be drawn2 Sample size calculation requires the collaboration of experienced biostatisticians and physician-researchers: expert medical knowledge is an essential part of it’2 Certain criteria are needed in order to predetermine the required sample size (cohort size) for a given study, including the expected effect size (difference between arms), the expected event rate in the control group, the desired power (80 or 90%) and the level of significance required (commonly 0.05) Sample size also has to factor estimated/assumed: drop in/drop out, non-adherence, attrition etc. The expected event rate is important in planning a CVOT and this rate will differ according to the population; patients at high baseline CV risk are likely to experience a higher number of CV events over the course of follow-up Hierarchical testing is commonplace among CVOTs. Most trials will first examine whether non-inferiority is achieved between the two arms. If non-inferiority is achieved, superiority can then be tested. Abbreviations CVD, cardiovascular disease CVOT, cardiovascular outcome trial MI, myocardial infarction T2D, type 2 diabetes 3P-MACE, 3-point major adverse cardiovascular events 4P-MACE, 4-point major adverse cardiovascular events 1. Dell et al. ILAR J. 2002;43:207– Eng. Radiology 2003;227:309– Preiss et al. Am Heart J 2011;161: e Zinman et al. Cardiovasc Diabetol 2014;13:102.

35 Overview of CVOTs of glucose-lowering drugs
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 two completed – SAVOR-TIMI 53 and EXAMINE) 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] EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of 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] 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 19. NCT Copyright Johansen. World J Diabetes 2015; 6:1092–96 HARMONY Outcomes19 (n = 9400) 3P-MACE Timings represent estimated completion dates as per ClinicalTrials.gov. Adapted from Johansen. World J Diabetes 2015;6:1092–96.(references 1–19 expanded in slide notes)

36 Module C: Summary Metformin exerts various CV effects
There is some evidence to suggest a CV benefit but there is a paucity of evidence from long-term CVOTs1 There is limited evidence evaluating the CV safety of profile of SUs2,3 There is a need for evaluation of the CV safety of SUs in a long-term dedicated CVOT The long-term CV safety profile of drugs within the TZD class remains controversial, emphasising the need for compounds within the same class to demonstrate CV safety4 The 2008 FDA guidance requires that new diabetes drugs demonstrate CV safety via meta-analysis and CVOT5 There are many considerations in interpreting the results of contemporary drug-specific CVOTs designed to assess the effect of a specific drug, added to background usual care, on MACE6 Abbreviations CV, cardiovascular; CVOT, cardiovascular outcomes trial; FDA, Food and Drug Administration; MACE, major adverse cardiovascular events; SU, sulphonylurea; TZD, thiazolidinedione. 1. Boussageaon et al. PLoS Med. 2012; 9:e UKPDS 34. Lancet 1998;352::837– ADVANCE. New Engl J Med 2008;358:2560– Rosenson et al. Am Heart J. 2012;164:672– FDA Guidance for Industry

37 Meta-analysis showed increased risk for congestive heart failure with both pioglitazone and rosiglitazone Comparison of risk of congestive heart failure Weight Risk ratio (95% CI) Rosiglitazone trials 46.2% 2.41 (1.61–3.61) Pioglitazone trials 53.8% 1.32 (1.04–1.68) Total 100.0% 1.74 (0.97–3.14) Test for overall effect: Z = 1.85 (p = 0.07) 0.1 0.2 0.5 1 2 5 10 Decreased risk Increased risk In a meta-analysis of 20,191 patients with pre-diabetes or T2D, the increased risk for congestive heart failure with TZDs did not differ between rosiglitazone and pioglitazone (p = 0.07) In 20,191 patients with prediabetes or type 2 diabetes in seven randomised trials, the risk of congestive heart failure was higher in patients given TZDs than in controls. The pooled RR for development of congestive heart failure was 2.18 (95% CI 1.44–3.32, p = ) in the five trials of rosiglitazone, and 1.32 (1.04–1.68, p = 0.02) in two studies with pioglitazone However, despite the higher incidence of congestive heart failure in patients given TZDs, these patients did not have a higher rate of cardiovascular death. The risk of cardiovascular death did not differ between both drug groups (p=0.96) The risk for congestive heart failure did not differ for rosiglitazone and pioglitazone (p=0.07). The meta-analysis included seven studies, all published since 2005 and followed up patients for between 12 and 48 months, with a mean of 29・7 months; trial populations ranged from 200 to 5269 participants, with a median of 4351. Risk ratios (RR) are shown on a logarithmic scale. The area of each square is proportional to the weight of the individual study, measured as the inverse of the estimated variance of the log risk ratio. The diamond represents the pooled relative risk and its width represents its 95% CI. Test for heterogeneity: 2 = 61.27, df = 1 (p = 0.01), I2 = 84.1% Abbreviations CI, confidence interval; df, degrees of freedom; RR, risk ratio; TZDs,thiazolidinediones. Copyright Lago et al. Lancet 2007; 370: Lago et al. Lancet 2007;370:1129–36.

38 Relative risk (95% credible interval)
Network meta-analysis suggested possible variation between SUs in effects on mortality Relative risk (95% credible interval) Chlorpropamide 1.34 (0.98–1.86) Tolbutamide 1.13 (0.90–1.42) Glibenclamide (reference group) Reference Glipizide 0.98 (0.80–1.19) Glimepiride 0.83 (0.68–1.00) Gliclazide 0.65 (0.53–0.79) 1.45 (0.88–2.44) 1.11 (0.79–1.55) 1.01 (0.72–1.43) 0.79 (0.57–1.11) 0.60 (0.45–0.84) All-cause mortality Cardiovascular 0.1 1.0 Lower risk than for reference group Higher risk than for reference group 10.0 0.5 2.0 Notes This study examined differences in CV event risk among sulfonylureas with random effects models for direct pairwise comparisons and network meta-analyses to incorporate direct and indirect data. The analysis included 24 studies The data indicate differences among the different types of SUs 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. Copyright Simpson et al. Lancet Diabetes Endocrinol 2015;3:43–51 Simpson et al. Lancet Diabetes Endocrinol 2015;3:43–51.


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