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Diabetes 2 Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes Rury R Holman, Harald Sourij, Robert M Califf Lancet 2014; 383: 2008–17 This online publication has been corrected. The corrected version first appeared at thelancet.com on June 27, 2014 See Editorial page 1945 This is the second in a Series of two papers about diabetes Diabetes Trials Unit, University of Oxford, Oxford, UK (Prof R R Holman FRCP, H Sourij MD); Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria (H Sourij); and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA (Prof R M Califf MD) Correspondence to: Prof Rury R Holman, Diabetes Trials Unit, OCDEM, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK
[email protected] Few trials of glucose-lowering drugs or strategies in people with type 2 diabetes have investigated cardiovascular outcomes, even though most patients die from cardiovascular causes despite the beneficial effects of lipid-reducing and blood pressure-lowering treatments. The evidence-based reduction in risk of microvascular disease with glucose lowering has resulted in guidelines worldwide recommending optimisation of glycosylated haemoglobin, but no trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c. The 2008 US Food and Drug Administration industry guidance for licensing of antidiabetic drugs greatly increased the number of cardiovascular outcome trials in diabetes, but most trials opted for non-inferiority designs aiming primarily to show absence of cardiovascular toxicity in the shortest possible time. This unintended consequence of the new regulations has meant that the potential long-term benefits, and the possible risks of new therapies, are not being assessed effectively. Also, essential head-to-head trials of therapies for this complex progressive disease, to answer issues such as how best to achieve and maintain optimum glycaemia without promoting weight gain or hypoglycaemia, are not being undertaken. In this Series paper, we summarise randomised controlled cardiovascular outcome trials in type 2 diabetes, provide an overview of ongoing trials and their limitations, and speculate on how future trials could be made more efficient and effective.
Introduction The rapidly emerging diabetes pandemic is one of the most challenging noncommunicable disease threats to public health in the 21st century. More than 380 million people worldwide have type 2 diabetes,1 most of whom will die from cardiovascular disease, the second most common cause of death being their increased risk of cancer.2 People with type 2 diabetes have a roughly
Search strategy and selection criteria We searched for cardiovascular outcome trials of glucose-lowering drugs or strategies in patients with type 2 diabetes with the following definition: randomised, controlled clinical trial, primary study endpoint “cardiovascular outcome”, sample size >1 000, patients followed-up for ≥12 months. We searched the Cochrane Central Register of Controlled Trials, Medline, and Embase for reports published in English between Jan 1, 1996, and Jan 4, 2014, with the search terms “diabetes”, in combination with the terms “cardiovascular”, “complications”, and “mortality”. Table 1 lists the results fitting the search criteria. To identify ongoing trials we used the “advanced search” tab at www.ClinicalTrials.gov on Jan 13, 2014, to search interventional trials, phase 3 or higher, with the keyword “diabetes”. We included ongoing trials registered between March 1, 2008, and Jan 10, 2014, investigating glucose-lowering pharmacological interventions, with a planned follow-up of at least 18 months and a recent update on the study status on www.ClinicalTrials.gov. Table 2 lists the results fitting these criteria.
2008
doubled risk of cardiovascular disease, compared with people without diabetes, even after adjustment for established cardiovascular risk factors.2 After diagnosis, patients have a lifetime of attempted strict lifestyle, escalating drug therapy to offset glycaemic progression, and management of several risk factors to minimise the risk of diabetes-related complications. Life expectancy of a person diagnosed with type 2 diabetes at age 40 years is estimated to be shortened by about 6–7 years, compared with people without type 2 diabetes.2 A major need exists for evidence-based type 2 diabetes treatment strategies that better manage this complex condition by reducing disease progression, improving quality of life, and extending longevity, without causing unwanted or harmful side-effects. Crucially, the precise ability of glucose-lowering per se to reduce the risk of cardiovascular disease in type 2 diabetes has not been elucidated. Despite the many people affected by type 2 diabetes, the huge disease burden, and the major health economic costs to society, few definitive outcome trials to properly inform clinical effectiveness of licensed therapies have been done. Before publication of the results of the UK Prospective Diabetes Study (UKPDS)3 and the Diabetes Control and Complications Trial,4 the prevailing opinion was that diabetic complications were primarily genetic in origin and unrelated to the “carbohydrate derangements of diabetes mellitus”.5 Although the UKPDS findings in type 2 diabetes showed that improved glycaemic control3 and blood pressure control6 could reduce the risk of diabetic complications, most drug trials undertaken for www.thelancet.com Vol 383 June 7, 2014
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Year of Population publication
N
Follow up
Intervention
Outcome
UKPDS3,12
1998
Newly diagnosed T2DM
4209
Median 10·0 years
Intensive versus conventional glucose lowering strategy
Fatal and nonfatal myocardial Infarction: Intensive (SFU/ Insulin) versus conventional: RRR 16% (p=0·052); intensive (metformin) versus conventional: RRR 39% (p=0·010) All-cause mortality: intensive (SFU/Insulin) versus conventional: RRR 6% (p=0·44); intensive (metformin) versus conventional: RRR 36% (p=0·011)
DIGAMI 213
2005
T2DM and acute MI
1253
Median 2·1 years
Intensive versus usual metabolic control versus after MI
All-cause mortality Group 1 versus 2: HR 1·03 (95% CI 0·79–1·34) Group 2 versus 3: HR 1·23 (95% CI 0·89–1·69)
PROactiv14
2005
T2DM with macrovascular disease
5238
Mean 34·5 months
Addition of pioglitazone or placebo to usual diabetes care
All-cause mortality, non-fatal MI, stroke: HR 0·84 (95% CI 0·72–0·98)
ADVANCE15
2008
T2DM, at least 55 years old, history of macrovascular or microvascular disease or at least one other CV risk factor
11 140
Median 5 years
Intensive (gliclazide plus other MACE: HR 0·94 (95% CI 0·84–1·06) drugs) versus standard glucose control strategy
ACCORD16
2008
T2DM with established CVD or additional CV risk factors
10 251
Mean 3·5 years
Intensive versus standard glucose control strategy
MACE: HR 0·90 (95% CI 0·78–1·04) All-cause mortality: HR 1·22 (95% CI 1·01–1·46)
HEART2D17
2009
T2DM after acute MI
1115
Mean 2·6 years
Prandial versus basal insulin strategy
Composite of CV death, MI, stroke, coronary revascularisation, or hospitalisation for ACS: HR 1·04 (95% CI 0·78–1·37)
VADT18
2009
T2DM
1791
Median 5·6 years
Intensive versus standard glucose control strategy
Composite of MI, stroke, CV death, new or worsening congestive heart failure, surgical intervention for cardiac, cerebrovascular or PAD, inoperable CAD, amputation for ischaemic gangrene): HR 0·88 (95% CI 0·74–1·05)
RECORD19
2009
T2DM on maximum tolerated dose of metformin or SFU
4447
Mean 5·5 years
Addition of rosiglitazone or combination of metformin and sulfonylurea
Composite of CV death and CV hospitalisations: HR 0·93 (0·74–1·15)
BARI 2D20
2009
T2DM and heart disease
2368
Mean 5·3 years
Insulin-sensitisation versus insulin-provision treatment strategy
No difference in survival: 88·2% versus 87·9%, p=0·89
ADDITION21
2011
Screen-detected T2DM
3055
Mean 5·3 years
Routine versus intensified multifactorial risk factor intervention
Composite of CV death, CV morbidity, revascularisation, and non-traumatic amputation: HR 0·83 (95% CI 0·65–1·05)
ORIGIN22
2012
CV risk factors plus T2DM or IFG or IGT
12 537
Median 6·2 years
Insulin glargine or standard glucose control
MACE: HR 1·02 (95% CI 0·94–1·11)
SAVOR-TIMI5323
2013
T2DM with history of CV event or at risk for
16 492
Median 2·1 years
Addition of Saxagliptin versus placebo to usual diabetes care
MACE: HR 1·00 (95% CI 0·89–1·12)
EXAMINE24
2013
T2DM with ACS within 15 to 90 before randomisation
5380
Median 1·5 years
Addition of Alogliptin versus placebo to usual diabetes care
MACE: HR 0·96 (upper bound of 95% CI ≤1·16)
LOOK-AHEAD25
2013
Overweight or obese T2DM with or without CVD history
5145
Median 9·6 years
Intensive versus standard lifestyle intervention strategy
Composite of CV death, MI, stroke and hospitalisation for angina: HR 0·95 (95% CI 0·83–1·09)
T2DM=type 2 diabetes mellitus. SFU=sulfonylurea. RRR=relative risk reduction. MI=myocardial infarction. CV=cardiovascular. MACE=cardiovascular mortality, myocardial infarction, stroke. CVD=cardiovascular disease. PAD=peripheral artery disease. CAD=coronary artery disease. IFG=impaired fasting glucose. IGT=impaired glucose tolerance. ACS=acute coronary syndrome. HR=hazard ratio.
Table 1: Randomised, controlled, cardiovascular outcome trials (>1000 subjects, >1 year of follow up) of glucose-lowering drugs or strategies in people with type 2 diabetes
regulatory purposes continued to be short term, usually in selected populations, and often focused primarily on biomarkers rather than on hard outcomes. This situation changed after the 2008 US Food and Drug Administration (FDA) mandate and subsequent European Medicines Agency requirements for cardiovascular outcome trials in licensing of new glucose-lowering drugs.7,8 These regulatory requirements, driven primarily by response to cardiovascular safety concerns associated with the antidiabetic drug rosiglitazone,9,10 have changed the diabetes trials landscape. The FDA require that clinical www.thelancet.com Vol 383 June 7, 2014
trials done before drug approval show a two-sided 95% confidence interval upper boundary of 1∙8 risk ratio for major adverse cardiovascular events, versus the control group, with subsequent outcomes trials having an upper boundary of 1∙3.7 Bethel and Sourij11 reviewed the effect of this two-stage route to type 2 diabetes drug approval. The regulatory need to obtain robust cardiovascular safety data to approve new diabetes drugs has led to a substantial increase in the number of type 2 diabetes cardiovascular outcome trials. However, most of these trials have simple, placebo-controlled, non-inferiority 2009
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designs aiming to show an absence of cardiovascular toxicity to satisfy regulatory requirements in the shortest possible time. This approach has meant that many essential questions are unanswered, such as comparative effectiveness, estimation of the balance of benefits to risks over time, identification of heterogeneity of treatment effects to establish best patient selection, and assessment of possible drug-related adverse events in the long term. In this Series paper, we review published cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes (table 1), provide an overview of ongoing trials and their limitations, and speculate on potentially more effective and efficient trial designs.
Published cardiovascular outcome trials in type 2 diabetes The University Group Diabetes Programme, published in 1970,26 was the first randomised multicentre head-tohead effectiveness trial of available type 2 diabetes glucose-lowering treatments that assessed cardiovascular outcomes. The trial randomly assigned about 200 patients to each of variable-dose insulin, standard-dose insulin, sulfonylurea (tolbutamide), biguanide (phenformin), and placebo. The trial was halted because of concerns that all of the therapies seemed to increase cardiovascular risk.26 Although the University Group Diabetes Programme was grossly underpowered, controversy still exists regarding its findings, and concerns about unexpected adverse outcomes might have inhibited industry funding of outcome trials for many years. The introduction of metformin to North America was delayed until 1994, and even in 2014, sulfonylureas carry a so-called black box in the USA, signifying FDA concern that, as a class, they might increase cardiovascular risk. The 1998 UK Prospective Diabetes Study3 provided the first robust outcome data to inform clinical practice about the efficacy and safety of the then-licensed type 2 diabetes treatments. The UKPDS randomly assigned 4209 of 5102 patients with newly-diagnosed type 2 diabetes to one of two different glucose-lowering strategies. The 1138 patients randomly assigned to the conventional treatment group were allocated to diet alone, with secondary randomisation to active glucoselowering treatments only if their fasting plasma glucose subsequently became greater than 15 mmol per L. The 3867 patients randomly assigned to the intensive treatment group were allocated to monotherapy with insulin (n=1156), sulfonylurea (n=1573), or metformin (only in those with an ideal bodyweight >120%, n=342). Further rescue treatments were added in both trial groups in the event that fasting plasma glucose concentrations again exceeded 15 mmol per L. A highly significant 25% relative risk reduction (p=0·0099) was noted in microvascular disease (retinopathy necessitating photocoagulation, vitreous haemorrhage, or fatal or nonfatal renal failure, or a combination) after a median 2010
follow-up of 10 years in those allocated to intensive treatment with insulin or sulfonylurea. For myocardial infarction, relative risk reduction was almost significant at 16% (p=0·052).3 However, after 10 years of post-trial observation, this difference became statistically significant with a 15% relative risk reduction for myocardial infarction (p=0·01), and an emerging 13% relative risk reduction for all-cause mortality (p=0·007).27 The trialists interpreted these findings as showing a socalled legacy effect of the earlier allocation to intensive glucose control within the trial period. In patients with an ideal bodyweight greater than 120% randomly assigned at diagnosis to metformin, a 39% relative risk reduction occurred in fatal and nonfatal myocardial infarction (p=0·010), and a 36% relative risk reduction in all-cause mortality (p=0·011).12 These welcome but unexpected findings, albeit in a small cohort (342 allocated metformin, 411 allocated diet), have helped support the adoption by most diabetes management guidelines of metformin as a foundation treatment for type 2 diabetes.28 Regrettably, no further cardiovascular outcome trials of metformin have been commissioned until now, with the Glucose Lowering in non-diabetic hyperglycaemia Trial study about to commence (ISRCTN 34875079). Results of the 1997 Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) study of patients with type 2 diabetes and acute myocardial infarction29 showed a 30% decrease in 1 year mortality with intensive insulin treatment, compared with usual care. The DIGAMI-2 trial13 randomly assigned a similar population to acute insulin followed by long-term insulin treatment, acute insulin followed by standard long-term treatment, or routine management, but did not show a difference in the primary all-cause mortality outcome. Although the interpretation of these two trials is controversial, notably in DIGAMI-2 the predefined degree of separation in glucose control between groups could not be achieved, and only 1253 of the necessary 3000 patients were recruited. The ACCORD,16 ADVANCE,15 and VADT18 trials, published in 2008, and 2009, each compared intensive versus standard glucose-lowering strategies. Despite their large sample sizes and up to 5 years of follow-up, all three trials showed only non-significant trends towards a reduced risk in their primary cardiovascular composite endpoints with allocation to intensive therapy. However, a meta-analysis of these three trials, done together with the first 5 years of follow-up data from the UKPDS, showed a significant 15% risk reduction in fatal and non-fatal myocardial infarction (95% CI 14–16%).30 Results of the ACCORD trial showed a significant decrease in the rate of non-fatal myocardial infarction, but was stopped prematurely because of an unexpected 22% increased relative risk of all-cause mortality from cardiovascular deaths in the intensive treatment group (95% CI 1–46%). Despite many analyses, investigators have not shown any conclusive explanatory relationships between the mortality difference and weight gain, diabetes duration, or www.thelancet.com Vol 383 June 7, 2014
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polypharmacy, although it is well known that identification of an empirical causal pathway within a clinical trial can be difficult. Patients in the intensive treatment group in which more deaths occurred had increased concentrations of glycaemia.31 Post-hoc analyses of ACCORD, ADVANCE, and ORIGIN have shown that episodes of severe hypoglycaemia are associated with adverse future cardiovascular outcome for the overall populations,32–34 but between-treatment group analyses in ACCORD conclude that previous episodes of severe hypoglycaemia do not account for the mortality difference recorded in this trial. The Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART 2D) trial compared basal and prandial insulin treatment strategies,17 and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial compared insulin-sensitising and insulin-providing treatment strategies in patients with type 2 diabetes and cardiovascular disease.20 Neither trial found a difference in primary cardiovascular composite endpoints between treatment groups. The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive),14 published in 2005, compared the effect of the addition of pioglitazone versus placebo to usual diabetes care. A non-significant trend (p=0·095) for a 10% relative risk reduction was recorded in the primary composite cardiovascular endpoint (allcause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention on the coronary or leg arteries, or amputations above the ankle). However, raised rates of heart failure and peripheral fractures in women, combined with a small but worrying excess of bladder cancer, are concerns for this thiazolidinedione compound.35,36 Results of several inter-related meta-analyses of rosiglitazone trials have suggested that rosiglitazone might increase the risk of myocardial infarction and heart failure.23,24 These findings have been confounded by allegations of improper study conduct and many conflicting observational studies, some of which suggested harmful effects. The only substantive randomised controlled cardiovascular outcome trial of rosiglitazone in type 2 diabetes is the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial.19 In this postmarketing study, no excess risk of cardiovascular events was noted, other than heart failure, and meta-analyses including RECORD have not shown convincing harm beyond the previously known excess risk of heart failure.37 RECORD was criticised for its open-label design and its low statistical power, especially because the cardiovascular event rate was substantially lower than was anticipated.19 The Thiazolidinedione Intervention with Vitamin D Evaluation TIDE Trial,38 commissioned by the FDA, was designed to directly compare rosiglitazone, pioglitazone, and placebo when added double-blind to usual care. The www.thelancet.com Vol 383 June 7, 2014
study was terminated before any meaningful results could be obtained because of controversy about the safety of thiazolidinediones and the tight restrictions made to the rosiglitazone label. The FDA has since relaxed their rosiglitazone restrictions on the basis of a thorough reexamination of all the data, including a re-adjudication of the RECORD endpoints. Unfortunately, no definitive cardiovascular outcome data exist and no new trials are planned.39 The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomly assigned 12 537 patients with type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance with additional cardiovascular disease risk factors to insulin glargine or to standard glucose control.22 No difference was recorded between these two groups in the primary cardiovascular disease outcome. Reassuringly, no increased risk of cancer morbidity or mortality with insulin glargine was noted, as epidemiological data had previously suggested.40,41 The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE),24 and the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)— Thrombolysis in Myocardial Infarction (TIMI) 53 study,23 both published in 2013, were the first two major cardiovascular outcome trials spawned by the 2008 FDA cardiovascular safety regulations to be reported. These dipeptidyl-peptidase-4 inhibitor trials both showed noninferiority with regard to cardiovascular safety, compared with placebo, when added to usual diabetes care. These findings overturned previous systematic reviews of small-scale dipeptidyl-peptidase-4 inhibitor trials, the results of which had suggested cardiovascular benefit.42,43 The analysis of pre-specified SAVOR Trial secondary endpoints showed an unexpected 27% significantly increased relative risk of hospitalisation for heart failure in patients treated with saxagliptin (p=0·007).23
Trials not exclusively investigating glucoselowering drugs or strategies ADDITION, a cluster-randomised trial, compared multifactorial intensive treatment with routine care in screen-detected type 2 diabetes.21 The results showed a non-significant 17% relative risk reduction in the composite cardiovascular endpoint (95% CI −35–5%) in favour of multifactorial intensive risk-factor management. This result might be because only marginal differences in cardiovascular risk-factor levels were achieved between the two groups. The LOOK-AHEAD trial compared the effect of randomly assigning people with type 2 diabetes to an intensive lifestyle intervention aiming for at least 7·0% weight loss, or to a diabetes support and education programme.25 Despite a greater weight reduction in the intensive lifestyle intervention group than in the support and education programme group throughout the study, the trial was stopped because of futility after a 2011
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median follow-up of 9·6 years with no difference in the composite cardiovascular primary outcome (HR for intensive lifestyle intervention 0·95; 95% CI 0·83–1·09). This difference might be because of greater use of proven risk-factor-reducing drugs in the diabetes education and support group.
Ongoing cardiovascular outcome trials in type 2 diabetes Increased research The 2008 FDA and European Medicines Agency guidance requiring proof of cardiovascular safety in addition to HbA1c lowering, as a prerequisite for approval of new antidiabetic drugs, changed the type 2 diabetes clinical
TECOS
trial landscape. Initial concerns that the costs of such large-scale trials might deter pharmaceutical companies from further investing in the diabetes specialty were proved wrong, with at least 16 cardiovascular outcome trials (that will report by 2020) ongoing in more than 150 000 patients with type 2 diabetes (table 2). These studies include four dipeptidyl-peptidase-4 inhibitor trials, six glucagon-like peptide(GLP)-1 receptor agonist trials, four sodium-glucose linked transporter 2-inhibitor trials, one trial comparing a thiazolidinedione with a sulfonylurea, and one trial comparing two long-acting insulin preparations. Driven by the new regulatory requirements, more cardiovascular outcome trials in type 2 diabetes have been commenced in the past 10 years
n
Intervention
Population
Primary outcome
Study status
Start and estimated end date
ClinicalTrials. gov identifier
14 000
Sitagliptin versus placebo
T2DM; HbA1c 6·5–8·0%; ≥50 years; CVD history
CV death, MI, UA, or stroke
Ongoing, not recruiting
12/2008–Q3/2014
NCT00790205
TOSCA IT
3371
Pioglitazone versus sulfonylurea
T2DM; HbA1c ≥7·0% and ≤9·0%; metformin monotherapy
Death, MI, stroke or coronary revascularisation
Recruiting
09/2008–12/2018
NCT00700856
CANVAS
4330
Canagliflozin 100 mg versus canagliflozin 300 mg versus placebo
T2DM; ≥30 years; HbA1c 7·0–10·5%; History of/high risk of CVD
CV death, MI, UA, or stroke
Ongoing, not recruiting
12/2009–03/2017
NCT01032629
ELIXA
6000
Lixisenatide versus placebo
T2DM; HbA1c 5·5–11·0%; ACS
CV death, MI, UA, or stroke
Ongoing, not recruiting
06/2010–01/2015
NCT01147250
14 000
Exenatide once weekly versus placebo
T2DM; HbA1c 6·5–10·0%; CVD in about 60%
CV death, MI, or stroke
Recruiting
06/2010–12/2017
NCT01144338
BI 10773 trial
7000
Empagliflozin 10 mg versus empagliflozin 25 mg versus placebo
T2DM; ≥18 years; HbA1c 7·0–10·0%; (7·0–9·0% drug naïve); high CV risk
CV death, MI, or stroke
Ongoing, not recruiting
07/2010–03/2018
NCT01131676
LEADER
9340
Liraglutide versus placebo
T2DM; HbA1c ≥7·0%; ≥50 years+CVD; CV death, MI, or stroke ≥60 years+CV risk factors
Ongoing, not recruiting
08/2010–10/2015
NCT01179048
CAROLINA
6000
Linagliptin versus glimepiride
T2DM; HbA1c 6·5–8·5%; 40–85 years; CV death, MI, UA, or stroke CVD/CV risk factors/diabetes end organ damage
Ongoing, not recruiting
10/2010–09/2018
NCT01243424
REWIND
9622
Dulaglutide versus placebo
T2DM; HbA1c ≤9·5%; 50 years+CVD; 55 years+subclinical CVD; ≥60 years+CV risk factors
Ongoing, not recruiting
07/2011–04/2019
NCT01394952
MK-3102 trial
4000
MK-3102 versus placebo
T2DM; CVD history
CV death, MI, UA, or stroke
Recruiting
10/2012–10/2017
NCT01703208
SUSTAIN6
3260
Semaglutide 0·5 mg versus semaglutide 1·0 mg versus placebo
T2DM; HbA1c ≥7·0%; age ≥50 years+CVD; age ≥60 years+subclinical CVD
CV death, MI, or stroke
Ongoing, not recruiting
02/2013–01/2016
NCT01720446
ITCA650 trial
2000
ITCA 650 (exenatide in DUROS) versus placebo
T2DM; HbA1c >6·5%; CVD history
CV death, MI, UA, or stroke
Recruiting
03/2013–07/2018
NCT01455896
Dapagliflozin 10 mg versus placebo
T2DM; ≥40 years; high CV risk
CV death, MI, or stroke
Recruiting
04/2013–04/2019
NCT01730534
Recruiting
07/2013–01/2018
NCT01897532
EXSCEL
DECLARE-TIMI 58
17 150
CV death, MI, or stroke
CARMELINA
8300
Linagliptin versus placebo
CV death, MI, UA, or stroke T2DM; HbA1c 6·5–10%; 18 years; microalbuminuri or macroalbuminuria and previous macrovascular disease; impaired renal function with predefined UACR
DEVOTE
7500
Insulin degludec versus insulin glargine
T2DM; HbA1c ≥7·0%; or HbA1c ≤7·0% and insulin treatment; ≥50 years and CV or renal disease or ≥60 years and CV risk factors
CV death, MI or stroke
Recruiting
10/2013–11/2018
NCT01959529
Ertugliflozin trial
3900
Ertugliflozin 5 mg versus ertugliflozin 15 mg versus placebo
T2DM; HbA1c 7·0 –10·5%; CVD history
CV death, MI, or stroke
Recruiting
11/2013–06/2020
NCT01986881
T2DM=type 2 diabetes. CVD=cardiovascular disease. CV=cardiovascular. MI=myocardial infarction. UA=unstable angina. ACS=acute coronary syndrome.
Table 2: Ongoing cardiovascular outcome trials of glucose-lowering drugs or strategies (in order of starting date)
2012
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Possible pleotropic effects With so many new treatment methods being assessed, a clear need exists to be alert for possible non-glycaemic benefits, such as improvements in blood pressure, lipid profiles, and bodyweight with GLP-1 receptor agonists, and the potential for off-target effects leading to unexpected beneficial or harmful outcomes. Equally, if glucose-lowering per se does reduce cardiovascular disease risk, the need to ensure glycaemic equipoise in studies of novel drugs will be of paramount importance in understanding of the results obtained.
Need for long-term follow-up The need for ongoing trials to satisfy new regulatory requirements has led to a design culture of risk-avoidance studies, coupled with a need for trials to be completed within the shortest possible time to maximise financial return on pharmaceutical investment. Type 2 diabetes is a chronic, progressive disease, with patients at increasing risk over time of both microvascular and macrovascular complications. The vascular effects of glucose-lowering treatments took about 5 years to emerge in both the UKPDS3 and the DCCT,4 and other effects such as cancer and fractures will probably take a similar period to be evident compared with placebo or comparators. These findings suggest that, although short-term trials can gather information on rapidly occurring adverse events, such as hypoglycaemia, infections, or peripheral oedema, medium-to-long-term trials could be essential in type 2 diabetes to obtain a fuller appreciation of the probable benefits and risks of glucose-lowering interventions. That most ongoing cardiovascular outcome trials are being carried out in populations at high cardiovascular risk who have had type 2 diabetes for many years is also a concern, perhaps limiting the trials’ ability to assess treatments that might be more effective for primary cardiovascular disease prevention, and identifying potentially greater benefits of intervention earlier in the progression of diabetes.27 The median follow-up of 1·5 years in the EXAMINE trial and 2·1 years in the SAVOR-TIMI 53 trial are testament to this concern. To motivate companies to invest in long-term trials, financial incentives, such as offering a longer patent life, could be considered. The number of trial participants needed to achieve the number of primary events ordained by the sample size calculation needs to be balanced by a median duration of follow-up to fully capture the probable benefits and risks. Age and disease severity-adjusted cardiovascular event rates are decreasing worldwide as evidence-based www.thelancet.com Vol 383 June 7, 2014
management of cardiovascular risk factors increases. In view of the lower event rates, the need for enough events to exclude a clinically meaningful excess of cardiovascular events, and the cardiovascular outcome studies driven by financial time pressure are required to enrol larger cohorts with more extensive pre-existing disease. Shortterm follow-up might be satisfactory when seeking to rule out direct cardiotoxicity, but short trials have little ability to fully assess potential long-term cardiovascular risks or benefits, or other type 2 diabetes complications. Equally, extended follow-up is necessary to examine the possible effect on incident cancer or emergence of unanticipated side-effects, as in the detection in the ADOPT trial of the unanticipated increased risk of bone fractures in women.45
Scarcity of active comparators A particular strength of the UKPDS was its head-to-head comparison of all licensed type 2 diabetes drugs during the trial period. Unfortunately, most new trials are testing novel drugs primarily for non-inferiority against placebo when administered in addition to usual diabetes care, thereby limiting their clinical interpretation, and providing no direct comparison with existing treatments. In this way the CAROLINA trial stands out, being an active comparator study of linagliptin versus glimepiride. Unfortunately, CAROLINA has no placebo group to calibrate any findings to the population being studied. If linagliptin were shown to be superior to glimepiride it would not be known whether linagliptin would be better than usual care (assuming glimepiride is the benchmark), or the same as usual care in the event that glimepiride has an adverse cardiovascular profile as the UGDP sulfonylurea data suggested.26 The FDA noted this omission and required the company to run an additional placebo-controlled trial 250 Cumulative number of cardiovascular trial participants (thousands)
than in the entire history of diabetes research (figure). Trial sample sizes have also substantially increased from median (IQR) 1116 (300–4447) to 6000 (4082–9313), and an increase in the average number (range) of countries per trial from 17 (1–20) to 27 (6–35),25,44 providing data for a wider range of racial and ethnic groups and variations in practice patterns than previously.
200
150
100
50
0 1996
2000
2004
2008 Year
2012
2016
2020
Figure: Cumulative number of participants in cardiovascular outcome trials over time Numbers of trial participants are added at the time of publication for historical trials (solid line) and at the estimated time of reporting for ongoing trials (dotted line). The red circle indicates when the new US Food and Drug Administration guidance for industry was issued.
2013
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(CARMELINA) to comply with their safety requirements.46 The DEVOTE trial is comparing insulin degludec directly with insulin glargine, after FDA cardiovascular safety concerns raised by post-hoc analyses of earlier regulatory studies,47 but a placebo group is not feasible in view of the need to maintain acceptable levels of glycaemia in patients who need insulin. The ongoing GRADE trial (ClinicalTrials.gov: NCT01794143) is a comparative effectiveness trial, examining the randomised addition of a DPP-4 inhibitor, a GLP-1 receptor agonist, a sulfonylurea, or long-acting insulin to metformin. Unfortunately the trial is not powered for cardiovascular outcomes, with the primary outcome limited to time to second-line treatment failure.
Challenges for cardiovascular outcome trials going forward A downside of long-term trials is that retention and adherence are increasingly difficult over time to maintain. Retention and adherence rates vary substantially among the trials we describe, with no clear trend or pattern, but with permanent drug discontinuation rates reaching about 10% per year in EXAMINE38 and SAVOR-TIMI 53.39 Although these drug discontinuation rates are consistent with clinical practice patterns, the traditional clinical trial method seeks to optimise adherence in trials more so than in clinical practice. Several challenges exist to participant retention and adherence: unwillingness to stick to a protocol for several years; the requirement to travel regularly to study sites; concerns about absence of effective treatment if participants perceive that they might be taking a placebo; open-label availability of the study drug as a routine treatment option, especially if reimbursed; and life events that might affect patients’ ability or willingness to continue in a trial. It is crucial that trial managers choose participating sites carefully, using previous retention and adherence metrics as a key selection parameter. Sites need to be supported during the trial by adequate financial and personal resources to retain participants over an extended period. Expert opinion from the Institute of Medicine48 and publicly expressed FDA opinion point out the analytical dilemma caused by missing data, which introduces an unresolvable potential bias to analyses. Although discontinuation of therapy often represents the appropriate therapeutic option or patient choice, maintainenance of follow-up and measurement of outcomes to the fullest extent possible in all study participants is essential. A misconception often exists among investigators and study coordinators, possibly fuelled by experience in early-phase trials, that participants in clinical outcome trials who discontinue study medication need no longer be followed.49 Constant emphasis is crucial to ensure that all participants continue to be followed as closely as possible until study end. Vital status should always be available, because in previous trials where legal opinion was sought the view 2014
was that no right of confidentiality about death exists because the death is part of the public record.50 True withdrawal of consent to follow-up should be exceptional, needs to be discussed in detail with participants, and with written records obtained should they genuinely wish to withdraw completely from the study.
Concepts for future outcome trials in patients with type 2 diabetes The concept of randomised controlled trials is the gold standard in clinical research to investigate outcomes attributable to a certain intervention, because of the many advantages of randomisation over mere registry analyses. Intervention allocation is too important to leave to chance. Randomisation helps to ensure that the groups being compared are balanced in terms of the known and unknown confounders, which information is not accessible to registry analyses. However, incremental changes in trial methods will not be sufficient to address the deficiencies of the present generation of clinical trials assessing clinical outcomes in patients with type 2 diabetes—transformational change is needed. The present approach produces trials that are too short, with measurement of limited outcomes at a high cost per patient. The genesis of these costs is a clinical trials system that initiates studies and collects data outside the routine system of clinical care, and relies on audit functions rather than quality by design to attempt to ensure reliable results. These costs can only be borne by industry as a function of its need to obtain approval for marketing. The huge market for type 2 diabetes drugs has enabled industry to bear these costs, but the situation prevents trials of adequate length from being truly informative for a lifelong disease, inhibits head-to-head comparisons and factorial designs, and constrains the exploration of more comprehensive clinical outcome assessments. Many countries are developing comprehensive electronic health record systems which enable various functions that will greatly reduce the cost of trials and enable comprehensive follow-up within the context of the health-care delivery system. Using so-called computable phenotypes derived from diagnostic codes in electronic health records, populations with diabetes can be identified, baseline characteristics produced, and follow-up events ascertained. Before these trials can begin, various measures must be taken to engage health system leaders, clinicians, and patients, in more of a systematic approach to learning about best therapies in practice. Regulatory systems must also be adapted to develop a more effective approach to quality by design. By reducing the cost of trials by an order of magnitude or more, these approaches could open up the system to the kinds of trials that would provide the much-needed information. The realistic probability of a transition in trial conduct is emphasised by the formation of the Patient Centered Outcomes Research www.thelancet.com Vol 383 June 7, 2014
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Network in the USA, with up to 100 million Americans in a network designed to do these types of trials.51 Proofof-concept has been achieved in several cardiovascular outcomes trials.52–54 Future trials should plan on long-term follow up, factorial designs, and embedded head-to-head comparisons. An especially interesting design beginning to be used in many trials in other disease areas begins with many groups that are within standard of care. Furthermore, continuous follow-up with electronic health records will enable multidimensional collection of various outcomes, including cancer, fractures, and psychiatric and neurological outcomes. Sample sizes can also be much larger because of the lower cost per patient when followed in usual care, thus enabling powerful assessments of heterogeneity of treatment effect. If different classes of drugs are found to be better for patients with different characteristics, such trials will be crucial in realisation of the aspiration for personalised medication. Another important element of future trials will be the direct involvement of patients and their advocates in the prioritisation, design, conduct, analysis, and dissemination of trials.55 This, combined with the wide-scale availability of personal monitoring devices, should enable a range of microvascular outcomes, symptoms, and quality-of-life factors to be measured.56 Because advocacy organisations are increasingly realising the importance of clinical research to guide decision making about best treatment, direct involvement of many affected individuals should foster the broad-scale enrolment of many participants prepared to share data to advance knowledge of diabetes and its treatment.57 The resulting mega-networks should also enable replication of findings across networks to ensure the validity of observations. This new world of large-scale, long-term trials will need the development of methods for assessment of several comparisons, appropriate handling of missing data, and examination of time-dependent variations in the benefitto-risk balance. As increasingly relevant populations are enrolled in real-world settings across different countries and cultures, the heterogeneity of treatment effect will become a multidimensional construct.58 This new approach to clinical trials will need to be phased in as systems develop and methods are tested and validated. In the interim, hybrid trials, in which electronic health records data are used to identify cohorts and measure some outcomes, will become more common.
Conclusions A critical view of the large cardiovascular trials done over the last four decades shows that, until recently, few had adequate statistical power to inform practice, and that the designs of the trials constrained the range of questions that could be addressed. The UKPDS taught us that improved glycaemic control in newly-diagnosed type 2 diabetes patients reduces the risk of microvascular www.thelancet.com Vol 383 June 7, 2014
complications, and, in the long term, of cardiovascular events and all-cause mortality.3,7 Findings from ACCORD,11 ADVANCE,10 and VADT13 showed that medium-term trials of intensive glucose lowering, in participants with long-established diabetes and with a history of cardiovascular disease, did not show similar beneficial cardiovascular effects. A clear need exists for better-designed trials with sufficient length of follow-up to more effectively address the crucial questions of the comparative balance of risk and benefit during substantial periods of follow-up. Smarter trials are necessary—such as factorial designs and trials nested into the rapidly evolving environment of electronic health records and data warehouses—that permit novel treatments to be compared more appropriately and more cost-effectively with existing treatments, and that seek to answer a wider range of clinically-relevant questions than do present trials. Contributors HS did the search, wrote the first draft, and revised the Series paper. RRH and RMC planned and revised the Series paper. Declaration of interests RRH received grants from Bristol-Myers Squibb, grants and personal fees from Bayer and Merck, and personal fees from Novartis and Jansen, all outside the submitted work. RMC received grants from Amylin, Novartis, Schering-Plough Research Institute, Scios, Eli Lilly, Johnsons & Johnson/ Scios, Aterovax, Bayer, the NIH, and the Patient-Centered Outcomes Research Institute; grants and personal fees from Bristol-Myers Squibb, Janssen Research & Development, Merck, and Roche; personal fees from Genentech, GlaxoSmithKline, Heart.org/Daiichi Sankyo, Kowa, Servier, Medscape, Regeneron, TMC, Pfizer, Gambro, Gilead, DSI-Lilly, CV Sight, Heart.org/Bayer, Bayer Pharma AG, Bayer Healthcare, Parkview, Pozen, Orexigen, Nile, and WebMD; and other financial support from N30 Pharma, Portola, and Nitrox LLC, all outside the submitted work. HS declares no conflicts of interest. References 1 International Diabetes Federation. Diabetes Atlas. http://www.idf. org/diabetesatlas (accessed Feb 23, 2014). 2 Seshasai SR, Kaptoge S, Thompson A, et al, and the Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364: 829–41. 3 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53. 4 Nathan DM, Cleary PA, Backlund JY, et al, and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643–53. 5 Siperstein MD, Unger RH, Madison LL. Studies of muscle capillary basement membranes in normal subjects, diabetic, and prediabetic patients. J Clin Invest 1968; 47: 1973–99. 6 UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13. 7 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf (accessed Feb 23, 2014). 8 European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. May 2012. http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2012/06/WC500129256.pdf (accessed Feb 23, 2014).
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