L ingering questions related to cardiovascular

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1 D I A B E T E S, O B E S I T Y & H Y P E R T E N S I O N O U T C O M E S T U D I E S Impat of the U.S. Food and Drug Administration Cardiovasular Assessment Requirements on the Development of Novel Antidiabetes Drugs BOAZ HIRSHBERG, MD 1 ITAMAR RAZ, MD 2 L ingering questions related to ardiovasular (CV) safety of type 2 diabetes treatments resulted in new U.S. Food and Drug Administration (FDA) regulations requiring areful assessment of CV risk. These new requirements will provide the medial ommunity with robust data to estimate CV risk assoiated with new therapeuti agents. To meet these requirements, phase 2 and 3 development programs will need to be larger and more omprehensive and will inlude high-risk patients. In addition, it is likely that most (if not all) newly approved drugs will be required to ondut post-approval CV safety outome studies. The purpose of this artile is to review the drivers for the new FDA requirements and how these new requirements will affet the development of novel antidiabetes drugs. The goals of antidiabetes treatment are to forestall the metaboli effets of high gluose levels and to prevent mirovasular and marovasular ompliations. Compelling data in type 2 diabeti patients support the onlusion that improved long-term glyemi ontrol redues the risk of mirovasular ompliations (1,2). Based on several large outome studies (e.g., the Diabetes Control Compliations Trial and the UK Prospetive Diabetes Study [UKPDS]), glyosylated hemoglobin (HbA 1 ) was established as a surrogate biomarker of glyemi ontrol and therapeuti goals were set aordingly (3). Cardiovasular disease is the leading ause of death in patients with type 2 diabetes; more than 60% die of CV disease, and an even greater proportion have serious CV-related ompliations. Diabetes is assoiated with a two- to fourfold inrease in the risk of oronary heart disease and death (4). Patients with type 2 diabetes who have not had a myoardial infartion (MI) have a risk of infartion similar to that of nondiabeti patients who have had a prior MI (5 7). Pooled data from patients with aute oronary syndrome (ACS) in 11 independent Thrombolysis in Myoardial Infartion (TIMI) study group linial trials from 1997 to 2006 suggest that, despite modern therapies for ACS, diabetes onfers a signifiant adverse prognosis, with mortality rates of 7.2 8% during the first year after an event (8). Thus, while mirovasular ompliations an lead to signifiant morbidity and premature mortality, the greatest ause of death in people with diabetes is by far CV disease (9). The ability of gluose lowering to alter CV outome is not as lear as its ability to redue mirovasular ompliations. The UKPDS (2) demonstrated a From 1 AstraZenea, Wilmington, Delaware; and the 2 Hadassah University Medial Center, Jerusalem, Israel. Corresponding author: Boaz Hirshberg, boaz.hirshberg@astrazenea.om. This publiation is based on the presentations at the 3rd World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publiation of this supplement were made possible in part by unrestrited eduational grants from AstraZenea, Boehringer Ingelheim, Bristol- Myers Squibb, Daiihi Sankyo, Eli Lilly, Ethion Endo-Surgery, Generex Biotehnology, F. Hoffmann-La Rohe, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtroni, and Pfizer. DOI: /d11-s by the Amerian Diabetes Assoiation. Readers may use this artile as long as the work is properly ited, the use is eduational and not for profit, and the work is not altered. See lienses/by-n-nd/3.0/ for details. nonsignifiant 16% redution in CV ompliations (ombined fatal or nonfatal MI and sudden death) with intensive glyemi treatment. In an analysis of the study ohort, a ontinuous assoiation was noted suh that, for every perentage point of median HbA 1 lowering, there was a statistially signifiant 18% redution in CV disease events, with no glyemi threshold (9). Long-term follow-up demonstrated a signifiant 15% redution in CV disease among patients in the intensive glyemi treatment group (10). The Diabetes Control and Compliations Trial/Epidemiology of Diabetes Interventions and Compliations (DCCT/EDIC) study, whih inluded 1,441 patients with type 1 diabetes, demonstrated a signifiant redution in CV events (57%) in the intensively treated group after.17 years of follow-up (11). Based on the proven orrelation between HbA 1 and mirovasular ompliations and lak of lear CV benefits, most linial development programs for novel antidiabetes drugs have foused on gluose lowering. As a onsequene, most patients reruited to onfirmatorystudies required for regulatory approval have had limited duration of diabetes and few ompliations. Although these types of onfirmatory studies established the gluose-lowering properties of novel drugs, CV safety assessment in the ontext of the linial development of gluose-lowering agents has been limited. Cardiovasular safety onerns have been raised with respet to several antidiabetes ompounds approved or under development for the treatment of type 2 diabetes. In July 2008, the FDA s Endorinologi and Metaboli Drugs Advisory Committee met to disuss the role of CV assessment in the premarketing and postmarketing settings. The FDA determined that onerns about CV risk should be more thoroughly addressed during drug development; their newly issued guidelines will result in profound hanges in are.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S101

2 FDA CV guidelines and antidiabetes drug development the ways new antidiabetes drugs are evaluated and brought to market in the future (12). GLUCOSE LOWERING AND CV DISEASE RISK REDUCTION The University Group Diabetes Program, launhed in 1960, was an early plaeboontrolled multienter linial trial devised to determine whih, if any, of the treatments for type 2 diabetes was effiaious in reduing CV risk (13). Patients treated with tolbutamide, a first-generation sulfonylurea drug, had a signifiantly higher rate of CV death than patients given plaebo or insulin. Resulting onerns over potential sulfonylurea-related ardiotoxiity led to additional studies that both supported and onflited with this finding. One study to examine this question was the UKPDS (2,14,15). Although gluose lowering, with sulfonylureas or insulin, was assoiated with a redution in the development and/or progression of retinopathy, nephropathy, and possibly neuropathy, the improvements in CV ompliations were not statistially signifiant. In a substudy of 342 overweight patients, treatment with metformin was assoiated with risk redutions for several CV end points ompared with the onventional treatment group as follows: MI (239%), any diabetes-related end point (232%), diabetes-related death (242%), and all-ause mortality (236%). However, early addition of metformin therapy for patients not ahieving glyemi targets with sulfonylurea treatment was assoiated with an inreased risk of diabetesrelateddeathomparedwithontinued sulfonylurea treatment alone (2). Metaanalysis raised the suspiion that metformin/sulfonylurea ombination therapy may be deleterious to the heart (16). Several large outome studies demonstrated no redution in CV events with intensive glyemi ontrol (9,17,18). In addition, the Ation to Control Cardiovasular Risk in Diabetes (ACCORD) study terminated its glyemi ontrol arm when inreased mortality was observed among partiipants randomized to the intensive glyemi ontrol treatment arm (target HbA 1,6%) (9,19). In the ACCORD study, 80% of patients were intensively treated with insulin. Reently, a retrospetive study that inluded tens of thousands of patients who were followed after starting insulin treatment (as an add-on to oral monotherapy) showed a U-shaped orrelation between HbA 1 values and mortality and CV events. Compared with oral ombination agents, there was a 50% inrease in mortality in insulin-treated patients. This result suggested the possibility that insulin treatment in ertain irumstanes may be deleterious to the heart (20). However, the interpretation of the study results is limited, sine this was a retrospetive study; therefore, large prospetive studies examining the orrelation between insulin therapy and CV events are needed. Although the primary end point (redution in a omposite of all-ause mortality, nonfatal MI [inluding silent MI], stroke, ACS, endovasular or surgial intervention in the oronary or leg arteries, and amputation above the ankle) was not met in the Prospetive Pioglitazone Clinial Trial in Marovasular Events (PROative) study, pioglitazone treatment did result in signifiant risk redution in major adverse CV event omposite seondary end points (21). Consistent with the reported side effet profile for pioglitazone, there was an inreased rate of edema and heart failure observed in that trial (22). In 2009, the Rosiglitazone Evaluated for Cardiovasular Outomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) study found that there was no inrease in CV hospitalization or death with rosiglitazone added to metformin or a sulfonylurea, ompared with the ombination of metformin and a sulfonylurea, but the rate of heart failure leading to hospital admission or death was signifiantly inreased (23). In addition, a meta-analysis of rosiglitazone treatment suggested an inreased CV risk with this therapy (24). The Bypass Angioplasty Revasularization Investigation 2 Diabetes (BARI 2D) trial was designed to test treatment strategies for patients with oronary artery disease and diabetes (25). Overall, there was no signifiant differene in the rates of death or major CV events between patients undergoing prompt revasularization (either oronary artery bypass grafting or perutaneous oronary intervention) and patients undergoing medial therapy or between strategies of insulin sensitization and insulin provision. The aim of the Hyperglyemia and Its Effet After Aute Myoardial Infartion on Cardiovasular Outomes in Patients with Type 2 Diabetes Mellitus (HEART2D) study was to demonstrate a differene between two insulin strategies one targeting postprandial hyperglyemia and the other targeting fasting and premeal hyperglyemia on time to first CV event in survivors of aute MI (26). There was no differene in CV event rates between the two strategies. Can CV safety biomarkers predit CV outome? The unertainly regarding CV safety raises questions of the reliability of CV biomarkers as preditors of linial events. Several examples suggest that even treatments with positive effets on CV safety biomarkers may not ultimately lead to redued CV risk: Asignifiant derease in ommon arotid intima-media thikness progression in nondiabeti oronary artery disease patients was observed after treatment for 48 weeks with rosiglitazone (27). However, as disussed, metaanalysis of the CV events observed in the linial studies raised questions as to the safety of this agent (24). Muraglitazar, a dual (a/g) peroxisome proliferator ativated reeptor (PPAR) ativator in the glitazar lass that ativates PPAR-a and -g, was shown to improve hyperglyemia and lipid abnormalities (i.e., redue triglyerides and inrease HDL holesterol levels) simultaneously (28). However, metaanalysis of the CV events observed in the linial studies (29) suggested an inreased risk of CV disease, leading to nonapproval of this investigational agent. Toretrapib, an inhibitor of holesterylester transfer protein (CETP), has been shown to inrease HDL holesterol by % and to lower LDL holesterol by up to 20% (30). However, a large outome study demonstrated that toretrapib therapy resulted in an inreased risk of mortality and morbidity (30). Sibutramine treatment is assoiated with a derease in body weight and waist irumferene as well as redution in fasting blood gluose and HbA 1. Treatment benefits were seen in plasma triglyerides and HDL, without signifiant variations in serum total or LDL holesterol (31). However, results from the Sibutramine Cardiovasular Outomes Trial (SCOUT), whih was a randomized double-blind omparison of sibutramine versus plaebo, in addition to standard are for weight management in overweight/obese subjets who are at inreased risk of a CV event, S102 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 are.diabetesjournals.org

3 suggested risk assoiated with this agent. The preliminary results led to taking sibutramine off the European market. New regulatory FDA requirements CV safety onerns have been raised with several antidiabetes ompounds (most notably with agonists of the PPAR lass) that were approved or under development for the treatment of type 2 diabetes (24,29). In July 2008, the Endorinologi and Metaboli Drugs Advisory Committee of the FDA met to disuss CV risk with oral antidiabetes agents and the role of risk assessment in the premarketing and postmarketing setting. After onsidering the disussion at this meeting, as well as other available data and information, the FDA determined that effets on CV risk should be more thoroughly addressed during antidiabetes agent development (12). The resulting FDA guidane doument identifies several key areas that will need to be addressed by study sponsors: 1. An upper bound of the 95% CI for the risk ratio of important CV events of,1.3 should be used as a key riterion for exluding unaeptable CV risk for new treatments of type 2 diabetes. 2. Study patients must inlude individuals with relatively advaned disease, elderly patients, and patients with some degree of renal impairment. 3. A minimum of 2 years CV safety data must be provided. 4. All phase 2 and 3 studies should inlude a prospetive independent adjudiation of CV events. Adjudiated events should inlude CV mortality, MI, and stroke and an inlude hospitalization for ACS, urgent revasularization proedures, and possibly other end points. 5. To satisfy the new statistial guidelines, the analysis of CV events may inlude a meta-analysis of all plaeboontrolled trials, add-on trials (i.e., drug vs. plaebo, eah added to standard therapy), and ative-ontrolled trials, and/or an additional single, large safety trial may be onduted that alone, or added to other trials, would be able to satisfy this upper bound before a new drug appliation/biologis liense appliation (NDA/BLA) is approved. 1. The most important hange is the need to establish lak of CV toxiity. The FDA guidelines provide statistial hurdles for approval. If the premarketing appliation ontains linial data showing that the upper bound of the two-sided 95% CI for the estimated inreased risk (i.e., risk ratio) is between 1.3 and 1.8, and the overall risk-benefit analysis supports approval, a postmarketing trial generally will be neessary to definitively demonstrate that the upper bound of the two-sided 95% CI for the estimated risk ratio is,1.3. If the premarketing appliation ontains linial data showing that the upper bound of the two-sided 95% CI for the estimated inreased risk (i.e., risk ratio) is,1.3 and the overall riskbenefit analysis supports approval, a postmarketing CV trial may not be neessary (Fig. 1). The impliations of this new stipulation are signifiant; to reah the initial approvability bar of 1.8, a linial development program will need to prospetively target CV events (Fig. 2). To ahieve the more stringent test of,1.3, a development program will need ; events. Reently approved antidiabetes drugs (i.e., saxagliptin, liraglutide), in ontrast, had ;40 major CV events eah, even though.5,000 subjets partiipated in the development program (saxagliptin). Thus, programs will need to enroll greater numbers of patients and will need to shift fous to inlude more high-risk CV patients, a fat that will result in far Hirshberg and Raz more omplex and expensive development plans. 2. Patient seletion will also hange. Until reently, many linial development programs onentrated on demonstrating an effet on the surrogate marker HbA 1. To register and obtain a produt label that inludes monotherapy and add-on therapy, most reruited subjets need have only limited diabetes duration (a few years), and most were treated with a single bakground antidiabetes mediation. These programs limited or exluded obviously high-risk and ompliated patients. Suh programs were ritiized for the limited information they provided, and their appliability to larger patient populations was questioned (32). The new guidelines mandate a shift in patient seletion. To demonstrate that the drug is safe in patients with higher CV risk and to allow for meaningful estimates of CV risk, phase 2 and 3 programs will need to inlude patients at higher CV risk, i.e., patients with relatively advaned disease, elderly patients, and patients with some degree of renal impairment. 3. Whereas prior development programs olleted data on ardia adverse events, these events were not independently adjudiated. Adjudiation is a proess by whih an independent CV researh group reviews eah presumed CV event and makes a deision whether the event truly represents a ardia event. This proess arguably provides a higher level of onfidene in the diagnosis. The Consequenes of the new guidelines The new guidelines will result in profound hanges to the way that novel antidiabetes drugs are developed: Figure 1 FDA CV safety: CI bars. The FDA guidelines provide statistial hurdles for approval. Five hypothetial examples of possible hazard ratios and the upper limit of the 95% CI of a development plan are shown as well as the regulatory onsequenes of eah outome. are.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S103

4 FDA CV guidelines and antidiabetes drug development Figure 2 Total CV events needed to fall below the FDA target utoff of 1.8. Assuming a novel antidiabetes drug is neutral in terms of CV disease, a program should arue ~120 CV events to provide adequate power to meet the FDA requirement. new guidelines require sponsors to establish an independent CV end point ommittee to prospetively adjudiate, in a blinded fashion, CV events during all phase 2 and 3 linial trials. Adjudiated events should inlude CV mortality, MI, and stroke and an inlude hospitalization for ACS, urgent revasularization proedures, and possibly other end points. 4. The FDA s prior guidelines at the time of submission of the marketing appliation for produts intended for the treatment of type 2 diabetes required that phase 2 and 3 trial data be available for at least 2,500 subjets exposed to the investigational produt, with at least 1,300 1,500 of these subjets exposed to the investigational produt for $1 year and at least subjets exposed to the investigational produt for $18 months. The new guidelines require longer ontrolled trials (e.g., minimum of 2 years) to obtain enough events and to provide data on longer-term CV risk for these hronially used therapies. This requirement obviously will translate into muh larger and longer phase 3 linial development programs. Current antidiabetes CV outome studies landsape Preregistration trials. To provide the required CV safety data, several pharmaeutial ompanies are now onduting CV outome studies as part of their phase 3 development plans (Table 1). Examples of suh studies are inluded below. The Canagliflozin Cardiovasular Assessment Study (CANVAS) will assess anagliflozin in the treatment of patients with type 2 diabetes, with regard to CV risk for major adverse ardia events. The study will evaluate anagliflozin ompared with plaebo on CV events, inluding CV death, heart attak, and stroke in patients with type 2 diabetes, whose diabetes is not well ontrolled at the beginning of the study and who have a history Table 1 Examples of ongoing pre- and postapproval outome studies Trial name Drug Primary endpoint Number of subjets (years) EXAMINE alogliptin MACE 5,400 (5) CANVAS anagliflozin MACE 4,500 (4) T-emerge 8 taspoglutide CV events 2,000 (2.5) ALECARDIO aleglitazar Superiority: MACE 6,000 ACS (4.5) TECOS sitagliptin Noninferiority: MACE + unstable angina 14,000 (5) SAVOR saxagliptin Superiority: MACE 12,000 (5) EXSCEL exenatide LAR Superiority: MACE 12,000 (5.5) LEADER liraglutide MACE 9,000 (5) of CV events or are at high risk for CV events. Patients will reeive apsules of anagliflozin (either 100 or 300 mg) or mathing plaebo; the study duration is estimated to be ~4 years (33). The EXAMINE study (Examination of Cardiovasular Outomes: Alogliptin vs. Standard of Care in Patients with Type 2 Diabetes Mellitus and Aute Coronary Syndrome) was designed to evaluate the CV safety of alogliptin versus plaebo in addition to standard are in subjets with type 2 diabetes and ACS. The study plans to enroll 5,400 subjets and last for ~4.75 years (34). Postregistration trials. Saxagliptin (Onglyza) was the first antidiabetes agent to reeive FDA approval after issuane of the new CV guidelines and thus represents a good example of the impat of the new regulations. Saxagliptin was approved by the FDA in July One of the postmarketing requirements was to demonstrate lak of CV toxiity. The Saxagliptin Assessment of Vasular Outomes Reorded (SAVOR-TIMI 53) study is thus the first example of a post-approval ommitment under the new guidane (35). SAVOR is a multienter randomized double-blind plaebo-ontrolled phase 4 study that evaluates treatment with saxagliptin, a dipeptidyl peptidase-4 inhibitor, in adult type 2 diabeti patients with CV risk fators. This 5-year study will follow ~12,000 patients with type 2 diabetes, who have either a history of previous CV events or multiple risk fators for vasular disease, and will inlude patients with renal impairment. Pooled analysis of all eight registrational trials omprising the saxagliptin linial program with 4,607 patients (5,051 patient-years) and multiple omparators suggested no inreased CV risk with saxagliptin treatment. In fat, although this systemati overview had inherent and important limitations, the data support a potential redution in CV events with saxagliptin (36). Based on this hypothesis-generating data, the objetives of the SAVOR-TIMI 53 trial are to test the hypothesis of whether treatment with 2.5 mg or 5 mg saxagliptin ompared with plaebo when added to a patient s urrent standard are will result in a redution in the omposite end point of CV death, nonfatal MI, or nonfatal ishemi stroke and exlude unaeptable CV toxiity. A seond example of the impat of the new guidelines is liraglutide. The linial development program for liraglutide, as S104 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 are.diabetesjournals.org

5 was the ase for saxagliptin, was ompleted before issuane of the FDA guidane, but analyses of CV events in the phase 2 and 3 trials of liraglutide showed that this drug met the standard for ruling out unaeptably inreased CV risk. The overall rates of CV events in the preapproval linial trials were low, however, and the more stringent riteria outlined for postapproval evaluations were not met; the FDA is therefore requiring a post-approval study of CV safety (37). CONCLUSIONS Lingering questions related to CV safety of type 2 diabetes treatments resulted in new FDA regulations to arefully assess CV risk. The new requirements will provide the medial ommunity with robust data to estimate CV risk assoiated with new therapeuti agents. To meet these requirements, phase 2 and 3 linial trial programs will be larger and more omprehensive and will inlude high-risk patients. In addition, sponsors of most, if not all, newly approved drugs will be required to ondut post-approval CV safety outome studies. Several questions remain: 1. Will the time, money, and resoures hanneled to address a theoretial CV risk for a new drug limit the assessment of drug-speifi issues and benefits? 2. How will the medial ommunity and health authorities assess the CV risk of generi drugs that do not have the CV safety data that will be generated by novel antidiabetes agents? 3. Potential time, ost, and risk impliations may limit inentives for ompanies to develop new antidiabetes therapies. The result may be development of fewer antidiabetes drugs and fewer ompanies apable of developing these drugs. Aknowledgments B.H. is an employee of AstraZenea. I.R. is the o-priniple investigator of SAVOR and has onsulted for AstraZenea and Bristol-Myers Squibb. No other potential onflits of interest relevant to this artile were reported. Referenes 1. 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