Prevention and Remission of Type 2 Diabetes with Lorcaserin in Overweight and Obese Patients

Erin A. Bohula MD1¥, Benjamin M. Scirica MD1¥, Silvio E. Inzucchi MD2*, Darren K. McGuire MD3*, Anthony C. Keech MD4*, Steven R. Smith MD5, Estella Kanevsky MS1, Sabina A. Murphy MPH1, Lawrence A. Leiter MD6*, Jamie P. Dwyer MD7*, Ramon Corbalan MD8, Christian Hamm MD9*, Lee Kaplan MD10, Jose Carlos Nicolau MD11*, Ton Oude Ophuis MD12, Kausik K. Ray FRCP13*, Mikhail Ruda MD14*, Jindrich Spinar MD15, Tushar Patel PhD16, Wenfeng Miao MD16, Carlos Perdomo MS16, Bruce Francis, M.D.16, Shobha Dhadda, Ph.D.16,

Marc P. Bonaca MD1, Christian T. Ruff MD1, Marc S. Sabatine MD1*†, and Stephen D. Wiviott MD1† for the CAMELLIA-TIMI 61 Steering Committee and Investigators

¥Contributed equally; †Contributed equally.*Full professor.

A complete list of the Cardiovascular And Metabolic Effects of Lorcaserin In Overweight And Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) steering committee and investigators is provided in the Supplementary Appendix

1TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA; 2Section of Endocrinology, Yale School of Medicine, New Haven, CT; 3Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX; 4NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; 5 Translational research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL 6Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada; 7Division of Nephrology/Hypertension, Vanderbilt University Medical Center, Nashville, TN, 8Department of Cardiovascular Diseases, Catholic University School of Medicine, Santiago, Chile; ; 9The Kerchoff Heart Center, Bad Bauheim, Germany; 10Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Boston, MA; 11Instituto do Coracao, Universidade de Sao Paulo, Sao Paulo , Brazil; 12CWZ Hospital, Nijmegen, the Netherlands; 13 Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College London, London, England; 14Russian Cardiologic Research and Production Complex of Rosmedtechnology, Moscow, Russia; 15Internal Cardiology Department, University Hospital Brno, Czech Republic; 16Eisai Inc, Woodcliff Lake, NJ

Corresponding Author:Erin A. Bohula MD DPhil, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 60 Fenwood Road, Suite 7022, Boston, MA 02115Phone: 617-278-0145 Fax: 617-734-7329Email: ebohula11@bwh.harvard.edu

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ABSTRACT

BACKGROUND: There is a direct relationship between body weight and risk of diabetes. In

CAMELLIA-TIMI 61, lorcaserin, a selective serotonin 2C receptor agonist that suppresses

appetite, facilitated sustained weight loss without an increased risk of major adverse

cardiovascular events in obese or overweight patients. The long-term effects of lorcaserin on

diabetes prevention and remission, however, are unknown.

METHODS: CAMELLIA-TIMI 61 was a multi-national trial of 12,000 overweight or obese

patients with or at high risk for atherosclerotic vascular disease randomized in a double-blind

fashion to lorcaserin or placebo on a background of lifestyle modification. The pre-specified

primary metabolic efficacy endpoint of incident diabetes was assessed in patients with pre-

diabetes at baseline. Other pre-specified outcomes for efficacy included remission of

hyperglycemia, achievement of normoglycemia, and diabetic microvascular complications, and

for safety, hypoglycemia.

FINDINGS: At 1 year, patients with baseline diabetes (N=6816, 57%), pre-diabetes (N=3991,

33%) and normoglycemia (N=1193, 10%) treated with lorcaserin had a 2.6 kg, 2.8 kg, and 3.3 kg

net weight loss, respectively (p<0.0001 for all). Over a median follow up of 3.3 years, lorcaserin

reduced the risk of incident diabetes by 19% in patients with pre-diabetes (8.5% vs 10.3%; HR

0.81; 95%CI, 0.66-0.99; p=0.038). Furthermore, lorcaserin tended to increase the rate of

achievement of normoglycemia in patients with pre-diabetes (9.2% vs. 7.6%; HR 1.20, 0.97-

1.49; p=0.093) and significantly increased the rate of remission of hyperglycemia in patients

with diabetes (7.1% vs. 6.0%; HR 1.21, 1.00-1.45; p=0.049). Lorcaserin reduced the risk of a

composite of microvascular events of incident microalbuminuria, diabetic retinopathy or

neuropathy by 21% in patients with diabetes (10.1% vs. 12.4%; HR 0.79, 0.69-0.92; p=0.0015).

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In patients with diabetes at baseline, severe hypoglycemia with serious complications was rare,

but more common with lorcaserin (12 vs 4 events, p=0.054).

INTERPRETATION: Lorcaserin decreases risk for incident diabetes, induces remission of

hyperglycemia and reduces the risk of microvascular complications in obese and overweight

patients.

FUNDING: Eisai Inc.

TRIAL REGISTRATION NUMBER: NCT02019264

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INTRODUCTION

The global prevalence of obesity has nearly tripled over the last 40 years; as of 2016, 13% of

adults are obese (body mass index [BMI] ≥30 kg/m2) and another 39% are overweight (BMI 25-

29 kg/m2).1-3 Obesity is associated with the development and progression of impaired glucose

tolerance and type 2 diabetes in patients without diabetes and worsening glycemic control among

patients with diabetes.4 Dysglycemia, a well-described risk factor for both micro- and

macrovascular disease, further compounds the risk in obese patients for co-morbid

complications, such as chronic kidney disease, neuropathy, coronary artery disease, stroke and

death.4-8

Pharmacological weight loss agents are guideline-recommended adjuncts to lifestyle

modification for long-term weight management and for the prevention of pre-diabetes and

diabetes.6,9 Predominantly short-term studies of pharmacologic weight loss agents have

demonstrated improvements in glycemic parameters, but long-term data from large randomized

trials are limited.6

Lorcaserin is a selective agonist of the 5-hydroxytryptamine 2C serotonin receptor (5-HT2C) that

regulates appetite through hypothalamic activation of the anorexigenic pro-opiomelanocortin

(POMC) pathway.10 Lorcaserin was approved by the US FDA as an adjunct to a reduced-calorie

diet and increased physical activity for chronic weight management.11-13 The Cardiovascular And

Metabolic Effects of Lorcaserin In Overweight And Obese Patients-Thrombolysis in Myocardial

Infarction 61 (CAMELLIA-TIMI 61) trial was designed to investigate the long-term CV and

metabolic safety and efficacy of lorcaserin in obese or overweight patients with or at high risk

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for diabetes and adverse CV events.14 On a background of lifestyle interventions, lorcaserin

improved long-term weight loss without any increase in the risk of major adverse CV events.15

Here, we report pre-specified metabolic efficacy and safety outcomes with lorcaserin in

overweight and obese patients.

METHODS

STUDY DESIGN AND OVERSIGHT

CAMELLIA-TIMI 61 was a randomized, double-blind, placebo-controlled, multinational

clinical trial in which patients at 473 sites in 8 countries underwent randomization. The study

was designed by the TIMI Study Group in conjunction with the executive committee and the trial

sponsor, Eisai Inc.14,15 The protocol and amendments were approved by the relevant ethics

committees for all participating sites. The first author wrote the initial draft of the manuscript.

All coauthors participated in subsequent manuscript revisions. The authors from the TIMI Study

Group assume responsibility for the accuracy and completeness of the data and all the analyses.

We encourage parties interested in collaboration and data sharing to contact the corresponding

author directly.

STUDY POPULATION

Eligible patients were obese or overweight with a BMI ≥27kg/m2 with either established

atherosclerotic CV disease or multiple CV risk factors. To qualify for established atherosclerotic

CV disease, patients had to be ≥40 years old with a history of coronary, cerebrovascular or

peripheral artery disease. To qualify for the multiple risk factor criteria, patients were ≥50 (men)

or ≥55 (women) years old with diabetes and at least one of the following other risk factors:

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dyslipidemia, hypertension, eGFR 30-60ml/min/1.73m2, hs-CRP >3mg/L or micro- or

macroalbuminuria. Patients with diabetes must have had a hemoglobin A1c of <10% at

screening and a stable clinical and treatment course of diabetes in the preceeding 3 months with

no hospitalizations for hypo- or hyperglycemia. Full eligibility criteria have been reported

previously.14,15 In the absence of prevalent diabetes, pre-diabetes was defined as a hemoglobin

≥5.7%-<6.5% or a fasting plasma glucose of 100-125mg/dL (5.6-6.9 mmol/L). To provide an

adequate sample size to power the efficacy endpoint of incident diabetes, enrollment was

targeted to achieve approximately 50% of patients without diabetes. Written informed consent

was obtained from all patients.

STUDY PROCEDURES

Eligible patients were randomly assigned in a 1:1 ratio to receive either lorcaserin 10mg twice

daily or placebo in a blinded fashion until the end of the follow-up period. Randomization was

stratified according to CV disease status (established CV disease or multiple CV risk factors

only). All patients were provided access to and encouraged to participate in a standardized

weight management program consisting of intensive multi-component behavior therapy that

included dietary and exercise information and unlimited telephonic access to a registered

dietician. Additional study procedures are previously described.14,15 After randomization,

medications for the treatment of diabetes may have been started, discontinued, or adjusted during

the study according to local standards of care (additional details in Supplementary Appendix).

Use of other pharmacologic weight loss agents was prohibited.

OUTCOMES

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The CV outcomes have been previously reported.15 The primary metabolic efficacy outcome

was the time to incident type 2 diabetes among patients with pre-diabetes at baseline. Based on

the American Diabetes Association guidelines, the primary definition for incident diabetes

required either a single occurrence of a random plasma glucose of ≥200mg/dL (11.1 mmol/L)

with symptoms of hyperglycemia, or another abnormal glycemic parameter (i.e. HbA1c≥6.5%,

fasting plasma glucose≥126mg/dL (7.0 mmol/L) or a 2-hour plasma glucose of ≥200mg/dL (11.1

mmol/L) during an oral glucose tolerance test) that was confirmed on simultaneous or

consecutive testing or with initiation of glucose-lowering medications (Supplementary

Appendix).16

Additional pre-specified metabolic secondary efficacy endpoints included incident diabetes in

the full non-diabetic population and achievement of normoglycemia (in the absence of any

glucose-lowering medications) in patients with pre-diabetes at baseline. In patients with

diabetes, pre-specified exploratory metabolic endpoints included achievement of normoglycemia

(in the absence of any glucose-lowering medications) and remission of hyperglycemia (i.e. shift

to pre-diabetes or normoglycemia in the absence of glucose-lowering medications).

Hypoglycemia was a pre-specified safety outcome of interest (see Supplementary Appendix).

Microvascular complications associated with diabetes, including retinopathy, neuropathy and

albuminuria, were pre-specified exploratory outcomes. Occurences of incident diabetic

retinopathy, and neuropathy were investigator-reported on a dedicated electronic case report

form. Incident persistent albuminuria was based on centrally-measured spot urinary albumin-to-

creatinine ratio (UACR)(definitions outlined in the Supplementary Appendix).

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A central clinical events adjudication committee, whose members were unaware of treatment

assignment, adjudicated events of incident diabetes using the primary trial definition

(Supplementary Appendix).16 Events using sensitivity definitions for diabetes and all definitions

for remission of pre-diabetes or diabetes were identified programatically based on the criteria

outlined in the Supplementary Appendix.

STATISTICAL ANALYSIS

CAMELLIA-TIMI 61 employed a two-step analysis procedure in which the primary assessment

was for CV safety, followed by an assessment of CV and metabolic efficacy, as previously

described.14 In the original protocol, study closure was dependent on accrual of a pre-specified

number both of CV (1401) and incident diabetes events (808) to provide 85% power to detect a

15% risk reduction in CV events at a 2-sided α=0.045 and 90% power to detect a 25% risk

reduction in incident diabetes at a 2-sided α=0.005.

In order to maintain trial timelines due to 1) a sponsor-mandated change in the primary analytic

population for incident diabetes from all patients without diabetes to only those with pre-diabetes

at baseline, and 2) a slower than anticipated accrual of incident diabetes events, the sponsor

amended the protocol prior to the interim data monitoring committee review to remove the

criterion for at least 808 patients developing incident diabetes. Prior to study closure, the

academic leadership elected to maintain CV and incident diabetes as co-primary efficacy

endpoints, each tested at a 2-sided alpha=0.05, estimating >450 events of conversion to diabetes

would provide >85% power to detect a 25% risk reduction.

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Definitions for glycemic subgroups, including patients with diabetes, pre-diabetes,

normoglycemia and no diabetes (i.e., pre-diabetes or normoglycemia) are detailed in the

Supplementary Appendix. The primary analysis for incident diabetes was in patients with pre-

diabetes at baseline with a secondary analysis in all patients without diabetes at baseline.

Efficacy analyses, including incident diabetes, were performed using the intention-to-treat

method, with on-treatment sensitivity analyses including events that occured prior to permanent

discontinuation of study drug. Safety analyses (i.e. hypoglycemic events) were conducted in the

safety population, defined as patients who underwent randomization, received at least one dose

of study drug and had at least one post-dose safety assessment, and included events during the

on-treatment period. Hazard ratios (HRs), 95% confidence intervals and p-values for time-to-

event analyses were generated with the use of Cox proportional-hazards model. The

stratification factor was included as a covariate in analyses of the full population. Additional

statistical procedures are described in the Supplementary Appendix.

RESULTS

A total of 12,000 patients who underwent randomization between January 2014 and November

2015 were followed for a median of 3.3 years (IQR, 3.0-3.5). Overall, the median age was 64

years, 64% were men, and the median BMI was 35kg/m2 (interquartile range, 32-39). As a

consequence of the enrollment criteria, at baseline, 6816 patients (57%) had diabetes, 3991

(33%) pre-diabetes and 1193 (10%) normoglycemia (Table 1). Also as a consequence of the

enrollment criteria, virtually all patients in the latter two cohorts had established CV disease:

91% had coronary artery disease, 10% cerebrovascular disease, and 6.4% peripheral artery

disease. Within the cohort with diabetes at baseline, 55% (N=3773) had established CV disease.

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Compared with patients without diabetes, patients with diabetes were more often female, with a

higher baseline weight and BMI. At baseline, the proportion of patients with diabetes on

metformin was 60%, insulin 29%, a sulfonylurea 25%, a glucagon-like peptide (GLP-1) receptor

agonist at diabetic dosing 8.9% and a sodium-dependent glucose cotransporter-2 (SGLT-2)

inhibtor 3.3%. (Table 1).

EFFECT ON WEIGHT PARAMETERS

The mean weight at baseline was 107.6±21.3 kg, 101.8±19.2 kg, and 97.8±17.0 kg in patients

with diabetes, pre-diabetes and normoglycemia, respectively (Table 1). At 1 year, the net weight

loss was significantly greater with lorcaserin compared with placebo for each of the 3 subgroups,

including those with diabetes (least-squares mean treatment difference at 1 year -2.6 kg [95% CI,

-2.9, -2.3], p<0.0001), pre-diabetes (-2.8 kg [-3.2, -2.5], p<0.0001) and normoglycemia (-3.3 kg

[-4.0, -2.6], p<0.0001)(Figure 1A, Supplementary Table 1). At 1 year, significantly more

patients randomized to lorcaserin versus placebo lost ≥5% of body weight in each subgroup:

diabetes (37% vs 17%, p<0.0001), pre-diabetes (40% vs 18%, p<0.0001) and normoglycemia

(42% vs 17%, p<0.0001; Supplementary Figure 1). The between-treatment group weight loss

remained significant within each glycemic subgroup over the duration of the trial (Figure 1A).

In patients with diabetes, weight loss was similar regardless of whether patients were taking

glucose-lowering medications at baseline that tend to promote weight gain (i.e. insulin,

sulfonylurea or thiazolidinedione) or glucose-lowering medications that tend to promote weight

loss (i.e. GLP-1 receptor agonist or SGLT-2 inhibitor) (Supplementary Figure 2).

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At 1 year, patients in the lorcaserin arms of each subgroup also had a greater reduction than

placebo in body mass index, waist circumference, and waist-to-hip ratio compared with placebo

in each of the glycemic subgroups (Supplementary Table 1).

EFFECT ON GLYCEMIC PARAMETERS

Median hemoglobin A1c at baseline was 6.8% (95% CI 6.2, 7.7), 5.8% (5.7, 5.8) and 5.4% (5.2,

5.5) in patients with diabetes, pre-diabetes and normoglycemia, respectively. At 1 year,

locarserin reduced hemoglobin A1c in patients with diabetes (least-squares mean treatment

difference at 1 year -0.3%, p<0.0001), with more modest but statistically significant effects in

patients with pre-diabetes (-0.1%, p<0.0001) and normoglycemia (-0.1%, p<0.0001)(Figure 1B,

Supplementary Table 2). The between-treatment differences in hemoglobin A1c remained

significant through at least 36 months follow-up (Figure 1B), in spite of upward trends in

hemoglobin A1c over time in all groups. In patients with diabetes with a baseline hemoglobin

A1c >8.0% (N=1166), the mean reduction in hemoglobin A1c at 1 year was substantially larger

at 0.9% (0.8, 1.0) with lorcaserin compared with 0.4% (0.2, 0.5) for placebo, translating to a net

reduction of 0.5% (0.4, 0.7; p<0.0001) (Supplementary Table 2). Fasting plasma glucose and

homeostatic model assessment of insulin resistance (HOMA-IR) were significantly improved

with lorcaserin compared with placebo, with the largest between treatment differences noted in

patients with diabetes at baseline (Figure 1C, Supplementary Table 2).

EFFECT ON GLUCOSE-LOWERING MEDICATIONS

Glucose-lowering medication utilization was lower in patients in the lorcaserin arm

(Supplementary Table 3). The proportion of patients with diabetes with initiation of a new

glucose-lowering medication was lower with lorcaserin than placebo at 1 year (13.1% vs 20.1%;

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p<0.0001), with a lower proportion of patients with new insulin initiation (1.6% vs. 3.9%;

p<0.0001) and new initiation of a non-insulin glucose-lowering medications (12.3% vs. 18.1%;

p<0.0001). Likewise, among patients with diabetes, there was a higher proportion of patients

with discontinuation of glucose lowering medications at 1 year with lorcaserin compared with

placebo (10.1% vs. 7.9%; p=0.0045).

PREVENTION OF INCIDENT DIABETES

Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes at baseline

(8.5% [172/2015] vs. 10.3% [204/1976]; HR 0.81; 95% CI, 0.66-0.99; p=0.0380; Figure 2 and

3), corresponding to a number-needed to treat of 56 to prevent one event of diabetes over 3

years. Similar results were observed in all patients without diabetes at baseline with a 23%

reduction (6.8% [174/2615] vs 8.4% [215/2569]; HR 0.77, 0.63-0.94; p=0.0116; Figure 3).

When analyzed while patients were on study-drug, lorcaserin reduced the incidence of diabetes

in patients with pre-diabetes by 25% (6.8% vs. 8.7%; HR 0.75, 0.60-0.94; p=0.0130) and in all

patients without diabetes by 28% (5.2% vs 6.9%; HR 0.72, 0.58-0.90; p=0.0042) (Figure 3).

Results were similar in sensitivity analyses using alternative definitions of incident diabetes,

including where confirmation of abnormal glycemic parameters was not required to be

consecutive (12.3% vs. 16.4%; HR 0.72, 0.61-0.85; p<0.0001) or not required (19.8% vs 25.7%;

HR 0.73, 0.64-0.83; p<0.0001) (Supplementary Figure 3). Effects of lorcaserin on incident

diabetes were largely consistent across subgroups (Supplementary Figure 4).

REMISSION OF DIABETES

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Rates of achievement of normoglycemia in patients with pre-diabetes (i.e. normalization of

glycemic parameters in the absence of any glucose-lowering medication utilization) were 9.2%

with lorcaserin and 7.6% with placebo (HR 1.20, 0.97-1.49; p=0.093; Figure 4) using persistent

criteria (i.e., requiring confirmation and maintainance throughout the duration of follow-up).

The magnitude of effect of lorcaserin was consistent in sensitivity analyses using sustained

achievement (i.e., confirmation on at least 2 consecutive assessments separated in time; HR 1.46;

1.29-1.65; p<0.0001) and any achievement (i.e., criteria met on at least 1 occaision; HR 1.26;

1.16-1.37; p<0.0001). Similar results were seen for locarserin facilitating achievement of

normoglycemia in patients with diabetes and in patients with either diabetes or pre-diabetes, both

using the intention-to-treat method and while patients were on study drug (Figure 4 and

Supplementary Table 4).

Lorcaserin resulted in more patients with diabetes experiencing remission of their hyperglycemia

(i.e. shift to pre-diabetes or normoglycemia) in the absence of any glucose-lowering medication

using persistent (HR 1.21, 1.00-1.45; p=0.049), sustained (p=0.0004) and any (p=0.0029) criteria

(Figure 4), with similar findings observed using an on-treatment analysis (Supplementary Table

4).

In patients with diabetes at baseline, the rates of remission of hyperglycemia and achievement of

normoglycemia were lower in patients with a longer duration of diabetes, less pancreatic reserve,

or use of one or more glucose-lowering agents at baseline, including insulin or a sulfonylurea,

but the relative benefits with lorcaserin compared with placebo were consistent across subgroups

(Supplementary Figure 5).

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DIABETIC MICROVASCULAR COMPLICATIONS

Lorcaserin reduced the risk of diabetic microvascular complications, a composite of incident

persistent microalbuminuria, diabetic retinopathy or diabetic neuropathy, by 21% in patients with

diabetes at baseline (10.1% vs 12.4%, HR 0.79, 0.69-0.92; p=0.0015) (Table 2). There was

directional consistency in the individual components, with a HR of 0.77 (95% CI 0.66-0.90) for

new microalbuminuria, 0.84 (95% CI 0.50-1.43) for retinopathy and 0.94 (95% CI 0.67-1.32) for

neuropathy.

HYPOGLYCEMIA

Hypoglycemia was reported in 223 (6.6%) patients with diabetes in the lorcaserin arm compared

with 199 (5.8%; p=0.18), with most (>85% of events) occurring in patients on either insulin or a

sulfonylurea at baseline (196 vs 171 events of hypoglycemia; p=0.18; Supplementary Table 5).

There was a numeric imbalance in severe hypoglycemia with serious complications, requiring

either hospitalization or considered life-threatening or disabling (12 [0.4%] with lorcaserin vs 4

[0.1%] with placebo; p=0.054). There were no fatal events of hypoglycemia. Hypoglycemia

was rare in patients who did not meet criteria for diabetes at baseline (9 [0.3%] vs 3 [0.1%]

events of hypoglycemia; p=0.10)

DISCUSSION

Lorcaserin, a 5HT2C receptor agonist, is effective for weight loss, and in contrast to many other

obesity medications to date, has proven safety for major adverse cardiovascular events, including

CV death, myocardial infarction or stroke.15 Now, in addition to proven persistent weight loss

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efficacy with extended duration use, we report that when added to lifestyle interventions,

lorcaserin significantly reduced the incidence of diabetes, tended to increase achievement of

normoglycemia in patients with pre-diabetes, increased the rate of remission of hyperglycemia in

patients with diabetes, and reduced the risk of diabetic microvascular complications. Taken

together, these findings reinforce the notion that modest, durable weight loss can improve

cardiometabolic health and supports the role of lorcaserin as an adjunctive therapy in chronic

weight management and metabolic health.

A significant body of literature supports the glycemic benefit of weight loss via lifestyle,

pharmacologic or surgical means. In the Diabetes Prevention Program (DPP) randomized trial,

lifestyle interventions resulted in an average net weight loss of 5.5kg and reduced the incidence

of diabetes by 58%.17,18 Similarly, intensive lifestyle modification in the LOOK AHEAD

randomized trial resulted in durable reduction in hemoglobin A1c compared with standard of

care, where greater weight loss was associated with more robust improvements in glycemic and

other parameters.19,20 A cluster-randomized trial in patients with type 2 diabetes and obesity had

a 20-fold greater odds of diabetes remission with a structured weight management program

compared with standard of care.21 Based on these and other studies, the NHLBI concluded that

2-5% weight loss by lifestyle interventions can lead to a 0.2-0.3% reduction in HbA1c and

weight losses of 5-10%, a 0.6-1.0% reduction in HbA1c.6 Another weight loss drug, orlistat,

reduced weight by close to 3 kg after 4 years and reduced the risk of incident diabetes by 37% in

obese patients with pre-diabetes at baseline.22 Not surprisingly, dedicated glucose-lowering

medications such as metformin and thiazolidinediones also reduce the incidence of diabetes in

patients with pre-diabetes.23,24 Moreover, the GLP-1 receptor agonist class of glucose-lowering

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medications also cause weight loss. Using the weight management dosing, liraglutide, resulted

in a 4.3% net weight loss and a 79% reduction in incident diabetes at 3 years in obese patients

with pre-diabetes.25 Bariatric surgery, which tends to result in more robust, sustained weight loss

than other strategies (typically ~15-60%), results in profound improvements in glycemic

parameters in the range of 1.5-3.0% decrease in HbA1c, a 60-80% reduction in incident diabetes

and 30-95% rate of remision in patients with diabetes.26-30 The observed reduction in incident

diabetes observed in CAMELLIA-TIMI 61 is consistent with this prior literature, in that

lorcaserin reduced weight by 2.8-3.3 kg and the risk of incident diabetes by 19% reduction in

patients with pre-diabetes and a 23% reduction in all patients without diabetes. Not surprisingly,

the benefit was more pronounced when analyzed in patients actually on study drug, showing a

25-28% relative reduction in risk of incident diabetes in patients with pre-diabetes or no diabetes

at baseline.

In CAMELLIA-TIMI 61, patients with diabetes were well-controlled at baseline with a mean

HbA1c of 7.0%. Despite this relatively low baseline HbA1c, the net decrease in hemoglobin

A1c of 0.3% at 1 year in patients with diabetes compares favorably to the other targeted weight

loss agents and with the HbA1c reductions observed in similarly designed outcome trials with

glucose-lowering agents.31,32 Notably, this reduction was observed in the setting of open titration

of background glucose-lowering medications, potentially attenuating the difference in HbA1c

between treatment arms. Furthermore, in patients with a baseline hemoglobin of >8.0%,

lorcaserin resulted in a net reduction in HbA1c of 0.5%. Moreover, lorcaserin resulted in fewer

new initiations of insulin and other glucose-lowering medications and more discontinuations of

glucose lowering medications in patients with diabetes. Lastly, lorcaserin demonstrated a

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favorable trend for achievement of normoglycemia in patients with pre-diabetes and increased

the likelihood of remission of hyperglycemia in patients with diabetes. Consistent point

estimates were observed across several definitions for glycemic outcomes, including ones more

stringent than are typically used in clinical practice.

Hypoglycemia was previously observed to be more frequent in patients with diabetes receiving

lorcaserin compared with placebo. In the current study, severe hypoglycemia with serious

complications was numerically increased with all but 1 event occuring in patients with diabetes

receiving insulin or sulfonylurea. This finding highlights the importance of careful titration of

agents known to cause hypoglycemia in the setting of major physiologic changes, such as weight

loss.

Given the previously discussed observations regarding the dose-response relationship between

the magnitude of weight loss and improvements in glycemic parameters, it is presumed that

much of the glycemic benefit is weight dependent. Of note, at 1 year, lorcaserin resulted in a

modest, but sustained weight loss in all glycemic subgroups. As has been observed with

lorcaserin previously and with other agents and weight loss strategies (e.g. lifestyle

interventions), the proportionate weight loss tended to be less in patients with dysglycemia. 4,11-13

Specifically, at 1 year, patients with diabetes had a net weight loss of 2.6% compared to 2.8% in

those with pre-diabetes and 3.3% in those with normoglycemia. The reason for this somewhat

lesser degree of weight loss in patients with diabetes has not been definitely elucidated.

Moreover, it is interesting to note that in the CAMELLIA-TIMI 61 study, reductions in glycemic

parameters were maximal as soon as 3 months, well in advance of the nadir in weight, which

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tended to occur at 12 months. Similar observations were made in BLOOM-DM, where fasting

plasma glucose decreased with lorcaserin compared with placebo as early as 2 weeks after

initiation of therapy, prior to any significant weight loss.33 Pre-clinical data suggests that central

and neurohormonal signaling pathways downstream of the 5HT-2C receptor can suppress

hepatic gluconeogenesis.34 It is not known whether the early glycemic changes are due to

decreased caloric intake and/or an alternative mechanism, such as suppression of hepatic

gluconeogenesis.

While it is well described that glycemic control reduces microvascular complications in patients

with diabetes, the data linking weight loss to a benefit in microvascular complications of diabetes

are limited.16 Lifestyle intervention in the DPP trial did not significantly reduce the rate of

microvascular complications after 15 years of follow, despite the lower rates of incident diabetes

compared with standard of care.35 The only randomized assessment for microvascular outcomes

after bariatric surgery comes from the STAMPEDE trial, which found numerically small but

statistically significant reductions in UACR in the normal range at 5 years with bariatic surgery

compared with medical therapy in patients with diabetes. 26 There was no difference in the

proprotion of subjects who remained free of albuminuria or retinopathy. Long-term

observational data from the Swedish Obese Study (SOS) found that bariatric surgery was

associated with a 56% lower incidence of microvascular complications at 20 years follow-up.36

Liraglutide, when studied at the lower dose approved for diabetes (1.8mg daily) resulted in a

reduction in nephropathy.37 In the CAMELLIA-TIMI 61 study, lorcaserin significantly reduced

the incidence of microvascular complications of diabetes, approximately 80% of which in this

trial were nephropathy as manifested by incident persistent microalbuminuria.

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There are limitations of this study. While UACR was measured centrally, the other

microvascular events of neuropathy and retinopathy were investigator-reported. In the absence

of protocol-specified screening procedures (e.g. retinal exam), there was a possibility of

undetected abnormalities at baseline as well as probable under-detection and reporting during

follow-up; nevertheless, the comparisons between treatment arms would remain un-biased.

Further, the benefits shown on microvascular events were driven numerically by effects on

albuminuria with far fewer retinopathy and neuropathy events reported. Even larger studies

would be needed to confirm the favorable trends in the latter outcomes. The specific

mechanism(s) of benefit for improvements in glycemic and microvascular outcomes cannot be

determined from this study. While the protocol offered guidelines for titration of glucose-

lowering medications in the setting of weight loss and improvements in glycemia, it is likely that

there was a range of approaches utilized with varied outcomes. For example, we observed more

discontinuation of glucose-lowering medications with lorcaserin than placebo. We also observed

a trend towards more serious hypoglycemia in patients on lorcaserin and agents known to

precipitate hypoglycemia (i.e. insulin and sulfonylureas), which may reflect reduced caloric

intake and/or greater weight loss with insufficient downtitration of those agents. While several

weight parameters were captured, including weight, body mass index, waist circumference and

waist-to-hip ratio, measures of body composition or fat distribution were not collected. Lastly,

there was no adjustment for multiplicity, where the co-primary efficacy endpoints of CV events

and incident diabetes were each tested at a nominal alpha of 0.05. This approach was felt to be

reasonable because of the 1) distinct hypotheses for the effect of lorcaserin on cardiovascular

events versus incident diabetes, 2) the fact that the hypothesis testing for incident diabetes was

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performed primarily in patients with pre-diabetes, a subpopulation distinct from the analytic set

used for CV outcomes, and 3) the well-validated association of weight loss and prevention of

incident diabetes with other modalities.6

CONCLUSIONS

On the background of lifestyle modification, lorcaserin resulted in modest, but durable, weight

loss in overweight and obese patients with and without diabetes and to overall improvements in

glycemic control, with lower rates of incident diabetes, higher rates of remission of

hyperglycemia, favorable trends for achievement of normoglycemia and a lower risk of diabetic

microvascular complications.

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Declaration of InterestsDr. Bohula reports grants from Eisai, during the conduct of the study; personal fees from Servier, personal fees from Merck, personal fees from NIH, personal fees from Lexicon, personal fees from Medscape, personal fees from Academic CME, personal fees from MD Conference Express, personal fees from Paradigm, personal fees from Novartis, grants from Amgen, grants from Astra Zeneca, grants from Merck, outside the submitted work. Dr. Bonaca reports grants from BWH/TIMI Study Group, during the conduct of the study; grants and other from Amgen, other from Aralez, grants and other from AstraZeneca, other from Bayer, other from Janssen, grants from MedImmune, grants, personal fees and other from Merck, grants from Pfizer, other from Sanofi, outside the submitted work. Dr. Corbalan and Dr. Dwyer report personal fees from Eisai Inc, during the conduct of the study. Dr. Inzucchi reports personal fees from Eisai, during the conduct of the study; personal fees from Merck, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Janssen, personal fees from AstraZeneca, personal fees from Novo Nordisk, personal fees from Sanofi/Lexicon, personal fees from Intarcia, personal fees from Daiichi Sankyo, personal fees from Alere, personal fees from VTV Therapeutics, outside the submitted work. Ms. Kanevsky reports grants from Abbott Laboratories, grants from Amgen, grants from AstraZeneca, grants from Critical Diagnostics, grants from Daiichi-Sankyo, grants from Eisai, grants from GlaxoSmithKline, grants from Intarcia, grants from Merck, grants from Roche Diagnostics, grants from Takeda, grants from Gilead, grants from Poxel, grants from Novartis, grants from MedImmune, grants from Janssen Research Development, grants from Genzyme, outside the submitted work. Dr. Keech reports other from Eisai, during the conduct of the study; grants and personal fees from Abbott, personal fees from Amgen, personal fees from Astra-Zeneca, grants and personal fees from Mylan, personal fees from Pfizer, grants from Sanofi, grants from Novartis, personal fees from Bayer, outside the submitted work. Dr. Leiter reports personal fees from Eisai Inc, during the conduct of the study; grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Eli Lilly, grants and personal fees from Janssen, grants and personal fees from Merck, grants and personal fees from Novo Nordisk, grants and personal fees from Sanofi, personal fees from Servier, grants from GSK, outside the submitted work. Dr. McGuire reports personal fees from Eisai Co., Ltd, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from Janssen Research and Development LLC, personal fees from Sanofi US, personal fees from Merck Sharp and Dohme Corp., personal fees from Eli Lilly and Company, personal fees from Novo Nordisk, personal fees from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Lexicon, personal fees from Eisai Co., Ltd, personal fees from Esperion, personal fees from Metavant, personal fees from Pfizer, outside the submitted work. Dr. Murphy reports grants from Abbott Laboratories, grants from Amgen, grants from AstraZeneca, grants from Critical Diagnostics, grants from Daiichi-Sankyo, grants from Eisai, grants from GlaxoSmithKline, grants from Intarcia, grants and honorarium from Merck, grants from Roche Diagnostics, grants from Takeda, grants from Gilead, grants from Poxel, grants from Novartis, grants from MedImmune, grants from Janssen Research Development, grants from Genzyme, outside the submitted work. Dr. Nicolau reports personal fees from AMGEN, grants from Astrazeneca, grants from Bayer, grants from BMS, grants from CLS Behring, grants from Dalcor, personal fees from Servier, grants from Novartis, grants and personal fees from Sanofi, grants from Vifor, grants from Pfizer, outside the submitted work. Drs. Patel, Miao and Perdomo report employment for Eisai. Dr. Ray reports personal fees from Abbvie, grants and personal fees from Amgen, personal fees

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from Astra Zeneca, grants and personal fees from Sanofi, grants and personal fees from Regeneron, grants and personal fees from MSD, grants and personal fees from Pfizer, personal fees from Medco, personal fees from Resverlogix, personal fees from Akcea, personal fees from Boehringer Ingelheim, personal fees from Novo Nordisk, personal fees from Takeda, personal fees from Kowa, personal fees from Cerenis, personal fees from Cipla, personal fees from Algorithm, from Esperion, outside the submitted work. Dr. Ruff reports grants from Eisai, during the conduct of the study; grants and personal fees from Boehringer-Ingelheim, personal fees from Bayer, personal fees from Janssen, personal fees from Portola, grants and personal fees from Daiichi Sankyo, outside the submitted work. Dr. Sabatine reports grants from Eisai, during the conduct of the study; grants and personal fees from Amgen, grants and personal fees from AstraZeneca, grants from Daiichi-Sankyo, grants from Eisai, grants from GlaxoSmithKline, grants and personal fees from Intarcia, grants and personal fees from Janssen Research and Development, grants and personal fees from Medicines Company, grants and personal fees from Medimmune, grants and personal fees from Merck, grants and personal fees from Novartis, grants from Pfizer, grants from Poxel, grants from Takeda, personal fees from Bristol-Myers Squibb, personal fees from CVS Caremark, personal fees from Dyrnamix, personal fees from Esperion, grants from Abbott Laboratories, grants from Critical Diagnostics, grants from Genzyme, grants from Gilead, grants from Roche Diagnostics, personal fees from Alnylam, personal fees from Ionis, personal fees from MyoKardia, outside the submitted work. Dr. Scirica reports grants from Eisai, during the conduct of the study; grants from AstraZenaca, grants from Novartis, grants from Merck, personal fees from AstraZeneca, personal fees from Biogen Idec, personal fees from Boehringer Ingelheim, personal fees from Covance, personal fees from Dr. Reddy’s Laboratory, personal fees from Eisai, personal fees from Elsevier Practice Update Cardiology, personal fees from GlaxoSmithKline, personal fees from Merck, personal fees from NovoNordisk, personal fees from Sanofi, personal fees from St. Jude's Medical, other from Health [at] Scale, outside the submitted work. Dr. Smith reports personal fees from Eisai, outside the submitted work. Dr. Wiviott reports grants from EISAI, during the conduct of the study; grants from AMGEN, grants and personal fees from Arena, grants and personal fees from AstraZeneca, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Daiichi Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Janssen, grants, personal fees and other from Merck, grants from Sanofi-Aventis, personal fees from Aegerion, personal fees from Allergan, personal fees from Angelmed, personal fees from Boehringer Ingelheim, personal fees from Boston Clinical Research Institute, personal fees from Icon Clinical, personal fees from Lexicon, personal fees from St Jude Medical, personal fees from Xoma, outside the submitted work.

Author ContributionsAll authors contributed to study oversight, data interpretation, manuscript writing and revisions. Erin A. Bohula, Benjamin M. Scirica, Marc S. Sabatine, Stephen D. Wiviott, Silvio E. Inzucchi, Darren K. McGuire, Anthony C. Keech, Steven R. Smith, Lawrence A. Leiter, Jamie Dwyer, Tushar Patel, Wenfeng Miao, Carlos Perdomo, Bruce Francis, Estella Kanevsky, Sabina A. Murphy and Shobha Dhadda contributed to study design, sutdy conduct, and data analysis. Marc P. Bonaca and Christian T. Ruff contributed to study conduct.

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TABLESTable 1: Baseline Characteristics by Glycemic Status

DiabetesN=6816 (57%)

Pre-DiabetesN=3991 (33%)

NormoglycemiaN=1193 (10%)

DemographicsAge in yrs (median, IQR) 64 [59, 69] 64 [58, 70] 62 [56, 68]Male 4069 (60) 2865 (72) 768 (64)Caucasian 5800 (85) 3718 (93) 1122 (94)Weight in kg (median, IQR) 105 [92, 120] 100 [88, 112] 96 [86, 107]BMI in kg/m2 (median, IQR) 36 [33, 41] 34 [31, 37] 33 [30, 37] BMI <30 kg/m2 654 (10) 668 (17) 253 (21) BMI 30-<40 kg/m2 4219 (62) 2734 (69) 802 (67) BMI ≥40 kg/m2 1943 (29) 589 (15) 138 (12)Region

North America 6290 (92) 2695 (68) 807 (68)Europe 198 (2·9) 633 (16) 154 (13)Central & South America 41 (0·6) 234 (5·9) 97 (8·1)Asia/Pacific 287 (4·2) 429 (11) 135 (11)

Co-morbiditiesHypertension 6389 (94) 3477 (87) 982 (82)Hyperlipidemia 6428 (94) 3722 (93) 1079 (90)eGFR < 60 ml/min/1·73 1565 (23) 614 (15) 178 (15)ACR30 mg/dL, no·/no· total (%) 1685/6806 (25) 490/3983 (12) 103/1192 (8·6)hsCRP>3mg/L, no·/no· total (%) 3060/6793 (45) 1244/3982 (31) 336/1192 (28)Hemoglobin A1c, % (median, 95% CI) 6.8 (6.2, 7.7) 5.8 (5.7, 5.8) 5.4 (5.2, 5.5)Duration of Diabetes, yrs (mean, SD) 10·4±8·6 - -CV StrataMultiple CV Risk Factors 3039 (45) 2 (0·1) 1 (0·1)Established CV Disease 3777 (55) 3989 (>99) 1192 (>99)

Coronary artery disease 3435 (50) 3666 (92) 1052 (88)Prior MI 1955 (29) 2204 (55) 613 (51)Prior coronary revascularization 3049 (45) 3301 (83) 947 (79)

Peripheral arterial disease 327 (4·8) 242 (6·1) 88 (7·0)Cerebrovascular disease 586 (8·6) 415 (10) 129 (11)

Baseline Medications Any diabetes medication 5670 (83) - - Insulin 1960 (29) - - GLP-1 receptor agonist 607 (8·9) - - SGLT-2 inhibitor 227 (3·3) - - Metformin 4115 (60) - - DPP4 inhibitor 662 (9·7) - - Sulfonylurea 1731 (25) - - TZD 315 (4·6) - - ASA 4584 (67) 3448 (86) 1015 (85) Statin 5657 (83) 3587 (90) 1008 (84) ACEi/ARB 5462 (80) 2794 (70) 750 (63)

Number denotes proportion (%) unless otherwise specified. P-value for trend <0·001 for all variables across glycemic subgroups. Baseline characteristics were well matched by randomization within each subgroup outside of clinically minimal differences for patients with diabetes in the rates of hypertension (93 vs 94%), in patients with pre-diabetes for weight (100 vs 99kg), and for patients with normoglycemia in ACEi/ARB use (60 vs 66%).

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Table 2: Incident Microvascular Complications of Diabetes in Patients with Diabetes at Baseline

Endpoint Lorcaserin(N=3385)

Placebo(N=3431)

HR (95% CI) p-value

Microvascular composite 341 (10.1) 427 (12.4) 0.79 (0.69, 0.92) 0.0015

Persistent microalbuminuria 265 (7·8) 343 (10·0) 0·77 (0·66, 0·90) 0·0015

Diabetic retinopathy 25 (0·7) 30 (0·9) 0·84 (0·50, 1·43) 0·53

Diabetic neuropathy 64 (1·9) 69 (2·0) 0·94 (0·67, 1·32) 0·71

Event rate (%) represents n/N in the total population using the intention-to-treat method. Microvascular composite of new microalbuminuria, retinopathy or neuropathy.

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FIGURE LEGENDS

Figure 1: Weight & Glycemic Parameters Over Time By Glycemic Subgroup. Change from baseline in A) weight (in kilograms), B) hemoglobin A1c (HbA1c) and C) fasting plasma glucose (FPG) in subgroup with diabetes, pre-diabetes and normoglycemia at baseline. All analyses conducted in the intention-to-treat population. Change from baseline shown as least-squared means and 95% confidence interval based on linear mixed effect model with repeated measures including model terms with treatment, visit, visit by treatment interaction, baseline value and randomization strata.

Figure 2: Cumulative Incidence of Incident Diabetes. In patients with pre-diabetes at baseline according to the intention-to-treat method. HR denotes hazard ratio.

Figure 3: Incident Diabetes by Randomized Treatment in Patients with Pre-Diabetes and Normoglycemia. Event rate (%) represents n/N. According to primary analysis based on ADA definition requiring confirmation of abnormal parameter (e.g. hemoglobin A1c, fasting plasma glucose or oral glucose tolerance test) with confirmation on simultaneous or consecutive testing (as defined in the Supplementary Appendix) in patients with pre-diabetes and patients without diabetes (No DM, i.e., pre-diabetes or normoglycemia) at baseline including events during complete follow-up (intention-to-treat) or only during the on-treatment window.

Figure 4: Remission of Diabetes or Pre-diabetes. Event rate (%) represents n/N in the total population using the intention-to-treat method. Remission of hyperglycemia is defined as HbA1c of <6·5% and fasting plasma glucose <126mg/dL (<7.0 mmol/L) in the absence of anti-hyperglycemia medication in patients with diabetes at baseline. Achievement of normoglycemia is defined as HbA1c of ≤5·6% and fasting plasma glucose <100mg/dL (<5.5 mmol/L) in the absence of anti-hyperglycemia medication in patients with diabetes and/or pre-diabetes at baseline. Both criteria (HbA1c and FPG) required only if both tests are available. “Persistent” requires criteria to be achieved, confirmed and maintained through the duration of the study. “Sustained” requires criteria to be achieved, confirmed and maintained for 2 consecutive measurements separated by 30 days or more. “Any” is defined by achievement of at least one criteria at one or more time points during the study.

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Figure 1: Weight & Glycemic Parameters Over Time By Glycemic Subgroup

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Figure 2: Cumulative Incidence of Diabetes

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Figure 3: Incident Diabetes by Randomized Treatment in Patients with Pre-Diabetes and Normoglycemia

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Figure 4: Remission of Diabetes or Pre-diabetes

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