Effect of Ranolazine Monotherapyon Glycemic Control in SubjectsWith Type 2 DiabetesDOI: 10.2337/dc14-2629

OBJECTIVE

Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiaclate sodium current. Although ranolazine is not approved for the treatment oftype 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine wasassociatedwith reductions in percent glycosylated hemoglobin (HbA1c) in subjectswith type 2 diabetes. The study prospectively assessed the safety and efficacy ofranolazine in subjects with type 2 diabetes with inadequate glycemic controlmanaged by lifestyle alone.

RESEARCH DESIGN AND METHODS

The studywas conductedworldwide in 465 subjects, with baseline HbA1c of 7–10%(53–86 mmol/mol) and fasting serum glucose of 130–240 mg/dL, randomized toplacebo versus ranolazine.

RESULTS

Compared with placebo, there was a greater decline in HbA1c at week 24 frombaseline (primary end point) in subjects taking ranolazine (mean difference20.56% [26.1 mmol/mol]; P < 0.0001). Moreover, the proportion of subjectsachieving an HbA1c <7.0% was greater with ranolazine (25.6% vs. 41.2%;P 5 0.0004). Ranolazine was associated with reductions in fasting (mean dif-ference28 mg/dL; P5 0.0266) and 2-h postprandial glucose (mean difference219 mg/dL; P 5 0.0008 vs. placebo). Subjects taking ranolazine trendedtoward a greater decrease from baseline in fasting insulin (P 5 0.0507), agreater decrease in fasting glucagon (P 5 0.0003), and a lower postprandial3-h glucagon area under the curve (P 5 0.0031 vs. placebo). Ranolazine wassafe and well tolerated.

CONCLUSIONS

Compared with placebo, use of ranolazine monotherapy over 24 weeks, in sub-jects with type 2 diabetes and inadequate glycemic control on diet and exercisealone, significantly reduced HbA1c and other measures of glycemic control.

Type 2 diabetes is a global health problem with increasing prevalence, associatedwith significant cardiovascular morbidity and mortality. The incidence of type 2diabetes is increased in patients with acute coronary syndrome (ACS) (1), andsuch patients also have increased risk for coronary artery disease (CAD), CAD-related death, and stroke (2). The presence of type 2 diabetes is associated with aworse prognosis in patients with stable and unstable CAD (3,4). Thus, it may bedesirable to have drugs that target both type 2 diabetes and CAD.

1Divisions of Endocrinology, Metabolism and Di-abetes and Cardiology, Department of Medicine,University of Colorado School of Medicine,Anschutz Medical Campus, Aurora, CO2Center for Metabolic Research, VA San DiegoHealthcare System, San Diego, CA3Division of Endocrinology andMetabolism, Uni-versity of California, San Diego, La Jolla, CA4Cardiovascular Clinical Research, Gilead Sci-ences, Foster City, CA5Department of Biology, Cardiovascular Thera-peutic Area, Gilead Sciences, Fremont, CA6Cardiovascular Therapeutic Area, Biostatistics,Gilead Sciences, Foster City, CA7Divisions of Endocrinology, Diabetes, and Me-tabolism, Pediatrics, and Psychology, Universityof Miami Miller School of Medicine, Miami, FL

Corresponding author: Robert H. Eckel, robert.eckel@ucdenver.edu.

Received 5 November 2014 and accepted 7January 2015.

Clinical trial reg. no. NCT01472185, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-2629/-/DC1.

© 2015 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

Robert H. Eckel, 1 Robert R. Henry, 2,3

Patrick Yue, 4 Arvinder Dhalla, 5

Pamela Wong, 6 Philip Jochelson, 4

Luiz Belardinelli, 4,5 and Jay S. Skyler 7

Diabetes Care 1

DIABETES

CARESYMPOSIU

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Diabetes Care Publish Ahead of Print, published online June 6, 2015

Ranolazine is a first-in-class antianginaldrug with cardioprotective propertiesthat does not affect heart rate or bloodpressure (5). The proposedmechanism ofits anti-ischemic effects is inhibitionof late sodium current due to blockadeof the cardiac isoform of the sodiumchannel, Nav1.5 (6). Ranolazine has beenshown to be safe and effective in treatingchronic angina both as monotherapy(Monotherapy Assessment of RanolazineIn Stable Angina [MARISA] trial) and incombination with commonly prescribedcardiovascular drugs (Combination As-sessment of Ranolazine In Stable Angina[CARISA] and Efficacy of Ranolazine InChronic Angina [ERICA] trials) in subjectswith established CAD, including sub-groups of those with diabetes (5,7–9).In clinical trials in chronic angina,

ranolazine treatment was associatedwith significant reductions in glycosyl-ated hemoglobin (HbA1c) (5,9–11).Data from the CARISA study showedthat ranolazine, in a dose-dependentmanner, lowered HbA1c in subjectswith chronic angina and type 2 diabetes(9). Data from the MERLIN-TIMI-36study revealed that ranolazine loweredHbA1c in subjects with diabetes and re-duced the incidence of newly elevatedHbA1c in initially normoglycemic sub-jects (10,11).In nonclinical studies, ranolazine was

found to lower fasting and nonfastingglucose levels and preserve pancreaticb-cells in streptozotocin-treated mice andZucker diabetic fatty rats (12,13). Morerecent data show that ranolazine inhibitsglucagon secretion by blocking the Nav1.3isoform of sodium channels in pancreatica-cells, leading to glucagon- and glucose-lowering effects in animal models ofdiabetes (13). Given that increases in glu-cagon secretion by a-cells and the failureof glucagon suppression following oralglucose are well documented in type 2diabetes (14,15), these data suggest anovel and plausible mechanism for rano-lazine’s putative antidiabetic properties.Although the HbA1c-lowering effect

of ranolazine has been observed infour previous clinical studies, thosestudies were not prospectively designedto determine the effect of ranolazine onglycemic parameters. In addition, the ef-fect of ranolazine on HbA1c in these tri-als was studied in the presence of otherantidiabetic medications (which werenot controlled). We present the first

double-blind, randomized, placebo-controlled trial evaluating the safetyand efficacy of ranolazine monotherapyin subjects with type 2 diabetes and in-adequate glycemic control with diet andexercise alone.

RESEARCH DESIGN AND METHODS

The ranolazine monotherapy study(ClinicalTrials.gov identifier NCT01472185)was one of three randomized, double-blind, placebo-controlled, multicenterphase 3 clinical trials conducted to in-vestigate the effect of ranolazine on gly-cemic control. This study enrolledsubjects with inadequately controlledtype 2 diabetes who were either treat-ment naıve or had been washed off oftheir background antihyperglycemicmedications.

SubjectsEligible subjects were men and womenaged 18–75 years, with an establisheddiagnosis of type 2 diabetes, an HbA1cof 7–10% (53–86 mmol/mol), and a fast-ing serumglucose (FSG) of 130–240mg/dLat screening and at the end of a preran-domization qualifying period (see STUDY

DESIGN below). Other inclusion criteriaincluded a BMI of 25–45 kg/m2 and afasting serum C-peptide $0.8 ng/mL.Key exclusion criteria included type 1 di-abetes, severe hypoglycemia, myocar-dial infarction (MI), ACS, coronaryrevascularization, stroke, or transient is-chemic attack (TIA) within 3 months,inadequately controlled hypertension(i.e., .160/100 mmHg), a QT interval.500 ms, bariatric surgery or significantweight change within 2 months, an es-timated glomerular filtration rate ,30mL/min/1.73 m2, and prior ranolazinetreatment.

Study DesignThe study consisted of a screeningperiod, a 14-day qualifying period, a24-week treatment period, and a14-day safety follow-up period. Poten-tially eligible subjects had to be eithertreatment na ıve or washed off of allantihyperglycemic therapy for 90 days(24 weeks for thiazolidinediones). Dur-ing the qualifying period, subjects weretreated with single-blind placebo, re-ceiving one tablet twice daily. At theend of the qualifying period, subjectswho were $80% compliant with dos-ing and continued to meet all eligibilitycriteria (including HbA1c 7–10% and

FSG 130–240 mg/dL) proceeded torandomization.

Subjects entering the treatment periodwere randomized in a 1:1 ratio to receiveeither ranolazine or matching placebo for24 weeks. Randomization was stratifiedby baseline HbA1c (#8 vs. .8% [64mmol/mol]); enrollment of subjects withHbA1c #8% was capped at half the totalenrollment. Ranolazine was started at500 mg twice daily and then uptitratedto 1,000 mg twice daily after 7 days. Sub-jects taking placebo were given matchingtablets during treatment. Subjects took1,000 mg twice daily throughout thetreatment period but were permitted todowntitrate to 500 mg twice daily (ormatched placebo) for tolerability at thediscretion of the site investigator. Sub-jects who continued to experience intol-erance to study drug underwent an earlytermination (ET) visit and were discontin-ued from the study.

During the treatment period, subjectsreturned to the clinic for efficacy andsafety assessments at weeks 6, 12, 18,and 24 and ET visits for subjects whoprematurely discontinued the study.HbA1c, FSG, fasting serum insulin, fast-ing serum C-peptide, fasting plasma glu-cagon, and safety laboratory valueswere measured. In addition, 12-leadelectrocardiograms (ECGs), fasting lipidprofiles, and mixed-meal tolerance test-ing (MMTT) were performed at weeks12 and 24 and at ET visits.

For the MMTTs, subjects were re-quired to fast for 8 h and take theirdose of study drug (single-blind placeboat randomization, double-blind ranolazine,or placebo at weeks 12 and 24 and ETvisits) at the study site 60 min prior totheMMTT. Subjects consumed a standardglucose-containing drink (i.e., Boost Plus)containing 15% protein, 50% carbohy-drate, and 35% fat, with a caloric contentof 360 kcal per 240mL. Serial postprandialblood samples were collected 15, 30, 45,60, 120, 150, and 180 min after the mealfor determinationof serumglucose, seruminsulin, serum C-peptide, and plasmaglucagon.

During the treatment period, subjectsfound to be persistently hyperglycemicwere given open-label rescuemedication,in addition to their blinded treatment reg-imen, to treat ongoing hyperglycemia.Eligibility for hyperglycemic rescuetherapy consisted of two consecutiveFSG measurements.270 mg/dL spaced

2 Ranolazine Monotherapy in Type 2 Diabetes Diabetes Care

#7 days apart from day 1 to week 6, ortwo consecutive FSGs .240 mg/dLspaced #7 days apart from weeks 7 to24. Subjects who continued to be hyper-glycemic and required the addition of asecond antihyperglycemic agent werediscontinued from the study.Following the last completed visit

(week 24 or ET), subjects were contacted14 days after the last dose of study drug.In addition, randomized subjects who dis-continued the study early were contacted24weeks after the first dose of studydrugfor ascertainment of vital status.The study was conducted according to

the guidelines of Good Clinical Practiceand the Declaration of Helsinki. The proto-col, amendments, and associated materialswere approvedby relevant regulatory agen-cies, institutional review boards, and ethicscommittees. All subjects provided writteninformed consent prior to study entry.

Study End PointsThe primary end point was the 24-weekchange from baseline in HbA1c. Prespeci-fied ordered secondary end points (all atweek 24) were 1) change frombaseline inFSG, 2) proportion of subjects with HbA1c,7.0% (53 mmol/mol), and 3) changefrom baseline in 2-h postprandial glucose(PPG). Additional non–alpha-controlledend points included by-visit changesfrom baseline in the primary and second-ary end points; change from baseline inincremental change of 2-h PPG; changesfrombaseline in fasting insulin, C-peptide,and glucagon; change from baseline in3-h area under the curve (AUC) for PPG,insulin, C-peptide, and glucagon; andchange from baseline in body weight.Safety assessments included adverse

events (AEs) (including adjudicatedMACE/MACE1; seebelow), the incidenceand severity of hypoglycemia (per Amer-ican Diabetes Association [ADA] criteria[16]), discontinuation for hyperglycemia,use of rescue medication for hyperglyce-mia, vital signs, body weight, physicalexam, ECG parameters, and laboratoryevaluations (including complete bloodchemistry, hematology, and urinalysis).Safety data were monitored by an in-

dependent data safety monitoringboard. Additionally, an independentclinical events committee adjudicatedwhether AEs were major adverse car-diac/cerebrovascular events (MACEand MACE1). Components of MACEwere cardiovascular-related mortality,

MI, and stroke/TIA. Components ofMACE1 included all MACE as well asunstable angina requiring hospitaliza-tion or urgent revascularization.

Statistical MethodsFour hundred subjects provided $90%power to detect a statistically significanttreatment difference in change frombaseline in HbA1c of 20.5% at week24, assuming a common SD of 1.2%and a two-sided type I error rate of 0.05.

Primary and secondary efficacy ana-lyses were performed on the followinganalysis sets.

Full Analysis Set

All randomized subjects received at leastone dose of study treatment, with a base-line and at least one postbaseline HbA1cmeasurement, and no major eligibilityviolations.

MMTT Full Analysis Set

All randomized subjects received at leastone dose of study treatment, with a base-line and at least one postbaseline 2-h PPGmeasurement, and no major eligibilityviolations.

MMTT AUC Full Analysis Set

All randomized subjects received at leastone dose of study treatment, with glucosemeasurements at 25, 60, and 120 min(or later) following the start of theMMTT during the baseline visit and atleast one postbaseline visit, and nomajoreligibility violations.

Primary and secondary efficacy endpoints were tested using a fixed-sequence closed testing procedure toadjust for multiplicity and preserve thefamily-wise type I error rate of 0.05.Continuous efficacy end points were

analyzed using amixed-models repeated-measures approach, which accountsfor correlations among observationswithin a subject, allows for baseline ad-justment, and uses all available data col-lected at various time points, includingdata from participants not completingweek 24. Effects included baselineHbA1c, baseline value of the end point(if not HbA1c), treatment, visit, and treat-ment by visit interaction term usingunstructured correlation matrices. Sub-group analyses included additionaleffects for subgroup, subgroup bytreatment, subgroup by visit, and sub-group by treatment by visit; subgroupanalysis by baseline HbA1c did not in-clude baseline HbA1c. For the proportionof subjects with HbA1c ,7%, treatmentswere compared using a Cochran-Mantel-Haenszel test stratified by baselineHbA1c (#8 vs. .8%). For efficacy analy-ses, measurements after the antihyper-glycemic rescuemedicationwere excluded.Values from ET, rescue, or unscheduledvisits occurring within 3 weeks of week24 were substituted for missing week24 values.

Safety analyses were performed on asafety analysis set consisting of all ran-domized subjects receiving at least onedose of study treatment.

RESULTS

Subject DispositionThe study was conducted in 133 sitesfrom nine countries worldwide betweenNovember 2011 and October 2013. De-tailed country-specific enrollment met-rics can be found in SupplementaryTable 1. Subjects (n 5 1,433) entered

Figure 1—Disposition of subjects. QP, qualifying period.

care.diabetesjournals.org Eckel and Associates 3

screening for the study (Fig. 1). Of these,605 subjects entered the qualifying pe-riod and 465 were randomized (232 toplacebo and 233 to ranolazine). A totalof 198 placebo subjects and 199 ranola-zine subjects completed the study, and34 (14.7%) placebo and 33 (14.2%) rano-lazine subjects were prematurely dis-continued from the study. The mostfrequent reason for ET was subject non-compliance (8 [3.4%] placebo and 15[6.5%] ranolazine), followed by nonhy-perglycemic AEs (3 [1.3%] placebo and10 [4.3%] ranolazine). The most com-mon nonhyperglycemic AE leading topermanent study drug discontinuationwas nausea (0 placebo and 3 [1.3%] ra-nolazine), followed by dizziness (0 pla-cebo and 2 [0.9%] ranolazine). Oneparticipant from the ranolazine groupdiscontinued the study drug due to hy-poglycemia. Otherwise, no other nonhy-perglycemic AE resulting in early studydrug discontinuation occurred in morethan one subject.

Baseline CharacteristicsOverall, baseline characteristicswere sim-ilar between treatment groups (Table 1).Subjects had a mean age of 56 years,with a range of 20–75 years. Approxi-mately half (50.9%)were female. Subjectshad a mean BMI of 32.8 kg/m2, and a

mean waist circumference of 105.8 cm.The mean baseline HbA1c was 8.04%(64 mmol/mol) (8.01% [64 mmol/mol] pla-cebo and 8.06% [65 mmol/mol] ranola-zine), and the mean FSG was 171.8 mg/dL(171.5 mg/dL placebo and 172.1 mg/dL ra-nolazine). The mean fasting serum insulin,fasting serumC-peptide, and fastingplasmaglucagon were also similar between treat-mentgroups.Most subjects (78.0%placeboand 80.2% ranolazine) were treatment na-ıve to previous diabetes medications; themost frequently used classes of antihyper-glycemic agents prior to study entry weremetformin (17.2%placeboand15.9% rano-lazine) and sulfonylureas (4.7% for bothgroups). Similar numbers of subjects wereon statins (17.7% and 18.1% in the placeboand ranolazine groups, respectively). Theoverall duration of diabetes prior to enroll-ment was similar (3.0 years). Few subjectsreported a history of MI (4.7% placebo and5.6% ranolazine) or stroke (3.0% placeboand 2.2% ranolazine).

Efficacy AssessmentsCompared with placebo, there was agreater decline in HbA1c at week 24frombaseline (primary efficacy endpoint)in subjects taking ranolazine monother-apy (placebo-corrected least squaresmean [LSM] difference 20.56% [26.1mmol/mol]; P , 0.0001) (Table 2). This

difference was first evident at week 12and persisted through week 24 (Fig.2A). The number of subjects achievingan HbA1c ,7.0% at week 24 was greaterin the ranolazine group (25.6% placeboand 41.2% ranolazine; P 5 0.0004) (Fig.2B). Subgroup analyses (i.e., by age, sex,region, renal function, baseline HbA1c,diabetes duration, and prior diabetesmedications) generally showed that sub-jects in the ranolazine group had greatermean reductions from baseline in HbA1cat week 24 than placebo subjects (Sup-plementary Fig. 1 and SupplementaryTable 2). Treatment-na ıve subjectstended to have a greater response toranolazine than those previously treatedfor type 2 diabetes (P 5 0.0865); other-wise there were no significant interac-tions noted for any single subgroup.

At week 24, FSG was decreased in sub-jects taking ranolazine compared withsubjects taking placebo (change frombaseline LSM difference 28 mg/dL;P5 0.0266) (Table 2). Similar to fastingglucose, the 2-h PPG (LSM difference219 mg/dL; P5 0.0008) and incremen-tal change in 2-h PPG (LSM difference29 mg/dL; P 5 0.0130) were also im-proved with ranolazine (Fig. 3A–C).Additionally, the placebo-correctedchange from baseline in total and incre-mental 3-h glucose AUCs derived fromMMTTs were significantly decreased inthe ranolazine group at week 12 andremained decreased at week 24.

Ranolazine lowered both fasting andpostprandial glucagon levels comparedwith placebo (Fig. 3D–F). The LSM differ-ences between treatment groups forthe changes in fasting plasma glucagonfrom baseline to weeks 6–24 rangedfrom 29 to 24 pg/mL; the treatmentdifference was statistically significantat weeks 6, 12, and 24 (P # 0.0035)but not week 18 (P 5 0.1165). DuringMMTT, change frombaseline in the total3-h AUC for glucagon was lower withranolazine versus placebo, with an LSMdifference of 220 h z pg/mL (P 50.0010) at week 12 and 219 h z pg/mL(P 5 0.0031) at week 24 (Supplemen-tary Table 2), but the changes frombaseline in incremental 3-h AUC for glu-cagonwere not statistically different be-tween treatments.

Relative to placebo, subjects taking ra-nolazine had a trend toward a greater de-crease from baseline in fasting seruminsulin at week 24 (LSM difference

Table 1—Demographics and baseline characteristics

Placebo (n 5 232) Ranolazine (n 5 232)

Age, years (mean 6 SD) 56 6 9.3 55 6 9.5

Female 48.7% 53.0%

White race 90.1% 91.8%

EthnicityHispanic or Latino 13.4% 12.5%Not Hispanic or Latino 86.6% 87.1%Not reported 0 0.4%

Weight, kg (mean 6 SD) 92.1 6 17.5 93.2 6 16.4

BMI, kg/m2 (mean 6 SD) 32.8 6 4.85 32.8 6 4.75

eGFR†, mL/min/1.73 m2 (mean 6 SD) 83.3 6 18.4 84.5 6 18.8

HbA1c, % (mean 6 SD) 8.01 6 0.727 8.06 6 0.732

HbA1c, mmol/mol (mean) 64 65

FSG, mg/dL (mean 6 SD) 171.5 6 34.45 172.1 6 34.32

Diabetes duration, years (mean 6 SD) 3.0 6 4.00 3.0 6 4.29

Took prior antihyperglycemic agent (any) 22.0% 19.8%Sulfonylureas 4.7% 4.7%Biguanides 17.2% 15.9%

Concomitant lipid-lowering therapy (any) 21.1% 21.1%Statins 17.7% 18.1%Fibrates 3.0% 2.2%Niacin 0 0Other 3.0% 2.2%

†eGFR, estimated glomerular filtration rate.

4 Ranolazine Monotherapy in Type 2 Diabetes Diabetes Care

Table 2—Efficacy and safety results

Efficacy data

Treatment assignment Placebo RanolazineHbA1cn 195 199Baseline mean 6 SD (%) 8.02 6 0.728 8.06 6 0.735Baseline mean (mmol/mol) 64 65Week 24 mean 6 SD (%) 7.70 6 1.183 7.26 6 1.101Week 24 mean (mmol/mol) 61 56LS change from baseline mean 6 SE (%) 20.20 6 0.073 20.76 6 0.073LS change from baseline mean (mmol/mol) 22.2 28.3Placebo-corrected LS change frombaselinemean (95% CI) (%) 20.56 (20.76, 20.36)Placebo-corrected LS change from baseline

mean (95% CI) (mmol/mol) 26.1 (28.3, 23.9)P value vs. placebo 0.0001

FSG (mg/dL)n 191 197Baseline mean 6 SD 171 6 34.6 172 6 34.5Week 24 mean 6 SD 169 6 40.3 165 6 40.4LS change from baseline mean 6 SE 2 6 2.7 26 6 2.6Placebo-corrected LS change from baseline mean (95% CI) 28 (216, 21)P value vs. placebo 0.0266

Fasting plasma glucagon (pg/mL)n 188 192Baseline mean 6 SD 86 6 26.1 85 6 28.9Week 24 mean 6 SD 93 6 32.3 84 6 28.5LS change from baseline mean 6 SE 9 6 1.8 21 6 1.8Placebo-corrected LS change from baseline mean (95% CI) 209 (214, 24)P value vs. placebo 0.0003

Fasting serum insulin (mIU/mL)n 166 168Baseline mean 6 SD 14.84 6 10.79 13.85 6 9.081Week 24 mean 6 SD 13.18 6 10.46 11.66 6 7.484LS change from baseline mean 6 SE 21.04 6 0.510 22.45 6 0.509Placebo-corrected LS change from baseline mean (95% CI) 21.41 (22.83, 0.00)P value vs. placebo 0.0507

Fasting serum C-peptide (ng/mL)n 186 189Baseline mean 6 SD 2.65 6 1.106 2.55 6 1.002Week 24 mean 6 SD 2.68 6 1.175 2.46 6 0.943LS change from baseline mean 6 SE 0.09 6 0.059 20.11 6 0.059Placebo-corrected LS change from baseline mean (95% CI) 20.20 (20.36, 20.04)P value vs. placebo 0.0158

Safety dataTreatment assignment (n) Placebo (n 5 232) Ranolazine (n 5 232)AEsSubjects with any AE, n (%) 89 (38.4%) 97 (41.8%)Hyperglycemia, n (%) 23 (9.9%) 19 (8.2%)Constipation, n (%) 10 (4.3%) 12 (5.2%)Nausea, n (%) 2 (0.9%) 9 (3.9%)Dizziness, n (%) 2 (0.9%) 6 (2.6%)

AEs related to study drugSubjects with any related AE, n (%) 9 (3.9%) 21 (9.1%)Constipation, n (%) 3 (1.3%) 5 (2.2%)Headache, n (%) 2 (0.9%) 6 (2.6%)Dizziness, n (%) 1 (0.4%) 5 (2.2%)

SAEs, n (%) 7 (3.0%) 6 (2.6%)AE leading to premature study drug discontinuation, n (%) 8 (3.4%) 12 (5.2%)Deaths during study, n (%) 0 1 (0.4%)

P value indicates difference in placebo-corrected LSM change from baseline; n of change from baseline at week 24. LS, least squares; SAEs, seriousadverse events.

care.diabetesjournals.org Eckel and Associates 5

21.41mIU/mL; P5 0.0507) (Supplemen-tary Table 3). Changes from baseline inpostprandial serum insulin 3-h AUC weresimilar between ranolazine and placebo.However, fasting serum C-peptide levelswere significantly lower in the ranolazinegroup versus placebo at week 24 (changefrombaseline LSMdifference20.20ng/mL;P 5 0.0158). Yet, no treatment differ-ences were observed in postprandialC-peptide 3-h AUC.

Safety Assessments

In general, ranolazine was well toleratedand safe (Table 2). The overall numberof subjects experiencing an AE was sim-ilar between groups (38.4% placebo and41.8% ranolazine). Although the propor-tion of subjects with study drug–relatedAEs was greater in the ranolazine group(3.9% placebo and 9.1% ranolazine), thenumber of subjects with serious AEs(3.0% placebo and 2.6% ranolazine)

and drug discontinuations due to AEs(3.4% placebo and 5.2% ranolazine)was broadly comparable between treat-ment arms. No serious AEs were relatedto study drug, and no single serious AEoccurred in more than one subject.

The most frequently reported AEswere hyperglycemia (9.9% placeboand 8.2% ranolazine), headache(4.3% vs. 5.2%), constipation (1.3%vs. 4.7%), and nausea (0.9% vs.3.9%). The most commonly reportedAEs related to study drug (either rano-lazine or placebo) were constipation,headache, nausea, and dizziness. Foursubjects, all randomized to ranolazine,experienced hypoglycemia during thetreatment period. No subject had se-vere or documented symptomatichypoglycemia.

Two subjects (one on placebo withunstable angina requiring hospitaliza-tion and one on ranolazine with urgentrevascularization and unstable anginarequiring hospitalization) had AEs thatwere adjudicated by the clinical eventscommittee as major cardiovascularevents. Otherwise there were no adju-dicated MIs, strokes/TIAs, or cardiovas-cular deaths. One death occurredduring the study, 92 days after the lastdose of study drug. The subject died ofcardiorespiratory failure as a conse-quence of pneumonia and was not con-sidered related to study drug. Thesubject, who was in the ranolazinegroup, had been inappropriately en-rolled into the study with advancedchronic kidney disease. The subject’senrollment was considered a protocolviolation, and study drug was discontin-ued after 5 days.

There were no notable changes frombaseline or differences between treat-ment groups in blood chemistries andhematology (including hemoglobin,white blood cell count, and platelets).No increases in urinary glucose, creati-nine, or microalbumin were observed.Similarly, there were no changes inheart rate or blood pressure. Althoughsubjects taking ranolazine had de-creased body weight at week 12 (LSMdifference 20.49 kg vs. placebo; P 50.0388), this difference was not sus-tained through week 24. During ECGmonitoring, ranolazine had no effecton PR, RR, or QRS; a 7-ms increase inQTc was seen in the ranolazine group,consistent with prior observations (17).

Figure 2—A: Effect of ranolazine on HbA1c by visit. B: Effect of ranolazine on proportion ofsubjects achieving HbA1c ,7.0%. Placebo, n 5 229; ranolazine, n 5 227. *P 5 0.0046 vs.placebo. †P , 0.0001 vs. placebo. ‡P 5 0.0004 vs. placebo.

Figure 3—FSG and glucose response to MMTT at baseline (A) and week 24 (B), as well as PPGchange from baseline at weeks 12 and 24 (C). Fasting plasma glucagon and glucagon response toMMTT at baseline (D) and week 24 (E), as well as postprandial glucagon change from baseline atweeks 12 and 24 (F). All values listed are least squares means 6 SE.

6 Ranolazine Monotherapy in Type 2 Diabetes Diabetes Care

CONCLUSIONSCAD and diabetes are nominally two dis-tinct disease entities; however, the twoare mechanistically and epidemiologi-cally linked. It is well appreciated thatthe metabolic derangements inherentin diabetes (including hyperglycemia, in-sulin resistance, and excess free fattyacids) lead to endothelial dysfunction,impaired vascular smooth muscle func-tion, and hypercoagulability, conditionsthat ultimately lead to atherogenesisand coronary events (18). It has beenestimated that 5.7 million U.S. adults$35 years with diabetes have coinci-dent cardiovascular disease (19). Amore recent analysis in 1,957 adultswith CAD from the National Health andNutrition Examination Survey (NHANES)cohort revealed that 619 (28%) had adiagnosis of diabetes (20). Of these,44% also had angina, suggesting a signif-icant overlap in the patient populationsaffected by these two diseases. Suchoverlap substantially increases the com-plexity of the management of patientswith both conditions. For instance, al-though b-blockers are an establishedcornerstone of antianginal therapy, tovarying extents they also worsen glyce-mic control and mask the symptoms ofhypoglycemia (21,22). On the otherhand, the development and use of effec-tive pharmacological agents for thetreatment of patients with type 2 diabe-tes has been limited by concerns overthe cardiovascular safety of such agents(23). Hence, given the high prevalenceof CAD and diabetes in contemporarysociety, there is thus a need for antian-ginal and antihyperglycemic medica-tions that do not have the safety andtolerability liabilities associated withcurrently available agents. In concertwith the results of the Type 2 DiabetesEvaluation of Ranolazine in SubjectsWith Chronic Stable Angina (TERISA)clinical trial (24), which demonstratedthe antianginal efficacy of ranolazine insubjects with comorbid type 2 diabetes,the results of the current study suggestthat ranolazine could potentially ad-dress both needs. It should be noted,however, that ranolazine is not ap-proved for the treatment of diabetes.This study is the first to demonstrate

that ranolazine monotherapy reducedHbA1c as a measure of ambient glycemiaassessed prospectively in a randomized,placebo-controlled fashion in subjects

with type 2 diabetes. This effect wasseen by 12 weeks in the absence ofother glucose-lowering medicationsand was sustainable up to 24 weeks. Inaddition, the percentage of subjectsachieving a guideline-directed HbA1c

goal of ,7.0% was nearly twice ashigh with ranolazine as placebo. Thislevel of glycemic control is accepted bythe ADA as a reasonable goal for mostpatients with type 2 diabetes (25). Over-all, ranolazine proved safe, with a lowdropout rate that was similar betweengroups.

Themechanism underlying the antidi-abetic effects of ranolazine has been de-scribed in detail in a recent preclinicalstudy (13). Ranolazine was shown to in-hibit glucagon secretion from pancreatica-cells by inhibiting their electrical ac-tivity via blockade of sodium channels(Nav1.3 isoform) (13). In animal modelsof diabetes, ranolazine lowered post-prandial and basal glucagon levels,which were associated with a reductionin hyperglycemia and lowering of HbA1c(13). The current study provides analo-gous findings in a population of subjectswith type 2 diabetes, suggesting confir-mation of this proposed mechanism ofaction in the clinical setting.

The relationship of glucagon to type 2diabetes merits discussion, as this wouldsuggest that ranolazine exhibits antihy-perglycemic effects via a novel mecha-nism. Hyperglucagonemia increases therates of glycogenolysis and gluconeogen-esis (26), thereby increasing hepatic glu-cose production in both fasting andpostprandial states, ultimately leadingto increases in both fasting glucose andPPG levels (14). The importance of hyper-glucagonemia as a contributor to thepathophysiology of type 2 diabetes (27)is further highlighted by the finding thatglucagon receptor deficiency is sufficientto abolish hyperinsulinemia and hy-perglycemia seen in fat-fed and leptinreceptor–deficient mice (27). The con-comitant reduction of both glucagonand glucose by ranolazine in this trial sug-gests that ranolazine might reduce bloodglucose by decreasing glucagon secretionfrom a-cells, as described above, andlowering circulating glucagon levels.Additional effects of ranolazine on otherelements known to influence either glu-cose or glucagon levels (such as glucagon-like peptide 1 and dipeptidyl peptidase 4)have not been ruled out.

Notably, ranolazine had a relativelygreater effect in lowering HbA1c com-pared with the reductions in FSG orPPG. This raises the question as towhether ranolazine lowers HbA1c viaone or more mechanisms other than re-ducing glucose levels. However, severallines of evidence argue against such al-ternate mechanisms. First, direct inter-ference by ranolazine on the HbA1c

assay was investigated and eliminatedin experiments measuring HbA1c in thepresence or absence of ranolazine(Gilead Sciences, data on file). Second,ranolazine does not affect the glycationof hemoglobin independent of changesin glucose concentration (Gilead Sciences,data on file). Third, ranolazine has notbeen associated with anemia in thisstudy or other clinical trials (5,7,28),making increased red cell turnover anunlikely cause for the association.Fourth, ranolazine has little to no effecton patients with lower blood/plasmaglucose (11). Finally, there are greaterranolazine-associated reductions inHbA1c seen in patients with higher glu-cose levels and more severe type 2 di-abetes (insulin use vs. nonuse) (9,11).Importantly, FSG and PPG as measuredin this study may not be ideal surrogatesfor mean glucose. Considering that theelimination half-life of ranolazine is7 h, a blood sample drawn 12 h afterdosing of ranolazine (i.e., at troughlevel) might yield a minimal reductionin glucose relative to samples drawn atearlier time points (at higher drug con-centrations). Future studies evaluatingglucose more intensively, either throughmultiple-point testing or continuous glu-cose monitoring, should be considered tofully understand ranolazine’s effect onglucose. The totality of current evidencesuggests that the lowering of HbA1c byranolazine is likely due to reductions inglucose. Regarding the management ofpatients with type 2 diabetes, the ADAand the European Association for theStudy of Diabetes (EASD) recommendusing HbA1c as the primary target forglycemic control.

To have a complete picture of rano-lazine’s antihyperglycemic properties, it isimportant to evaluate its efficacy notonly as monotherapy but also as anadd-on to established therapies suchas biguanides and sulfonylureas. Trialsevaluating ranolazine on a backgroundof either glimepiride (NCT01494987) or

care.diabetesjournals.org Eckel and Associates 7

metformin (NCT01555164) have beenconducted. The results of these two stud-ies are available on www.clinicaltrials.gov, with publication of their resultsforthcoming.In summary, in subjects with type 2

diabetes on no glucose-lowering phar-macological agents, ranolazine loweredHbA1c by a mean difference of 20.56%with a near doubling of subjects achiev-ing an HbA1c,7.0%. Ranolazine also de-creased fasting glucose and PPG andfasting and postprandial glucagon lev-els. The results of this study suggest ra-nolazine could be an option for themanagement of patients with concur-rent chronic angina and type 2 diabetes.Given the neutral-to-negative glycemiceffects of currently available antianginaldrugs, such patients may be uniquelysuited to be managed with ranolazine.

Duality of Interest. R.H.E. has received con-sulting fees from Amgen, Amylin Pharmaceu-ticals, Esperion, Johnson & Johnson, NovoNordisk, FoodMinds, Regeneron, Sanofi, Vivus,and Eli Lilly and Company and has received re-search funding from GlaxoSmithKline, Sanofi,Esperion, and Janssen. R.R.H. has received con-sulting/advisory board honoraria from Amgen,Boehringer Ingelheim, Eli Lilly and Company,F.Hoffmann-LaRoche/Genentech,GileadSciences,Intarcia, Isis, Johnson & Johnson, Merck, NovoNordisk, and Sanofi; has received research fund-ing from Amylin Pharmaceuticals, AstraZeneca,Bristol-Myers Squibb, Eli Lilly and Company,Medtronic, and Sanofi; and has receivedspeaker honoraria from Boehringer Ingelheim.A.D., L.B., P.Y., P.W., and P.J. are employeesand stockholders of Gilead Sciences. J.S.S. ischairman of the Type 1 Diabetes TrialNet clinicaltrials network, supported by the National Insti-tute of Diabetes and Digestive and Kidney Dis-eases, National Institutes of Health; has servedas a boardmember for Amylin Pharmaceuticals,Dexcom, Moerae Matrix, and Paean Therapeu-tics; has received consulting fees from BD Tech-nologies, Boehringer Ingelheim, Bristol-MyersSquibb, Cebix, DiaVacs, Elcelyx, Exsulin, GileadSciences, Halozyme Therapeutics, Ideal Life, In-tarcia Therapeutics, MannKind, Mellitech,Merck, Orgenesis, Sanofi, Sekris Biomedical,Takeda, Valeritas, and ViaCyte; has received re-search funding from Halozyme Therapeutics,Intuity Medical, Mesoblast, and Osiris Thera-peutics; has received speaker honoraria fromNovo Nordisk and Sanofi; has received royaltiesfor editing a book from Springer; and is a stock-holder of Amylin Pharmaceuticals, Dexcom,Ideal Life, Moerae Matrix, OPKO Health, PattonMedical Devices, and Tandem Diabetes Care.No other potential conflicts of interest relevantto this article were reported.Author Contributions. R.H.E. and A.D. draftedthe manuscript. R.R.H., L.B., and J.S.S. designedthe study. P.Y. participated in the conduct of thestudy and drafted the manuscript. P.W. and P.J.

designed the study and participated in theconduct of the study. All authors analyzedthe data and provided editorial assistance withthe manuscript. All authors are the guarantorsof this work and, as such, had full access to allthe data in the study and take responsibility forthe integrity of the data and the accuracy of thedata analysis.Prior Presentation. This study was presentedat the 75th Scientific Sessions of the AmericanDiabetesAssociation, Boston,MA, 5–9 June2015.

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8 Ranolazine Monotherapy in Type 2 Diabetes Diabetes Care