weight loss, lower insulin doses,weight loss, lower insulin doses, and no increased hypoglycemia...

Improved Glucose Control WithWeight Loss Lower Insulin Dosesand No Increased HypoglycemiaWith Empaglif lozin Added toTitrated Multiple Daily Injectionsof Insulin in Obese InadequatelyControlled Type 2 DiabetesDiabetes Care 2014371815ndash1823 | DOI 102337dc13-3055

OBJECTIVE

We investigated the efficacy and safety of the sodium glucose cotransporter 2inhibitor empagliflozin added to multiple daily injections of insulin (MDI insulin)in obese patients with type 2 diabetes mellitus (T2DM)

RESEARCH DESIGN AND METHODS

Patients inadequately controlled on MDI insulin 6 metformin (mean HbA1c 83[67 mmolmol] BMI 348 kgm2 insulin dose 92 international unitsday) wererandomized and treated with once-daily empagliflozin 10 mg (n = 186) empagli-flozin 25mg (n = 189) or placebo (n = 188) for 52weeks Insulin dosewas to remainstable in weeks 1ndash18 adjusted to meet glucose targets in weeks 19ndash40 thenstable in weeks 41ndash52 The primary end point was change from baseline in HbA1c

at week 18 Secondary end points were changes from baseline in insulin doseweight and HbA1c at week 52

RESULTS

Adjustedmean6 SE changes frombaseline in HbA1c were20506 005 (255605 mmolmol) for placebo versus 2094 6 005 (2103 6 05 mmolmol) and2102 6 005 (2111 6 05 mmolmol) for empagliflozin 10 mg and empagli-flozin 25 mg respectively at week 18 (both P lt 0001) At week 52 furtherreductions with insulin titration resulted in changes from baseline in HbA1c of20816 008 (2896 09mmolmol)21186 008 (21296 09mmolmol)and21276 008 (21396 09mmolmol)with placebo empagliflozin 10mg andempagliflozin 25 mg respectively and final HbA1c of 75 (58 mmolmol) 72(55 mmolmol) and 71 (54 mmolmol) respectively More patients attainedHbA1c lt7 (lt53 mmolmol) with empagliflozin (31ndash42) versus placebo (21 bothP lt 001) Empagliflozin 10 mg and empagliflozin 25mg reduced insulin doses (29 to211 international unitsday) and weight (224 to 225 kg) versus placebo (all P lt

001) at week 52

CONCLUSIONS

In obese difficult-to-treat patients with T2DM inadequately controlled on highMDI insulin doses empagliflozin improved glycemic control and reduced weightwithout increasing the risk of hypoglycemia and with lower insulin requirements

1Dallas Diabetes and Endocrine Center at Medi-cal City Dallas TX2Boehringer Ingelheim Pharmaceuticals IncRidgefield CT3Boehringer Ingelheim France Reims France4Boehringer Ingelheim Pharma GmbH amp Co KGIngelheim Germany

Corresponding author Julio Rosenstockjuliorosenstockdallasdiabetescom

Received 31 December 2013 and accepted 25April 2014

Clinical trial reg no NCT01306214 clinicaltrialsgov

This article contains Supplementary Data onlineat httpcarediabetesjournalsorglookupsuppldoi102337dc13-3055-DC1

A slide set summarizing this article is availableonline

copy 2014 by the American Diabetes AssociationSee httpcreativecommonsorglicensesby-nc-nd30 for details

Julio Rosenstock1 Ante Jelaska2

Guillaume Frappin3 Afshin Salsali2

Gabriel Kim4 Hans J Woerle4 and

Uli C Broedl4 on behalf of the EMPA-REG

MDI Trial Investigators

Diabetes Care Volume 37 July 2014 1815

DIABETES

CARESYMPOSIU

M

Guidelines from the American DiabetesAssociation and the European Associa-tion for the Study of Diabetes recom-mend the initiation of basal insulinusually in conjunction with oral antidia-betes agents in patients with type 2 di-abetes mellitus (T2DM) who havemarked hyperglycemia when it is un-likely that another drug will be of suffi-cient additional benefit (1) However inclinical practice insulin therapy is oftendelayed or not optimized Barriers to theinitiation and optimization of insulintherapy include fear of hypoglycemiaand weight gain and concerns over thecomplexity of the treatment regimen(23) Approximately 40ndash50 of patientswith T2DM fail to achieve glycemic con-trol with basal insulin plus oral anti-diabetes agents after 24 weeks oftreatment (4) Further intensificationof the insulin regimen to control hyper-glycemia is traditionally achieved withprogressive additions of prandial insulinup to multiple daily injections of insulin(MDI insulin) However MDI insulin isoverwhelming for most patients anddespite combination with metformininsulin requirements are often highand patients are still unable to achieveglycemic control In addition these pa-tients are typically insulin resistant (5)and comorbidities such as obesity andhypertension are very common Weightgain associatedwith theuseof high insulindoses may make it even more difficult toachieve glycemic control (5) Accordinglythere is a high unmet need for antidiabe-tes therapies that can be used in combi-nation with MDI insulin to improveglycemic control in patients with T2DMwithout exacerbating comorbiditiesEmpagliflozin a potent and selective

sodium glucose cotransporter 2 (SGLT2)inhibitor (6) reduces hyperglycemia byreducing renal glucose reabsorptioncausing urinary glucose excretion (7)In phase III studies empagliflozin usedas monotherapy or as an add-on to met-formin metformin plus sulfonylureapioglitazone (with or without metfor-min) or basal insulin improved glycemiccontrol and consistently reduced bodyweight and blood pressure (8ndash12) Em-pagliflozin is potentially an attractive op-tion for use in combination with insulinas itsmechanism of action is independentofb-cell function (13) it generatesweightloss and it is associated with a low risk ofhypoglycemia (8ndash12)

The EMPA-REG MDI trial was under-taken to evaluate the efficacy andsafety of empagliflozin 10 mg and em-pagliflozin 25 mg versus placebo asan add-on to MDI insulin with or with-out metformin for 52 weeks in patientswith T2DM and insufficient glycemiccontrol We hypothesized that empa-gliflozin would improve glycemiccontrol and body weight in this difficult-to-treat obese population of pa-tients with T2DM and high insulinrequirements


Study DesignThis was a randomized double-blindplacebo-controlled parallel-groupstudy conducted from March 2011 toApril 2013 in 104 centers across 14countries The clinical trial protocolwas approved by the institutional re-view boards and independent ethicscommittees and competent authoritiesof the participating centers and thestudy was conducted in accordancewith the Declaration of Helsinki andthe International Conference on Harmo-nization Harmonized Tripartite Guide-line for Good Clinical Practice The trialwas registered with ClinicalTrialsgov(NCT01306214) All patients providedwritten informed consent

Inclusion and Exclusion CriteriaThis study enrolled obese adults (BMI$30 and 45 kgm2) with T2DM andinsufficient glycemic control (HbA1c

$75 to10 [$58 to86 mmolmol]at screening) despite diet and exercisecounseling and treatment with MDI in-sulin (total daily dose 60 internationalunits) alone or in combination with met-formin (immediate or extended release$1500 mgday maximum tolerateddose or maximum dose according tothe local label) For $12 weeks priorto randomization insulin dose was notto be changed by 10 and metformindose was to be unchanged Premixed in-sulins were not permitted

Exclusion criteria included uncon-trolled hyperglycemia (glucose level133 mmolL after an overnight fastduring the placebo run-in confirmedby a second measurement) acute coro-nary syndrome stroke or transient is-chemic attack within 3 months prior toconsent indication of liver disease im-paired renal function during screeningor run-in (estimated glomerular filtration

rate [eGFR] using the modification ofdiet and renal disease equation 60mLmin173 m2) gastrointestinal sur-geries that induce malabsorption his-tory of cancer (except for basal cellcarcinoma) within 5 years disorderscausing hemolysis or unstable erythro-cytes treatment with systemic steroidsat time of consent change in dosage ofthyroid hormones within 6 weeks priorto consent treatment with antiobesitydrugs or alcohol or drug abuse within 3months of consent and investigationaldrug intake within 30 days of intake ofstudy drug

Treatment and InterventionsFollowing a 2-week open-label placeborun-in period patients still meeting theinclusionexclusion criteria were ran-domized (111) to receive once-dailyempagliflozin 10 mg empagliflozin 25mg or placebo as an add-on to MDI in-sulin with or without metformin for 52weeks Randomization was undertakenusing a third-party interactive voice- andweb-response system and was stratifiedby HbA1c (85 $85 [69 $69mmolmol]) eGFR (chronic kidney dis-ease stage 1 $90 mLmin173 m2chronic kidney disease stage 2 60ndash89mLmin173m2) region (Europe NorthAmerica Latin America) and back-ground antidiabetes therapy (insulinalone insulin plus metformin) Patientsreceived diet and exercise counselingbased on local recommendations atthe start of the run-in period and werereminded to follow their diet and exer-cise plan at every study visit For the first18 weeks the total daily dose of insulinwas to remain within 10 of the pre-scribed dose at randomization Duringthe titrated treat-to-target period(weeks 19ndash40) insulin dose was to beadjusted to achieve a preprandial glu-cose target of 55 mmolL (100mgdL) and a postprandial glucose tar-get of 78 mmolL (140 mgdL) Be-tween weeks 41 and 52 the total dailydose of insulin was to remainwithin 10of the insulin dose prescribed at week40 except for adjustments for safetyreasons Metformin dose was to remainunchanged throughout the study Studyvisits were scheduled at screening thestart of the placebo run-in randomiza-tion after 4 8 12 18 24 32 40 46 and52 weeks of treatment and 4 weeks af-ter the last dose of study drug

1816 Empagliflozin as Add-on to MDI Insulin Diabetes Care Volume 37 July 2014

Rescue could be initiated at any timeduring the treatment period if a patienthad hypoglycemia that would put themat risk During weeks 1ndash12 rescue med-ication could be initiated if a patienthad a glucose level of 133 mmolL(240 mgdL) after an overnight fastDuring weeks 13ndash24 rescue therapycould be initiated if confirmed fastingglucose levels were 111 mmolL(200 mgdL) During weeks 24ndash52rescue therapy could be initiated if a pa-tient had a confirmed glucose level100 mmolL (180 mgdL) after anovernight fast or HbA1c 80 (64mmolmol) after an overnight fast Theinitiation choice (excluding other SGLT2inhibitors) and dosage of rescue medi-cation were at the discretion of the in-vestigator according to local prescribinginformation Changes in dose of metfor-min for $7 days or addition of a newantidiabetes agent for $7 days wereconsidered rescue therapy Beforeweek 18 changes in total insulin dailydose 10 of the baseline dose for$7 days were considered rescue ther-apy changes in insulin dose were notconsidered rescue therapy for the effi-cacy analyses after week 18

End Points and AssessmentsThe primary end point was the changefrom baseline in HbA1c at week 18 Sec-ondary end points were changes frombaseline at week 52 in insulin daily dosebody weight and HbA1c Exploratory endpoints included changes from baseline inbody weight at week 18 changes frombaseline at weeks 18 and 52 in fastingplasma glucose (FPG) systolic blood pres-sure (SBP) and diastolic blood pressure(DBP) percentage of patients withHbA1c $7 ($53 mmolmol) at baselinewho had HbA1c7 at weeks 18 and 52and use of rescue therapySafety end points included vital signs

clinical laboratory parameters and ad-verse events (AEs) up to 7 days after thelast dose of study drug (preferred termscoded according to the Medical Dictio-nary for Drug Regulatory Activities ver-sion 151) AEs of special interestincluded confirmed hypoglycemic AEs(plasma glucose 39 mmolL andorrequiring assistance) and events consis-tent with urinary tract and genital infec-tions identified using prospectivelydefined search categories based on 73and 89 preferred terms respectively

Statistical Analysis

Sample size calculations indicated that555 patients (185 per treatment group)would provide 90 power to detect adifference between empagliflozin andplacebo in the primary end pointwith a two-sided significance level of0025 assuming a dropout of 15

The primary efficacy analysis was per-formed on the full analysis set (FAS)which included patients treated with$1 dose of study drug who had a base-line HbA1c value Secondary end pointsand changes in insulin dose correctedfor body weight were analyzed in theldquoPPS-completers-52rdquo set defined as pa-tients in the FAS whowere on treatmentup to day 357 and did not have impor-tant protocol violations (such aschanges in insulin dose of10 of pre-scribed dose at week 40 for $7 daysduring the last 12 weeks) Efficacy anal-yses of other end points were per-formed on the FAS at week 18 and inthe PPS-completers-52 set at week 52Safety analyses were performed on thetreated set (patients treated with $1dose of study drug)

The primary end point was assessedusing an ANCOVA model with treat-ment region background antidiabetestherapy and eGFR as fixed effects andbaseline HbA1c as a linear covariate Sec-ondary end points continuous explor-atory end points and changes ininsulin dose corrected for body weightwere analyzed using the statisticalmodel described for the primary endpoint with the baseline value for theend point in question as an additionallinear covariate Categorical change inHbA1c was analyzed using logistic re-gression including the same factors ascovariates

Values after rescue therapy were setto missing and imputed using the lastobservation carried forward (LOCF) ap-proach except for the analysis of lipidparameters for which LOCF was usedand values after rescue therapy were in-cluded (LOCF-IR) Changes over timein HbA1c and insulin daily dose wereanalyzed using restricted maximumlikelihoodndashbased mixed-model repeatedmeasures (MMRM) using observedcases (OCs) Categorical response inHbA1c was analyzed using a noncomp-leters considered failures imputationwhich assumed that patients who pre-maturely discontinued the trial andor

received rescue therapy did not achievethe HbA1c target

Treatment differences versus placebofor primary and secondary end pointswere tested using a hierarchical testingapproach for each dose using pairwisecomparisons between each dose of em-pagliflozin and placebo using the ad-justed means from the model at asignificance level of 25 (two-sided)to maintain the overall type I error at5 in the following sequence empagli-flozin versus placebo in change frombaseline in HbA1c at week 18 empagli-flozin versus placebo in change frombaseline in insulin dose at week 52 em-pagliflozin versus placebo in changefrom baseline in body weight at week52 empagliflozin versus placebo inchange from baseline in HbA1c at week52 (one-sided noninferiority test at levelof 125) empagliflozin versus placeboin change from baseline in HbA1c atweek 52 (superiority) Exploratory testswere two-sided at a 5 level (no multi-plicity adjustment)

RESULTS

PatientsA total of 563 patients were randomizedand treated with placebo (n = 188) em-pagliflozin 10 mg (n = 186) or empagli-flozin 25 mg (n = 189) (SupplementaryFig 1) Overall 475 (84) patients com-pleted the 52-week treatment periodBaseline mean 6 SD characteristicsshown in Supplementary Table 1 areage 567 6 95 years BMI 348 6 41kgm2 FPG 852 6 264 mmolL HbA1c83 6 07 [67 6 77 mmolmol] with33 of patients with HbA1c 8 (64mmolmol) and 23 with HbA1c $9($75 mmolmol) SBP 1333 6 155mmHg DBP 788 6 86 mmHg andbaseline insulin dose 92 6 44 interna-tional units Baseline basal insulin doseswere 53 6 32 49 6 23 and 51 6 25international unitsday with placeboempagliflozin 10 mg and empagliflozin25 mg respectively Baseline prandialinsulin doses were 40 6 29 40 6 29and 41 6 35 international unitsdaywith placebo empagliflozin 10 mg andempagliflozin 25 mg respectively

Efficacy Week 18During the first 18 weeks of treatmentthe total insulin daily dose was to remainwithin 10 of the prescribed dose at ran-domization Atweek18 adjustedmean6SE changes from baseline in HbA1c were

carediabetesjournalsorg Rosenstock and Associates 1817

20506 005 (2556 05 mmolmol)with placebo compared with 2094 6005 (2103 6 05 mmolmol) withempagliflozin 10 mg and 2102 6005 (2111 6 05 mmolmol) withempagliflozin 25 mg (P 0001 forboth) (Table 1 Fig 1A)Adjusted mean 6 SE changes from

baseline in FPG were 019 6 016mmolL with placebo compared with2098 6 016 mmolL with empagliflo-zin 10 mg and 2136 6 016 mmolLwith empagliflozin 25 mg at week 18

(P 0001 vs placebo for both) (Table1 Supplementary Fig 2A)

Body weight increased from baselinewith placebo (adjusted mean 6 SE034 6 018 kg) compared with a de-crease with empagliflozin 10 mg(2097 6 018 kg) and empagliflozin25 mg (2154 6 018 kg) at week 18(P 0001 vs placebo for both) (Table1 Fig 1B)

Adjusted mean 6 SE changes frombaseline in SBP were 212 6 08 mmHgwith placebo compared with2366 08

mmHg with empagliflozin 10 mg (P =0037) The change from baseline inSBP with empagliflozin 25 mg did notreach significance versus placebo (Sup-plementary Table 2 Supplementary Fig3A) Adjusted mean 6 SE changes frombaseline in DBP did not reach signifi-cance for either empagliflozin dose(Supplementary Table 2 Supplemen-tary Fig 3B)

During the first 18 weeks 15 patients(80) on placebo 3 patients (16) onempagliflozin 10 mg and 5 patients

Table 1mdashSummary of changes in HbA1c plasma glucose insulin dose and body weight

Placebo

Empagliflozin

10 mg 25 mg

Primary end pointHbA1c at baseline (mmolmol)

(week 18 analysis set)833 6 005 (68 6 05) 839 6 005 (68 6 05) 829 6 005 (67 6 05)

HbA1c at week 18 (mmolmol) 784 6 007 (62 6 08) 744 6 005 (58 6 05) 729 6 006 (56 6 07)Change from baseline in HbA1c

(mmolmol)2050 6 005 (255 6 05) 2094 6 005 (2103 6 05) 2102 6 005 (2111 6 05)

Difference vs placebo (95 CI)() [mmolmol]

2044 6 008 (2059 to 2029)[248 6 09 (264 to 232)]

2052 6 007 (2067 to 2037)[257 6 08 (273 to 240)]

P value 0001 0001

Secondary end pointsInsulin dose at week 52

international unitsday995 6 49 904 6 40 894 6 41

Change from baseline in insulin doseinternational unitsday

102 6 22 13 6 21 211 6 21

Difference vs placebo (95 CI) 288 6 31 (2148 to 228) 2112 6 31 (2172 to 252)P value 0004 0001

HbA1c at baseline (mmolmol)(week 52 analysis set)

825 6 007 (67 6 08) 840 6 007 (68 6 08) 837 6 006 (68 6 07)


(mmolmol)2081 6 008 (289 6 09) 2118 6 008 (2129 6 09) 2127 6 008 (2139 6 09)


2038 6 011 (2059 to 2016)[242 6 12 (264 to 217)]

2046 6 011 (2067 to 2025)[250 6 12 (273 to 227)]

P value 0001 0001Body weight at week 52 kg 9666 6 172 9457 6 147 9341 6 172Change from baseline in body weight kg 044 6 036 2195 6 036 2204 6 036Difference vs placebo (95 CI) 2239 6 051 (2340 to 2139) 2248 6 051 (2348 to 2147)P value 0001 0001

Exploratory end pointsBody weight at week 18 kg 9583 6 127 9571 6 130 9437 6 126Change from baseline in body weight kg 034 6 018 2097 6 018 2154 6 018Difference vs placebo (95 CI) 2131 6 026 (2182 to 2080) 2188 6 026 (2239 to 2137)P value 0001 0001

FPG at baseline mmolL 841 6 019 883 6 020 834 6 020FPG at week 18 mmolL 868 6 022 766 6 019 709 6 017Change from baseline in FPG mmolL 019 6 016 2098 6 017 2136 6 016Difference vs placebo (95 CI) 2117 6 023 (2162 to 2071) 2155 6 023 (2200 to 2109)P value 0001 0001

FPG at week 52 mmolL 795 6 022 746 6 022 713 6 019Change from baseline in FPG mmolL 2063 6 019 2132 6 019 2143 6 019Difference vs placebo (95 CI) 2069 6 027 (2123 to 2015) 2079 6 027 (2133 to 2026)P value 0012 0004

Data are mean6 SE except for change from baseline values and difference vs placebo which are adjusted mean6 SE HbA1c FPG and body weightat week 18 were assessed with ANCOVA in FAS using LOCF HbA1c insulin dose FPG and bodyweight at week 52 were assessedwith ANCOVA in PPS-completers-52 using LOCF The FAS is patients treated with study medication who had a baseline HbA1c measurement The PPS-completers-52 set ispatients in the FAS who were on treatment up to day 357 and did not have important protocol violations


(26) on empagliflozin 25 mg receivedrescue therapy The rescue therapy usedmost often was an increase in insulindose

Efficacy Week 52Insulin dose was to be adjusted duringweeks 19ndash40 to reach glucose targetsand then to remain within 10 of theprescribed dose at week 40 duringweeks 41ndash52 Adjusted mean dailydose of insulin over time is shown inFig 2A Adjusted mean HbA1c levelsover 52 weeks are shown in Fig 2B Atweek 52 adjusted mean 6 SE changesfrom baseline were 102 6 22 interna-tional unitsday with placebo comparedwith 13 6 21 international unitsdaywith empagliflozin 10 mg and 211 621 international unitsday with empa-gliflozin 25 mg (P = 0004 for empagliflo-zin 10 mg P 0001 for empagliflozin25 mg) (Table 1 Fig 2C) Corrected forbody weight adjusted mean 6 SEchanges from baseline were 010 6002 international unitskg with placebocompared with 003 6 002 interna-tional unitskg with empagliflozin 10mg (difference of adjusted means vsplacebo 2007 international unitskg[95 CI 2012 to 2001] P = 0023)and 000 6 002 international unitskgwith empagliflozin 25 mg (differenceof adjusted means vs placebo 2010international unitskg [95 CI 2015 to2004] P 0001) Mean6 SE changesfrom baseline in basal insulin dose atweek 52 were 92 6 19 internationalunitsday for placebo 37 6 15 interna-tional unitsday for empagliflozin 10 mgand 256 15 international unitsday forempagliflozin 25 mg For prandial insulindose mean 6 SE changes from baselineat week 52 were 03 6 13 internationalunitsday for placebo2196 10 interna-tional unitsday for empagliflozin 10 mgand 235 6 13 international unitsdayfor empagliflozin 25 mg There were nochanges from baseline in the number ofprandial insulin shots per day in any treat-ment group

At week 52 due to the insulin titra-tion in the placebo group the adjustedmean 6 SE change from baseline inHbA1c was 2081 6 008 (289 6 09mmolmol) With much lower insulin ti-tration in the empagliflozin groupschanges were 21186 008 (2129 609 mmolmol) with empagliflozin 10mg and 2127 6 008 (2139 6 09

Figure 1mdashEffect of empagliflozin on efficacy parameters at week 18 A Change from baseline inHbA1c (ANCOVA FAS LOCF imputation at week 18) B Change from baseline in body weight(ANCOVA FAS LOCF) Data are mean6 SE at baseline and adjusted mean 6 SE on treatmentBlue bars represent MDI insulin + placebo purple bars represent MDI insulin + empagliflozin 10mg and green bars represent MDI insulin + empagliflozin 25 mg


Figure 2mdashEffect of empagliflozin on efficacy parameters at week 52 A Insulin dose over time (MMRM FAS OCs) B HbA1c over time (MMRM FASOCs) C Change from baseline in insulin dose (ANCOVA PPS-completers-52 LOCF imputation) D Change from baseline in HbA1c (ANCOVA PPS-completers-52 LOCF) E Percentage of patients with HbA1c $7 ($53 mmolmol) at baseline who reached HbA1c 7 at week 52 (logisticregression FAS noncompleters considered failures) F Change from baseline in body weight (ANCOVA PPS-completers-52 LOCF) Data are mean6SE at baseline and adjusted mean 6 SE on treatment PPS-completers-52 set is patients who were on treatment up to day 357 and did not haveimportant protocol violations Blue circlesbars represent MDI insulin + placebo purple trianglesbars represent MDI insulin + empagliflozin 10 mgand green trianglesbars represent MDI insulin + empagliflozin 25 mg IU international units


mmolmol) with empagliflozin 25 mg(P 0001 for both) (Table 1 Fig 2D) Ofnote a significant proportion of patientswith HbA1c $70 ($53 mmolmol) atbaseline reached HbA1c 70 with em-pagliflozin 10 mg (314) and empagliflo-zin 25 mg (417 P 001 for odds ratiovs placebo [210]) (Fig 2E)Adjusted mean 6 SE changes from

baseline in FPG at week 52 were2063 6 019 mmolL with placebocompared with 2132 6 019 mmolLwith empagliflozin 10 mg (P = 0012)and 2143 6 019 mmolL with empa-gliflozin 25 mg (P = 0004) (Table 1 Sup-plementary Fig 2B)Treatment with empagliflozin signifi-

cantly reduced body weight at week 52Adjustedmean6 SE changes from base-line were 044 6 036 kg with placebocomparedwith21956 036 kg with em-pagliflozin 10 mg and 2204 6 036 kgwith empagliflozin 25 mg (differences ofadjusted means vs placebo were 2239kg [95 CI 2340 to 2139] for empagli-flozin 10 mg and2248 kg [95 CI2348to 2147] for empagliflozin 25 mg P 0001 for both) (Table 1 Fig 2F)Changes from baseline in SBP with

both doses of empagliflozin and in DBPwith empagliflozin 10 mg did not reachsignificance versus placebo at week 52(Supplementary Table 2 Supplementary

Fig 3C and D) Mean 6 SE change frombaseline in DBP was greater with empa-gliflozin 25 mg than placebo (225 606 vs 205 6 06 mmHg P = 0035)at week 52 (Supplementary Table 2Supplementary Fig 3D) No clinicallymeaningful changes in pulse rate werenoted

SafetyData on AEs are shown in Table 2 Overthe 52-week treatment period the pro-portions of patients with $1 AE $1serious AE or $1 AE leading to discon-tinuation were similar across the treat-ment groups with 90 of patientsreporting only mild or moderate eventsOne death occurred (metastatic lungcancer in a patient in the empagliflozin25 mg group)

The proportion of patients with con-firmed hypoglycemic AEs up to week 18was slightly higher in the empagliflozin10 mg group (74 patients [398]) andthe empagliflozin 25 mg group (78 pa-tients [413]) compared with the pla-cebo group (70 patients [372])However only one patient in each ofthe three treatment groups had severehypoglycemic AEs (requiring assis-tance) Over the full 52-week treatmentperiod including the treat-to-target pe-riod the proportion of patients with

confirmed hypoglycemic AEs was similarin all treatment groups (placebo 109patients [580] empagliflozin 10 mg95 patients [511] empagliflozin 25mg 109 patients [577]) Three pa-tients each in the placebo and empagli-flozin 10 mg groups and one in theempagliflozin 25 mg group had severehypoglycemia (requiring assistance)

Over the 52-week treatment periodevents consistent with urinary tract in-fection were reported in similar propor-tions of patients on placebo (154)empagliflozin 10 mg (156) and empa-gliflozin 25 mg (153) More female pa-tients (248ndash270) than male patients(0ndash52) reported these events acrossall treatment groups The majority ofpatients who reported any events con-sistent with urinary tract infection re-ported only mild events One patient(on empagliflozin 25 mg) reported a se-vere event one patient (on empagliflo-zin 25 mg) reported $1 event thatrequired hospitalization and no urinarytract infection events led to study dis-continuation Events consistent withgenital infections were reported inmore patients in the empagliflozin 10mg (43) and empagliflozin 25 mg(95) groups compared with the pla-cebo group (16) These events werereported in a greater proportion of

Figure 2mdashContinued


female patients on empagliflozin 10 mg(789 [79]) or empagliflozin 25 mg(11105 [105]) than on placebo(2118 [18]) and in a greater propor-tion of male patients on empagliflozin25mg (784 [83]) than onempagliflozin10 mg (197 [10]) or placebo (175[13]) All such events were mild ormoderate in intensity only one patient(on empagliflozin 25 mg) experienced anevent that led to discontinuation and nopatients reported events that requiredor prolonged hospitalizationChanges in laboratory parameters are

shown in Supplementary Table 3 Therewere small decreases from baseline inuric acid and small increases from base-line in hematocrit (4) with empagli-flozin Electrolyte levels were unchangedacross treatment groups There weresmall decreases from baseline to end of

treatment in mean eGFR in all treatmentgroups which returned to baseline levelsat follow-up in the empagliflozin groupsNo major differences between placeboand empagliflozin in mean changesfrom baseline in total cholesterol LDLcholesterol HDL cholesterol or triglycer-ides were noted

CONCLUSIONS

This is the first dedicated trial to deter-mine the efficacy and safety of an SGLT2inhibitor in the difficult-to-treat popula-tion of obese insulin-resistant patientswith insufficient glycemic control de-spite high-dose MDI insulin Comparedwith insulin titrations alone which re-sulted in HbA1c reductions to 75 (58mmolmol) the addition of empagliflo-zin 10 mg and empagliflozin 25 mg totitrated MDI insulin improved glycemic

control further despite lower insulindoses to achieve HbA1c levels of 72and 71 (55 and 54mmolmol) respec-tively with no increase in the risk ofhypoglycemia and with weight loss

The use of insulin in patients withT2DM is associated with a high risk ofhypoglycemic events and weight gaincomplicating the management of hyper-glycemia (14) Fear of hypoglycemiaand weight gain decrease adherenceto medication (1516) while insulin-induced weight gain in patients withT2DM is associated with worsening ofinsulin resistance (1) resulting in a vi-cious cycle This study investigating theeffect of empagliflozin as an add-on toMDI insulin is unique in its study designas it comprised three distinct insulindosing periods In a stable MDI insulinperiod during the first 18 weeks empa-gliflozin resulted in significant HbA1c re-duction and weight loss compared withplacebo with a slightly increased fre-quency of mild hypoglycemic eventsbut no increase in severe hypoglycemicevents An increased frequency of hypo-glycemia has previously been reportedwhen antidiabetes agents with a low riskof hypoglycemia are added to insulin(1718) Of note over the full 52-weektreatment period including the treat-to-target period the proportion of pa-tients with confirmed hypoglycemic AEswas similar in all treatment groups Thismight be explained by differences ininsulin titration in the empagliflozinand placebo arms due to the insulin-independent mechanism of action ofempagliflozin (13) the incomplete in-hibition of renal glucose reabsorptionby empagliflozin (19) a diminished ef-fect of SGLT2 inhibition at low glucoselevels due to physiological decline inglomerular filtration rate (due to sympa-thetic nervous system activation) (20) acompensatory increase in hepatic gluco-neogenesis (21) or a combination ofthese factors

The change from baseline in HbA1c inthe placebo group at week 18 was morepronounced than previously observed instudies with empagliflozin We mayspeculate that changes in diet and life-style due to participation in a dedicatedMDI insulin trial may itself have resultedin improved glycemic control in thisobese insulin-resistant population re-inforcing the general paradigm thatpharmacological treatment of diabetes

Table 2mdashSummary of AEs

Placebo(n = 188)

Empagliflozin

10 mg(n = 186)

25 mg(n = 189)

One or more AEs 169 (899) 160 (860) 160 (847)

One or more drug-related AEs 64 (340) 56 (301) 76 (402)

AEs leading to discontinuation 9 (48) 10 (54) 9 (48)

One or more serious AEs 22 (117) 20 (108) 22 (116)

Deaths 0 (0) 0 (0) 1 (05)

AEs with frequency $5 in any group(by preferred term)

Hypoglycemia 111 (590) 97 (522) 110 (582)Nasopharyngitis 40 (213) 34 (183) 27 (143)Urinary tract infection 23 (122) 24 (129) 24 (127)Diarrhea 17 (90) 12 (65) 18 (95)Back pain 14 (74) 12 (65) 15 (79)Arthralgia 10 (53) 18 (97) 11 (58)Influenza 12 (64) 7 (38) 14 (74)Bronchitis 12 (64) 10 (54) 8 (42)Headache 9 (48) 8 (43) 11 (58)Hyperglycemia 14 (74) 6 (32) 8 (42)Hypertension 10 (53) 9 (48) 7 (37)Dizziness 2 (11) 5 (27) 13 (69)Gastroenteritis 10 (53) 8 (43) 1 (05)

Special interest categoriesConfirmed hypoglycemic AEsdagger 109 (580) 95 (511) 109 (577)Severe hypoglycemic AEsDagger 3 (16) 3 (16) 1 (05)

Events consistent with urinary tract infectionsect 29 (154) 29 (156) 29 (153)Male 0 (0) 5 (52) 3 (36)Female 29 (257) 24 (270) 26 (248)Acute pyelonephritis or urosepsis 0 (0) 0 (0) 0 (0)

Events consistent with genital infectionP 3 (16) 8 (43) 18 (95)Male 1 (13) 1 (10) 7 (83)Female 2 (18) 7 (79) 11 (105)

Data are n () for patients treated with $1 dose of trial medication As assessed by theinvestigator daggerAEs consistent with hypoglycemia and with plasma glucose 70 mgdL andorrequiring assistance DaggerAEs consistent with hypoglycemia and with plasma glucose 70 mgdLand requiring assistance sectReports of urinary tract infection were based on 70 preferred termsPReports of genital infection were based on 89 preferred terms


has to be accompanied by diet and life-style interventionEmpagliflozin was well tolerated

when used in combination with MDI in-sulin with or without metformin for 52weeks Empagliflozin was not associatedwith a higher rate of events consistentwith urinary tract infections but was as-sociated with an increased risk of eventsconsistent with genital infection ashas been observed in other studies ofSGLT2 inhibitors (22) However no eventsconsistent with genital infection were se-vere and such events led to prematurediscontinuation in only one patient Smalldecreases in eGFR during treatment withempagliflozin likely reflected hemody-namic changes as eGFR had returned tobaseline levels 4 weeks after treatmentdiscontinuation consistent with the re-sults of another phase III study that exam-ined the effect of empagliflozin on renalfunction over time (23)Limitations of this trial include that

insulin titration was at the investigatorrsquosdiscretion based on prespecified treat-ment goals and was not defined or en-forced by an independent insulin titrationmonitoring committee Therefore thefull effect of empagliflozin on titrated in-sulin doses cannot be fully assessed Fur-thermore the conclusions from this studyare limited to the population studied andare not applicable to the general popula-tion of patients with T2DMIn conclusion in obese patients with

T2DM and inadequate glycemic controldespiteMDI insulin empagliflozin 10mgand empagliflozin 25 mg once daily for52 weeks improved glycemic control andreduced body weight without increasingthe risk of hypoglycemia and with lowerinsulin requirements This suggests thatempagliflozin may provide a new treat-ment option for this challenging-to-treatpatient population

Acknowledgments Medical writing assis-tance was provided by Clare Ryles and WendyMorris of Fleishman-Hillard Group Ltd duringthe preparation of this articleDuality of Interest This study was fundedby Boehringer Ingelheim and Eli Lilly AJ GFAS GK HJW and UCB are employees ofBoehringer Ingelheim JR has served on scien-tific advisory boards and received honoraria orconsulting fees from companies involved indevelopment of SGLT2 inhibitors includingBristol-Myers Squibb Roche GlaxoSmithKlineJohnson amp Johnson Boehringer Ingelheim andLexicon and has also received grantsresearch

support from Pfizer Roche Bristol-MyersSquibb GlaxoSmithKline AstraZeneca Johnsonamp Johnson Boehringer Ingelheim and LexiconMedical writing assistance was supported finan-cially by Boehringer Ingelheim No other poten-tial conflicts of interest relevant to this articlewere reportedAuthor Contributions JR contributed to theacquisition and interpretation of data anddrafted the manuscript AJ GF AS and GKcontributed to the interpretation of data andreviewededited the manuscript HJW andUCB contributed to the study design and inter-pretation of data and reviewededited themanuscript The authors are fully responsiblefor all content and editorial decisions wereinvolved at all stages of manuscript develop-ment and have approved the final version GFis the guarantor of this work and as such hadfull access to all the data in the study and takesresponsibility for the integrity of the data andthe accuracy of the data analysisPrior Presentation Parts of this study werepresented at the 74th Scientific Sessions of theAmerican Diabetes Association San FranciscoCA 13ndash17 June 2014

References1 Inzucchi SE Bergenstal RM Buse JB et alManagement of hyperglycaemia in type 2 dia-betes a patient-centered approach Positionstatement of the American Diabetes Associa-tion (ADA) and the European Association forthe Study of Diabetes (EASD) Diabetologia2012551577ndash15962 Donner T Mu~noz M Update on insulin ther-apy for type 2 diabetes J Clin Endocrinol Metab2012971405ndash14133 Guler S Vaz JA Ligthelm R Intensificationlessons with modern premixes from clinical tri-al to clinical practice Diabetes Res Clin Pract200881(Suppl 1)S23ndashS304 RiddleMC Rosenstock J Gerich J Insulin Glar-gine 4002 Study Investigators The treat-to-targettrial randomized addition of glargine or humanNPH insulin to oral therapy of type 2 diabeticpatients Diabetes Care 2003263080ndash30865 Pickup JC Renard E Long-acting insulin ana-logs versus insulin pump therapy for the treat-ment of type 1 and type 2 diabetes DiabetesCare 200831(Suppl 2)S140ndashS1456 Grempler R Thomas L Eckhardt M et alEmpagliflozin a novel selective sodium glucosecotransporter-2 (SGLT-2) inhibitor character-isation and comparison with other SGLT-2 inhib-itors Diabetes Obes Metab 20121483ndash907 Heise T Seewaldt-Becker E Macha S et alSafety tolerability pharmacokinetics and phar-macodynamics following 4 weeksrsquo treatmentwith empagliflozin once daily in patients withtype 2 diabetes Diabetes Obes Metab 201315613ndash6218 Roden M Weng J Eilbracht J et al EMPA-REG MONO Trial Investigators Empagliflozinmonotherapy with sitagliptin as an active com-parator in patients with type 2 diabetes a ran-domised double-blind placebo-controlledphase 3 trial Lancet Diabetes Endocrinol 20131208ndash2199 Haring H-U Merker L Seewaldt-Becker Eet al EMPA-REGMET Trial Investigators Empa-gliflozin as add-on tometformin in patients with

type 2 diabetes a 24-week randomized double-blind placebo-controlled trial Diabetes Care2014371650ndash165910 Haring H-U Merker L Seewaldt-Becker Eet al EMPA-REGMETSU Trial Investigators Em-pagliflozin as add-on to metformin plus sulfonyl-urea in patients with type 2 diabetes a 24-weekrandomized double-blind placebo-controlledtrial Diabetes Care 2013363396ndash340411 Kovacs CS Seshiah V Swallow R et alEMPA-REG PIO Trial Investigators Empagliflozinimproves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plusmetformin in patients with type 2 diabetesa 24-week randomized placebo-controlled tri-al Diabetes Obes Metab 201416147ndash15812 Rosenstock J Jelaska A Wang F et alEMPA-REG BASAL Trial Investigators Empagli-flozin as add-on to basal insulin for 78 weeksimproves glycemic control with weight loss ininsulin-treated type 2 diabetes (T2DM) (Ab-stract) Diabetes 201362(Suppl 1)A28513 Kim Y Babu AR Clinical potential of sodium-glucose cotransporter 2 inhibitors in the manage-ment of type 2 diabetes Diabetes Metab SyndrObes 20125313ndash32714 Bailey CJ The challenge of managing coex-istent type 2 diabetes and obesity BMJ 2011342d199615 Hauber AB Mohamed AF Johnson FRFalvey H Treatment preferences and medica-tion adherence of people with type 2 diabetesusing oral glucose-lowering agents Diabet Med200926416ndash42416 Moghissi E Ismail-Beigi F Devine RC Hypo-glycemia minimizing its impact in type 2 diabe-tes Endocr Pract 201319526ndash53517 Charbonnel B DeFronzo R Davidson Jet al PROactive Investigators Pioglitazoneuse in combination with insulin in the prospec-tive pioglitazone clinical trial in macrovascularevents study (PROactive19) J Clin EndocrinolMetab 2010952163ndash217118 Vilsboslashll T Rosenstock J Yki-Jarvinen H et alEfficacy and safety of sitagliptin when added toinsulin therapy in patients with type 2 diabetesDiabetes Obes Metab 201012167ndash17719 Liu JJ Lee T DeFronzo RA Why Do SGLT2inhibitors inhibit only 30-50 of renal glucosereabsorption in humans Diabetes 2012612199ndash220420 Patrick AW Hepburn DA Swainson CPFrier BM Changes in renal function during acuteinsulin-induced hypoglycaemia in patients withtype 1 diabetes Diabet Med 19929150ndash15521 Ferrannini E Muscelli E Frascerra S et alMetabolic response to sodium-glucose cotrans-porter 2 inhibition in type 2 diabetic patientsJ Clin Invest 2014124499ndash50822 Musso G Gambino R Cassader M et al Anovel approach to control hyperglycemia intype 2 diabetes sodium glucose co-transport(SGLT) inhibitors systematic review and meta-analysis of randomized trials AnnMed 201244375ndash39323 Barnett AH Mithal A Manassie J et alEMPA-REG RENAL Trial Investigators Efficacyand safety of empagliflozin added to existingantidiabetes treatment in patients with type 2diabetes and chronic kidney disease a rando-mised double-blind placebo-controlled trialLancet Diabetes Endocrinol 20142369ndash384


Guidelines from the American DiabetesAssociation and the European Associa-tion for the Study of Diabetes recom-mend the initiation of basal insulinusually in conjunction with oral antidia-betes agents in patients with type 2 di-abetes mellitus (T2DM) who havemarked hyperglycemia when it is un-likely that another drug will be of suffi-cient additional benefit (1) However inclinical practice insulin therapy is oftendelayed or not optimized Barriers to theinitiation and optimization of insulintherapy include fear of hypoglycemiaand weight gain and concerns over thecomplexity of the treatment regimen(23) Approximately 40ndash50 of patientswith T2DM fail to achieve glycemic con-trol with basal insulin plus oral anti-diabetes agents after 24 weeks oftreatment (4) Further intensificationof the insulin regimen to control hyper-glycemia is traditionally achieved withprogressive additions of prandial insulinup to multiple daily injections of insulin(MDI insulin) However MDI insulin isoverwhelming for most patients anddespite combination with metformininsulin requirements are often highand patients are still unable to achieveglycemic control In addition these pa-tients are typically insulin resistant (5)and comorbidities such as obesity andhypertension are very common Weightgain associatedwith theuseof high insulindoses may make it even more difficult toachieve glycemic control (5) Accordinglythere is a high unmet need for antidiabe-tes therapies that can be used in combi-nation with MDI insulin to improveglycemic control in patients with T2DMwithout exacerbating comorbiditiesEmpagliflozin a potent and selective

sodium glucose cotransporter 2 (SGLT2)inhibitor (6) reduces hyperglycemia byreducing renal glucose reabsorptioncausing urinary glucose excretion (7)In phase III studies empagliflozin usedas monotherapy or as an add-on to met-formin metformin plus sulfonylureapioglitazone (with or without metfor-min) or basal insulin improved glycemiccontrol and consistently reduced bodyweight and blood pressure (8ndash12) Em-pagliflozin is potentially an attractive op-tion for use in combination with insulinas itsmechanism of action is independentofb-cell function (13) it generatesweightloss and it is associated with a low risk ofhypoglycemia (8ndash12)

The EMPA-REG MDI trial was under-taken to evaluate the efficacy andsafety of empagliflozin 10 mg and em-pagliflozin 25 mg versus placebo asan add-on to MDI insulin with or with-out metformin for 52 weeks in patientswith T2DM and insufficient glycemiccontrol We hypothesized that empa-gliflozin would improve glycemiccontrol and body weight in this difficult-to-treat obese population of pa-tients with T2DM and high insulinrequirements


Study DesignThis was a randomized double-blindplacebo-controlled parallel-groupstudy conducted from March 2011 toApril 2013 in 104 centers across 14countries The clinical trial protocolwas approved by the institutional re-view boards and independent ethicscommittees and competent authoritiesof the participating centers and thestudy was conducted in accordancewith the Declaration of Helsinki andthe International Conference on Harmo-nization Harmonized Tripartite Guide-line for Good Clinical Practice The trialwas registered with ClinicalTrialsgov(NCT01306214) All patients providedwritten informed consent

Inclusion and Exclusion CriteriaThis study enrolled obese adults (BMI$30 and 45 kgm2) with T2DM andinsufficient glycemic control (HbA1c

$75 to10 [$58 to86 mmolmol]at screening) despite diet and exercisecounseling and treatment with MDI in-sulin (total daily dose 60 internationalunits) alone or in combination with met-formin (immediate or extended release$1500 mgday maximum tolerateddose or maximum dose according tothe local label) For $12 weeks priorto randomization insulin dose was notto be changed by 10 and metformindose was to be unchanged Premixed in-sulins were not permitted

Exclusion criteria included uncon-trolled hyperglycemia (glucose level133 mmolL after an overnight fastduring the placebo run-in confirmedby a second measurement) acute coro-nary syndrome stroke or transient is-chemic attack within 3 months prior toconsent indication of liver disease im-paired renal function during screeningor run-in (estimated glomerular filtration

rate [eGFR] using the modification ofdiet and renal disease equation 60mLmin173 m2) gastrointestinal sur-geries that induce malabsorption his-tory of cancer (except for basal cellcarcinoma) within 5 years disorderscausing hemolysis or unstable erythro-cytes treatment with systemic steroidsat time of consent change in dosage ofthyroid hormones within 6 weeks priorto consent treatment with antiobesitydrugs or alcohol or drug abuse within 3months of consent and investigationaldrug intake within 30 days of intake ofstudy drug

Treatment and InterventionsFollowing a 2-week open-label placeborun-in period patients still meeting theinclusionexclusion criteria were ran-domized (111) to receive once-dailyempagliflozin 10 mg empagliflozin 25mg or placebo as an add-on to MDI in-sulin with or without metformin for 52weeks Randomization was undertakenusing a third-party interactive voice- andweb-response system and was stratifiedby HbA1c (85 $85 [69 $69mmolmol]) eGFR (chronic kidney dis-ease stage 1 $90 mLmin173 m2chronic kidney disease stage 2 60ndash89mLmin173m2) region (Europe NorthAmerica Latin America) and back-ground antidiabetes therapy (insulinalone insulin plus metformin) Patientsreceived diet and exercise counselingbased on local recommendations atthe start of the run-in period and werereminded to follow their diet and exer-cise plan at every study visit For the first18 weeks the total daily dose of insulinwas to remain within 10 of the pre-scribed dose at randomization Duringthe titrated treat-to-target period(weeks 19ndash40) insulin dose was to beadjusted to achieve a preprandial glu-cose target of 55 mmolL (100mgdL) and a postprandial glucose tar-get of 78 mmolL (140 mgdL) Be-tween weeks 41 and 52 the total dailydose of insulin was to remainwithin 10of the insulin dose prescribed at week40 except for adjustments for safetyreasons Metformin dose was to remainunchanged throughout the study Studyvisits were scheduled at screening thestart of the placebo run-in randomiza-tion after 4 8 12 18 24 32 40 46 and52 weeks of treatment and 4 weeks af-ter the last dose of study drug












RESULTS












Placebo

Empagliflozin

10 mg 25 mg




(mmolmol)2050 6 005 (255 6 05) 2094 6 005 (2103 6 05) 2102 6 005 (2111 6 05)


2044 6 008 (2059 to 2029)[248 6 09 (264 to 232)]

2052 6 007 (2067 to 2037)[257 6 08 (273 to 240)]

P value 0001 0001




102 6 22 13 6 21 211 6 21



825 6 007 (67 6 08) 840 6 007 (68 6 08) 837 6 006 (68 6 07)


(mmolmol)2081 6 008 (289 6 09) 2118 6 008 (2129 6 09) 2127 6 008 (2139 6 09)


2038 6 011 (2059 to 2016)[242 6 12 (264 to 217)]

2046 6 011 (2067 to 2025)[250 6 12 (273 to 227)]




























CONCLUSIONS






Placebo(n = 188)

Empagliflozin

10 mg(n = 186)

25 mg(n = 189)

One or more AEs 169 (899) 160 (860) 160 (847)




Deaths 0 (0) 0 (0) 1 (05)



























RESULTS












Placebo

Empagliflozin

10 mg 25 mg




(mmolmol)2050 6 005 (255 6 05) 2094 6 005 (2103 6 05) 2102 6 005 (2111 6 05)


2044 6 008 (2059 to 2029)[248 6 09 (264 to 232)]

2052 6 007 (2067 to 2037)[257 6 08 (273 to 240)]

P value 0001 0001




102 6 22 13 6 21 211 6 21



825 6 007 (67 6 08) 840 6 007 (68 6 08) 837 6 006 (68 6 07)


(mmolmol)2081 6 008 (289 6 09) 2118 6 008 (2129 6 09) 2127 6 008 (2139 6 09)


2038 6 011 (2059 to 2016)[242 6 12 (264 to 217)]

2046 6 011 (2067 to 2025)[250 6 12 (273 to 227)]




























CONCLUSIONS






Placebo(n = 188)

Empagliflozin

10 mg(n = 186)

25 mg(n = 189)

One or more AEs 169 (899) 160 (860) 160 (847)




Deaths 0 (0) 0 (0) 1 (05)

























Placebo

Empagliflozin

10 mg 25 mg




(mmolmol)2050 6 005 (255 6 05) 2094 6 005 (2103 6 05) 2102 6 005 (2111 6 05)


2044 6 008 (2059 to 2029)[248 6 09 (264 to 232)]

2052 6 007 (2067 to 2037)[257 6 08 (273 to 240)]

P value 0001 0001




102 6 22 13 6 21 211 6 21



825 6 007 (67 6 08) 840 6 007 (68 6 08) 837 6 006 (68 6 07)


(mmolmol)2081 6 008 (289 6 09) 2118 6 008 (2129 6 09) 2127 6 008 (2139 6 09)


2038 6 011 (2059 to 2016)[242 6 12 (264 to 217)]

2046 6 011 (2067 to 2025)[250 6 12 (273 to 227)]




























CONCLUSIONS






Placebo(n = 188)

Empagliflozin

10 mg(n = 186)

25 mg(n = 189)

One or more AEs 169 (899) 160 (860) 160 (847)




Deaths 0 (0) 0 (0) 1 (05)






































CONCLUSIONS






Placebo(n = 188)

Empagliflozin

10 mg(n = 186)

25 mg(n = 189)

One or more AEs 169 (899) 160 (860) 160 (847)




Deaths 0 (0) 0 (0) 1 (05)

















weight loss, lower insulin doses,weight loss, lower insulin doses, and no increased hypoglycemia...

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