Clinical trial NCT01719003: Safety and Efficacy Study of Empagliflozin and Metformin for 24 Weeks in Treatment Naive Patients With Type 2 Diabetes
Official title: A 24-week Phase III Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Twice Daily Oral Administration of Empagliflozin + Metformin Compared With the Individual Components of Empagliflozin or Metformin in Drug Naive Patients With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Hyperglycemia
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2012-11-01
Enrollment: 1413
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will investigate the efficacy and safety of two doses (high and low) of empagliflozin in combination with metformin (500 mg and 1000 mg) administered twice daily in patients with type 2 diabetes mellitus (T2DM). Study will compare four dose combinations of empagliflozin + metformin versus each individual component after 24 weeks of treatment.


Eligibility criteria: Inclusion criteria:

1. Diagnosis of type 2 diabetes mellitus prior to informed consent
2. Male and female patients on diet and exercise regimen who are drug-naive, defined as absence of any oral antidiabetic therapy for 12 weeks prior to randomization
3. HbA1c \>=7.5% and \<= 12% (\>=58.5 mmol/mol and \<=107.7 mmol/mol)
4. Body Mass Index (BMI) \<= 45 kg/m2 at screening

Exclusion criteria:

1. Uncontrolled hyperglycemia with a glucose level \>240 mg/dl (\>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second laboratory measurement (not on the same day)
2. Any antidiabetic drug within 12 weeks prior to randomization
3. Impaired renal function, defined as estimated creatinine clearance rate (eCCr) \<60 ml/min (Cockcroft-Gault formula) as determined during screening and/or run-in period
4. Contraindications to metformin according to the local label

Primary outcomes:
measure: HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24
timeFrame: baseline and 24 weeks
Secondary outcomes:
measure: FPG (Fasting Plasma Glucose) Change From Baseline at Week 24
timeFrame: baseline and 24 weeks
measure: Body Weight Change From Baseline at Week 24
timeFrame: baseline and 24 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 1276.1.10014 Boehringer Ingelheim Investigational Site
state: Alabama
city: Birmingham
country: United States
facility: 1276.1.10019 Boehringer Ingelheim Investigational Site
state: Alabama
city: Hot Springs
country: United States
facility: 1276.1.10044 Boehringer Ingelheim Investigational Site
state: Alaska
city: Glendale
country: United States
facility: 1276.1.10010 Boehringer Ingelheim Investigational Site
state: Arizona
city: Searcy
country: United States
facility: 1276.1.10035 Boehringer Ingelheim Investigational Site
state: Arkansas
city: Chula Vista
country: United States
facility: 1276.1.10046 Boehringer Ingelheim Investigational Site
state: California
city: Huntington Beach
country: United States
facility: 1276.1.10006 Boehringer Ingelheim Investigational Site
state: California
city: La Mesa
country: United States
facility: 1276.1.10043 Boehringer Ingelheim Investigational Site
state: California
city: Los Angeles
country: United States
facility: 1276.1.10009 Boehringer Ingelheim Investigational Site
state: California
city: Los Angeles
country: United States
facility: 1276.1.10040 Boehringer Ingelheim Investigational Site
state: California
city: Oceanside
country: United States
facility: 1276.1.10045 Boehringer Ingelheim Investigational Site
state: California
city: Colorado Springs
country: United States
facility: 1276.1.10042 Boehringer Ingelheim Investigational Site
state: Colorado
city: Denver
country: United States
facility: 1276.1.10001 Boehringer Ingelheim Investigational Site
state: Colorado
city: Northglenn
country: United States
facility: 1276.1.10003 Boehringer Ingelheim Investigational Site
state: Colorado
city: Fort Lauderdale
country: United States
facility: 1276.1.10026 Boehringer Ingelheim Investigational Site
state: Florida
city: Oldsmar
country: United States
facility: 1276.1.10024 Boehringer Ingelheim Investigational Site
state: Florida
city: Port Orange
country: United States
facility: 1276.1.10027 Boehringer Ingelheim Investigational Site
state: Florida
city: Marietta
country: United States
facility: 1276.1.10023 Boehringer Ingelheim Investigational Site
state: Georgia
city: Evansville
country: United States
facility: 1276.1.10034 Boehringer Ingelheim Investigational Site
state: Indiana
city: Fall River
country: United States
facility: 1276.1.10032 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Bridgman
country: United States
facility: 1276.1.10036 Boehringer Ingelheim Investigational Site
state: Michigan
city: Hazelwood
country: United States
facility: 1276.1.10037 Boehringer Ingelheim Investigational Site
state: Missouri
city: Las Vegas
country: United States
facility: 1276.1.10007 Boehringer Ingelheim Investigational Site
state: Nevada
city: Union
country: United States
facility: 1276.1.10015 Boehringer Ingelheim Investigational Site
state: New Jersey
city: Asheboro
country: United States
facility: 1276.1.10033 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Burlington
country: United States
facility: 1276.1.10022 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Lenoir
country: United States
facility: 1276.1.10002 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: 1276.1.10005 Boehringer Ingelheim Investigational Site
state: Ohio
city: Gallipolis
country: United States
facility: 1276.1.10011 Boehringer Ingelheim Investigational Site
state: Ohio
city: Columbia
country: United States
facility: 1276.1.10030 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Greer
country: United States
facility: 1276.1.10008 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Hodges
country: United States
facility: 1276.1.10013 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Humboldt
country: United States
facility: 1276.1.10017 Boehringer Ingelheim Investigational Site
state: Tennessee
city: Houston
country: United States
facility: 1276.1.10018 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1276.1.10025 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1276.1.10028 Boehringer Ingelheim Investigational Site
state: Texas
city: Kingwood
country: United States
facility: 1276.1.10016 Boehringer Ingelheim Investigational Site
state: Texas
city: San Antonio
country: United States
facility: 1276.1.10021 Boehringer Ingelheim Investigational Site
state: Texas
city: San Antonio
country: United States
facility: 1276.1.10041 Boehringer Ingelheim Investigational Site
state: Texas
city: Manassas
country: United States
facility: 1276.1.10004 Boehringer Ingelheim Investigational Site
state: Virginia
city: Wenatchee
country: United States
facility: 1276.1.10012 Boehringer Ingelheim Investigational Site
state: Washington
city: Belém
country: Brazil
facility: 1276.1.55008 Boehringer Ingelheim Investigational Site
city: Brasilia
country: Brazil
facility: 1276.1.55003 Boehringer Ingelheim Investigational Site
city: Fortaleza
country: Brazil
facility: 1276.1.55006 Boehringer Ingelheim Investigational Site
city: Fortaleza
country: Brazil
facility: 1276.1.55007 Boehringer Ingelheim Investigational Site
city: Fortaleza
country: Brazil
facility: 1276.1.55009 Boehringer Ingelheim Investigational Site
city: Goiania
country: Brazil
facility: 1276.1.55004 Boehringer Ingelheim Investigational Site
city: Porto Alegre
country: Brazil
facility: 1276.1.55002 Boehringer Ingelheim Investigational Site
city: Sao Paulo
country: Brazil
facility: 1276.1.55001 Boehringer Ingelheim Investigational Site
city: Coquitlam
country: Canada
facility: 1276.1.20003 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Coquitlam
country: Canada
facility: 1276.1.20012 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Victoria
country: Canada
facility: 1276.1.20008 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Antigonish
country: Canada
facility: 1276.1.20004 Boehringer Ingelheim Investigational Site
state: Nova Scotia
city: Hawkesbury
country: Canada
facility: 1276.1.20005 Boehringer Ingelheim Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: 1276.1.20013 Boehringer Ingelheim Investigational Site
state: Ontario
city: Strathroy
country: Canada
facility: 1276.1.20010 Boehringer Ingelheim Investigational Site
state: Ontario
city: Thornhill
country: Canada
facility: 1276.1.20006 Boehringer Ingelheim Investigational Site
state: Ontario
city: Mirabel
country: Canada
facility: 1276.1.20007 Boehringer Ingelheim Investigational Site
state: Quebec
city: Saskatoon
country: Canada
facility: 1276.1.20001 Boehringer Ingelheim Investigational Site
state: Saskatchewan
city: Quebec
country: Canada
facility: 1276.1.20002 Boehringer Ingelheim Investigational Site
city: Benatky nad Jizerou
country: Czech Republic
facility: 1276.1.42002 Boehringer Ingelheim Investigational Site
city: Olomouc
country: Czech Republic
facility: 1276.1.42008 Boehringer Ingelheim Investigational Site
city: Ostrava
country: Czech Republic
facility: 1276.1.42007 Boehringer Ingelheim Investigational Site
city: Plzen
country: Czech Republic
facility: 1276.1.42009 Boehringer Ingelheim Investigational Site
city: Praha 10
country: Czech Republic
facility: 1276.1.42004 Boehringer Ingelheim Investigational Site
city: Praha 1
country: Czech Republic
facility: 1276.1.42010 Boehringer Ingelheim Investigational Site
city: Praha 3
country: Czech Republic
facility: 1276.1.42003 Boehringer Ingelheim Investigational Site
city: Abbasia Cairo, Egypt
country: Egypt
facility: 1276.1.95001 Boehringer Ingelheim Investigational Site
city: Al Manial, Cairo, Egypt
country: Egypt
facility: 1276.1.95003 Boehringer Ingelheim Investigational Site
city: Alexandria
country: Egypt
facility: 1276.1.95004 Boehringer Ingelheim Investigational Site
city: El Darasa Cairo Egypt
country: Egypt
facility: 1276.1.95002 Boehringer Ingelheim Investigational Site
city: Behren Les Forbach
country: France
facility: 1276.1.33004 Boehringer Ingelheim Investigational Site
city: Bersée
country: France
facility: 1276.1.33012 Boehringer Ingelheim Investigational Site
city: Cournonterral
country: France
facility: 1276.1.33005 Boehringer Ingelheim Investigational Site
city: Hautmont
country: France
facility: 1276.1.33007 Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1276.1.33013 Boehringer Ingelheim Investigational Site
city: Poitiers
country: France
facility: 1276.1.33001 Boehringer Ingelheim Investigational Site
city: Savonnières
country: France
facility: 1276.1.33003 Boehringer Ingelheim Investigational Site
city: St Genis des Fontaines
country: France
facility: 1276.1.33006 Boehringer Ingelheim Investigational Site
city: Thouars
country: France
facility: 1276.1.33002 Boehringer Ingelheim Investigational Site
city: Thun St amand
country: France
facility: 1276.1.33011 Boehringer Ingelheim Investigational Site
city: Tours
country: France
facility: 1276.1.33010 Boehringer Ingelheim Investigational Site
city: Vandome
country: France
facility: 1276.1.33009 Boehringer Ingelheim Investigational Site
city: Vieux Condé
country: France
facility: 1276.1.33008 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1276.1.49005 Boehringer Ingelheim Investigational Site
city: Celle
country: Germany
facility: 1276.1.49008 Boehringer Ingelheim Investigational Site
city: Dortmund
country: Germany
facility: 1276.1.49006 Boehringer Ingelheim Investigational Site
city: Dresden
country: Germany
facility: 1276.1.49011 Boehringer Ingelheim Investigational Site
city: Essen
country: Germany
facility: 1276.1.49003 Boehringer Ingelheim Investigational Site
city: Ingelheim
country: Germany
facility: 1276.1.49007 Boehringer Ingelheim Investigational Site
city: Neuwied
country: Germany
facility: 1276.1.49014 Boehringer Ingelheim Investigational Site
city: Offenbach
country: Germany
facility: 1276.1.49004 Boehringer Ingelheim Investigational Site
city: Stuhr-Brinkum
country: Germany
facility: 1276.1.49002 Boehringer Ingelheim Investigational Site
city: Teuchern
country: Germany
facility: 1276.1.49012 Boehringer Ingelheim Investigational Site
city: Barbena Santa Rosa
country: Guatemala
facility: 1276.1.50002 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 1276.1.50003 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 1276.1.50005 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 1276.1.50006 Boehringer Ingelheim Investigational Site
city: Quetzaltenango
country: Guatemala
facility: 1276.1.50001 Boehringer Ingelheim Investigational Site
city: Deagu
country: Korea, Republic of
facility: 1276.1.82006 Boehringer Ingelheim Investigational Site
city: Goyang
country: Korea, Republic of
facility: 1276.1.82010 Boehringer Ingelheim Investigational Site
city: Incheon
country: Korea, Republic of
facility: 1276.1.82001 Boehringer Ingelheim Investigational Site
city: Pusan
country: Korea, Republic of
facility: 1276.1.82009 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1276.1.82002 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1276.1.82004 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1276.1.82005 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1276.1.82007 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1276.1.82008 Boehringer Ingelheim Investigational Site
city: Wonju
country: Korea, Republic of
facility: 1276.1.82003 Boehringer Ingelheim Investigational Site
city: Beirut
country: Lebanon
facility: 1276.1.96001 Boehringer Ingelheim Investigational Site
city: El Chouf
country: Lebanon
facility: 1276.1.96002 Boehringer Ingelheim Investigational Site
city: Saida
country: Lebanon
facility: 1276.1.96003 Boehringer Ingelheim Investigational Site
city: Saida
country: Lebanon
facility: 1276.1.96004 Boehringer Ingelheim Investigational Site
city: Ipoh, Perak
country: Malaysia
facility: 1276.1.60002 Boehringer Ingelheim Investigational Site
city: Johor Bahru
country: Malaysia
facility: 1276.1.60001 Boehringer Ingelheim Investigational Site
city: Kubang Kerian
country: Malaysia
facility: 1276.1.60003 Boehringer Ingelheim Investigational Site
city: Aguascalientes
country: Mexico
facility: 1276.1.52004 Boehringer Ingelheim Investigational Site
city: Aguascalientes
country: Mexico
facility: 1276.1.52007 Boehringer Ingelheim Investigational Site
city: Ciudad de Mexico
country: Mexico
facility: 1276.1.52002 Boehringer Ingelheim Investigational Site
city: Guadalajara
country: Mexico
facility: 1276.1.52003 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 1276.1.52001 Boehringer Ingelheim Investigational Site
city: San Lucas tepetlcalco
country: Mexico
facility: 1276.1.52006 Boehringer Ingelheim Investigational Site
city: Zapopan
country: Mexico
facility: 1276.1.52005 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 1276.1.51001 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 1276.1.51002 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 1276.1.51003 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 1276.1.51004 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 1276.1.51005 Boehringer Ingelheim Investigational Site
city: Cebu City, Cebu
country: Philippines
facility: 1276.1.63009 Boehringer Ingelheim Investigational Site
city: Cebu City, Philippines
country: Philippines
facility: 1276.1.63002 Boehringer Ingelheim Investigational Site
city: Davao City
country: Philippines
facility: 1276.1.63004 Boehringer Ingelheim Investigational Site
city: Iloilo City
country: Philippines
facility: 1276.1.63003 Boehringer Ingelheim Investigational Site
city: Manila
country: Philippines
facility: 1276.1.63006 Boehringer Ingelheim Investigational Site
city: Marikina City
country: Philippines
facility: 1276.1.63001 Boehringer Ingelheim Investigational Site
city: Maybunga, Pasig City
country: Philippines
facility: 1276.1.63005 Boehringer Ingelheim Investigational Site
city: San Juan City
country: Philippines
facility: 1276.1.63007 Boehringer Ingelheim Investigational Site
city: Tarlac
country: Philippines
facility: 1276.1.63008 Boehringer Ingelheim Investigational Site
city: Barnaul
country: Russian Federation
facility: 1276.1.70012 Boehringer Ingelheim Investigational Site
city: Kemerovo
country: Russian Federation
facility: 1276.1.70011 Boehringer Ingelheim Investigational Site
city: Novosibirsk
country: Russian Federation
facility: 1276.1.70015 Boehringer Ingelheim Investigational Site
city: Novosibirsk
country: Russian Federation
facility: 1276.1.70016 Boehringer Ingelheim Investigational Site
city: Novosibirsk
country: Russian Federation
facility: 1276.1.70018 Boehringer Ingelheim Investigational Site
city: Petrozavodsk
country: Russian Federation
facility: 1276.1.70007 Boehringer Ingelheim Investigational Site
city: Saratov
country: Russian Federation
facility: 1276.1.70009 Boehringer Ingelheim Investigational Site
city: Smolensk
country: Russian Federation
facility: 1276.1.70010 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 1276.1.70005 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 1276.1.70006 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 1276.1.70017 Boehringer Ingelheim Investigational Site
city: Yaroslavl
country: Russian Federation
facility: 1276.1.70013 Boehringer Ingelheim Investigational Site
city: Belgrade
country: Serbia
facility: 1276.1.38104 Boehringer Ingelheim Investigational Site
city: Belgrade
country: Serbia
facility: 1276.1.38105 Boehringer Ingelheim Investigational Site
city: Belgrade
country: Serbia
facility: 1276.1.38106 Boehringer Ingelheim Investigational Site
city: Belgrade
country: Serbia
facility: 1276.1.38107 Boehringer Ingelheim Investigational Site
city: Kragujevac
country: Serbia
facility: 1276.1.38103 Boehringer Ingelheim Investigational Site
city: Nis
country: Serbia
facility: 1276.1.38101 Boehringer Ingelheim Investigational Site
city: Novi Sad
country: Serbia
facility: 1276.1.38108 Boehringer Ingelheim Investigational Site
city: Zajecar
country: Serbia
facility: 1276.1.38102 Boehringer Ingelheim Investigational Site
city: Alicante
country: Spain
facility: 1276.1.34048 Boehringer Ingelheim Investigational Site
city: Alzira
country: Spain
facility: 1276.1.34050 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1276.1.34028 Boehringer Ingelheim Investigational Site
city: pozuelo de Alarcon
country: Spain
facility: 1276.1.34045 Boehringer Ingelheim Investigational Site
city: Sabadell (Barcelona)
country: Spain
facility: 1276.1.34034 Boehringer Ingelheim Investigational Site
city: Salamanca
country: Spain
facility: 1276.1.34027 Boehringer Ingelheim Investigational Site
city: Tarragona
country: Spain
facility: 1276.1.34052 Boehringer Ingelheim Investigational Site
city: Zaragoza
country: Spain
facility: 1276.1.34051 Boehringer Ingelheim Investigational Site
city: Kaohsiung City,
country: Taiwan
facility: 1276.1.88005 Boehringer Ingelheim Investigational Site
city: New Taipei City
country: Taiwan
facility: 1276.1.88002 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1276.1.88001 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1276.1.88003 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1276.1.88004 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1276.1.88006 Boehringer Ingelheim Investigational Site
city: Bangkok, Thailand
country: Thailand
facility: 1276.1.66001 Boehringer Ingelheim Investigational Site
city: Bangkok, Thailand
country: Thailand
facility: 1276.1.66003 Boehringer Ingelheim Investigational Site
city: Nakhon Ratchasima
country: Thailand
facility: 1276.1.66002 Boehringer Ingelheim Investigational Site
city: Ankara
country: Turkey
facility: 1276.1.90003 Boehringer Ingelheim Investigational Site
city: Antalya
country: Turkey
facility: 1276.1.90004 Boehringer Ingelheim Investigational Site
city: Denizli
country: Turkey
facility: 1276.1.90006 Boehringer Ingelheim Investigational Site
city: Erzurum
country: Turkey
facility: 1276.1.90002 Boehringer Ingelheim Investigational Site
city: Istanbul
country: Turkey
facility: 1276.1.90005 Boehringer Ingelheim Investigational Site
city: Izmir
country: Turkey
facility: 1276.1.90001 Boehringer Ingelheim Investigational Site
city: Bolton
country: United Kingdom
facility: 1276.1.44002 Boehringer Ingelheim Investigational Site
city: Bradford on Avon
country: United Kingdom
facility: 1276.1.44001 Boehringer Ingelheim Investigational Site
city: Chippenham
country: United Kingdom
facility: 1276.1.44005 Boehringer Ingelheim Investigational Site
city: Dagenham
country: United Kingdom
facility: 1276.1.44006 Boehringer Ingelheim Investigational Site
city: Doncaster
country: United Kingdom
facility: 1276.1.44004 Boehringer Ingelheim Investigational Site
city: Glasgow
country: United Kingdom
facility: 1276.1.44008 Boehringer Ingelheim Investigational Site
city: Leeds
country: United Kingdom
facility: 1276.1.44003 Boehringer Ingelheim Investigational Site
city: Manchester
country: United Kingdom
facility: 1276.1.44007 Boehringer Ingelheim Investigational Site
city: Mortimer
country: United Kingdom
facility: 1276.1.44011 Boehringer Ingelheim Investigational Site
city: Sandbach
country: United Kingdom
facility: 1276.1.44009 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Hadjadj S, Rosenstock J, Meinicke T, Woerle HJ, Broedl UC. Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes. Diabetes Care. 2016 Oct;39(10):1718-28. doi: 10.2337/dc16-0522. Epub 2016 Aug 4.