Clinical trial NCT04242758: Phthalates Exposure in Type 2 Diabetic Patients and Diuretic Therapy
Official title: Exploring the Association Between Phthalates Exposure, Measured Through Their Urinary Metabolites, and Renal Function Impairment in Individuals With TYpe 2 Diabetes - SGLT2 Subprotocol
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Renal Function Disorder
Glucose Metabolism Disorders
Lead sponsor: University of Pisa
Sponsor class: OTHER
First posted: 2020-01-27
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: In this open clinical trial, 30 subjects with inadequately controlled T2D and eligible, as per good clinical practice, for therapy with SGLT-2 inhibitor, will be randomized to receive a SGLT-2 inhibitor vs other oral-antidiabetic drugs (OADs) therapy for 3 months. Measures will be performed at baseline, after 2 days, after one month and at the end of the study protocol, as per good clinical practice

Detailed description: * Total concentrations of MEHP, MEOHP and MEHHP will be quantified, in the laboratories of the Institute of Clinical Physiology, National Research Council, Pisa, in a spot morning urine sample by ultra-HPLC coupled with electrospray ionization/quadrupole time-of-flight mass spectrometry (Agilent UHPLC 1290 infinity coupled to an Agilent 6540 MS-QTOF, Santa Clara, CA) using stable isotope labeled substrates, i.e. MEHP (ring-1,2-13C2, dicarboxyl-13C2), MEHHP, MEHHP 13C4, MEOHP and MEOHP 13C4 that will be purchased from Cambridge Isotope Laboratories (Tewksbury, MA).
* Urinary creatinine concentrations will be measured to adjust urinary concentrations of DEHP metabolite (Beckman Coulter AU400, Brea, CA), thus minimizing the inﬂuence of urine volume.
* Serum and urinary inflammatory markers and adipocytokines will be quantitatively determined using sandwich enzyme-linked immunosorbent assays kits according to the manufacturer's instructions. Optical density will be measured using a microplate reader.
* Serum and urinary markers of oxidative stress will be measured by gold standard techniques. In detail, MDA will be quantified by TBARS reactive substances measured by optical density; GSH-Px by a specific assay kit according to the manufacturer's instruction; SOD activity will be determined using a specific SOD kit; urinary 8-isoprostane concentration will be measured by a specific affinity sorbent. (Cayman Chemical, Ann Harbor, MI, USA) according to the manufacturer's instructions.
* To analyze mitochondrial DNA we will apply a triplex design previously reported to amplify mitochondria loci located within the MinorArc and MajorArc, respectively. To assess nuclear DNA, we will use RNase P Copy Number Reference.
* The phthalates-free diet will be self-administered by the individuals under intervention, following a set of instruction and rules provided by the physicians based on the current literature data.

Eligibility criteria: Inclusion Criteria:

* Individuals of both sex;
* Age between 18 and 85 years;
* T2D
* T2D duration \> 6 months
* BMI ≤ 40 Kg/m2,
* HbA1c \> 48 mmol/mol
* Eligible for SGLT-2i therapy

Exclusion criteria

* age \>85 years,
* eGFR \<60 ml/min/1.73 m2,
* occurring acute complications

Primary outcomes:
measure: Urinary Phthalates concentration
timeFrame: Changes between baseline and 1 month
measure: Urinary Phthalates concentration
timeFrame: Changes between baseline and 3 month
Secondary outcomes:
measure: Fasting glucose
timeFrame: 1 and 3 months
measure: Glycated Haemoglobin
timeFrame: 1 and 3 months
measure: Renal function
timeFrame: 1 and 3 months
measure: Macrovascular events
timeFrame: 1 and 3 months
measure: Albumin excretion
timeFrame: 1 and 3 months
Other outcomes:
Locations:
city: Pisa
country: Italy
facility: University of Pisa
Study officials:
affiliation: University of Pisa
name: Anna Solini, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dales RE, Kauri LM, Cakmak S. The associations between phthalate exposure and insulin resistance, beta-cell function and blood glucose control in a population-based sample. Sci Total Environ. 2018 Jan 15;612:1287-1292. doi: 10.1016/j.scitotenv.2017.09.009. Epub 2017 Sep 8.
citation: Lind PM, Zethelius B, Lind L. Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Diabetes Care. 2012 Jul;35(7):1519-24. doi: 10.2337/dc11-2396. Epub 2012 Apr 12.
citation: Mengozzi A, Carli F, Biancalana E, Della Latta V, Seghieri M, Gastaldelli A, Solini A. Phthalates Exposure as Determinant of Albuminuria in Subjects With Type 2 Diabetes: A Cross-Sectional Study. J Clin Endocrinol Metab. 2019 May 1;104(5):1491-1499. doi: 10.1210/jc.2018-01797.
citation: Kato K, Silva MJ, Reidy JA, Hurtz D 3rd, Malek NA, Needham LL, Nakazawa H, Barr DB, Calafat AM. Mono(2-ethyl-5-hydroxyhexyl) phthalate and mono-(2-ethyl-5-oxohexyl) phthalate as biomarkers for human exposure assessment to di-(2-ethylhexyl) phthalate. Environ Health Perspect. 2004 Mar;112(3):327-30. doi: 10.1289/ehp.6663.
citation: Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect. 2004 Dec;112(17):1734-40. doi: 10.1289/ehp.7212.
citation: Zota AR, Singla V, Adamkiewicz G, Mitro SD, Dodson RE. Reducing chemical exposures at home: opportunities for action. J Epidemiol Community Health. 2017 Jul 29;71(9):937-40. doi: 10.1136/jech-2016-208676. Online ahead of print.
citation: Frederiksen H, Nielsen O, Koch HM, Skakkebaek NE, Juul A, Jorgensen N, Andersson AM. Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009-2017. Int J Hyg Environ Health. 2020 Jan;223(1):93-105. doi: 10.1016/j.ijheh.2019.10.002. Epub 2019 Oct 25.