plasma triglycerides and hdl-c levels predict the ... · plasma triglycerides and hdl-c levels...
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Plasma Triglycerides and HDL-CLevels Predict the Developmentof Diabetic Kidney Diseasein Subjects With Type 2 Diabetes:The AMD Annals InitiativeDiabetes Care 2016;39:2278–2287 | DOI: 10.2337/dc16-1246
OBJECTIVE
Despite the achievement of blood glucose, blood pressure, and LDL cholesterol(LDL-C) targets, the risk for diabetic kidney disease (DKD) remains high amongpatients with type 2 diabetes. This observational retrospective study investigatedwhether diabetic dyslipidemiadthat is, high triglyceride (TG) and/or low HDLcholesterol (HDL-C) levelsdcontributes to this high residual risk for DKD.
RESEARCH DESIGN AND METHODS
Among a total of 47,177 patients attending Italian diabetes centers, 15,362patients with a baseline estimated glomerular filtration rate (eGFR) ‡60 mL/min/1.73 m2, normoalbuminuria, and LDL-C £130 mg/dL completing a 4-year follow-upwere analyzed. The primary outcome was the incidence of DKD, defined as eitherlow eGFR (<60 mL/min/1.73 m2) or an eGFR reduction >30% and/or albuminuria.
RESULTS
Overall, 12.8% developed low eGFR, 7.6% an eGFR reduction >30%, 23.2% albumin-uria, and 4% albuminuria and either eGFR <60 mL/min/1.73 m2 or an eGFRreduction >30%. TG ‡150 mg/dL increased the risk of low eGFR by 26%, of an eGFRreduction >30% by 29%, of albuminuria by 19%, and of developing one abnormalityby 35%. HDL-C <40 mg/dL in men and <50 mg/dL in women were associated with a27% higher risk of low eGFR and a 28% risk of an eGFR reduction >30%, with a 24%higher risk of developing albuminuria and a 44% risk of developing one abnormality.These associations remained significant when TG and HDL-C concentrations wereexamined as continuous variables and were only attenuated by multivariate adjust-ment for numerous confounders.
CONCLUSIONS
In a large population of outpatients with diabetes, low HDL-C and high TG levelswere independent risk factors for the development of DKD over 4 years.
Chronic diabetic kidney disease (DKD) is the major cause of end-stage renal diseaseworldwide (1). Hyperglycemia and hypertension are the main risk factors for DKDdevelopment and progression (2). However, in spite of the achievement of recom-mended targets for blood glucose and blood pressure, the residual risk for diabeticnephropathy remains high among patients with type 2 diabetes (3,4).
1Department of Clinical and Experimental Med-icine, University of Messina, Messina, Italy2Department of Medical Sciences, ScientificInstitute “Casa Sollievo della Sofferenza,” SanGiovanni Rotondo, Italy3Universita degli Studi and IRCCS Azienda Ospe-daliera Universitaria San Martino-IST, Genova,Italy4Institut d’Investigacions Biomediques AugustPi i Sunyer (IDIBAPS) and Centro de InvestigacionBiomedica en Red de Diabetes y EnfermedadesMetabolicas Asociadas (CIBERDEM), Barcelona,Spain5Department of Cardiovascular and MetabolicDiseases, IRCCS Gruppo Multimedica, Sesto SanGiovanni, Italy6Associazione Medici Diabetologi, Rome, Italy7Diabetes and Metabolism Unit, ASL Turin 5,Chieri, Italy8Department of Medicine, University of Padua,Padua, Italy
Corresponding author: Giuseppina T. Russo,[email protected].
Received 10 June 2016 and accepted 8 Septem-ber 2016.
This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc16-1246/-/DC1.
© 2016 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. More infor-mation is available at http://www.diabetesjournals.org/content/license.
Giuseppina T. Russo,1
Salvatore De Cosmo,2 Francesca Viazzi,3
Antonio Pacilli,2 Antonio Ceriello,4,5
Stefano Genovese,5 Pietro Guida,6
Carlo Giorda,7 Domenico Cucinotta,1
Roberto Pontremoli,3 Paola Fioretto,8 and
the AMD-Annals Study Group
2278 Diabetes Care Volume 39, December 2016
PATH
OPHYS
IOLO
GY/COMPLICATIONS
Diabetic dyslipidemiadhigh triglyc-erides (TGs) and/or low HDL-cholesterol(HDL-C) levelsdmay be one of the fac-tors responsible for this high residualrisk (4). Interestingly, recent studiesdemonstrated that intrarenal accumula-tion of lipids may contribute to glomerularinjury (5–7) through the induction of oxi-dative stress or the release of proinflam-matory cytokines and growth factors(8–10). Alterations in synthesis, uptake,or efflux of lipids may be responsible forthis accumulation (8,11–13). Thus it wasrecently demonstrated that the expres-sion in mesangial and tubular cells ofkey proteins in HDL metabolism, such asABCA1, ABCG1, and SR-BI, was reduced indiabetic mice with nephropathy, sug-gesting a contribution of impaired HDL-mediated cellular cholesterol efflux inthe development of DKD (14).Epidemiological studies have demon-
strated a link between diabetic dyslipide-mia and DKD. High TG and low HDL-Cconcentrations were associated withDKD in a post hoc analysis of large inter-vention studies of high-risk patients withdiabetes (15–17). The Action in Diabetesand Vascular Disease: Preterax andDiamicron-MR Controlled Evaluation(ADVANCE) Study demonstrated thatlower baseline HDL-C levels were a sig-nificant and independent predictor ofDKD, whereas no association was foundwith the risk of diabetic retinopathy, sug-gesting that differences may exist in thepathophysiology of these microvascularcomplications (15). Furthermore, thehypotriglyceridemic drug fenofibratehas been shown to slow the decline ofrenal function and to reduce albuminuria(16,17) in patients with type 2 diabetes.Several other, smaller epidemiologicalstudies have pointed to the role of dia-betic dyslipidemia in the incidence andprogression of DKD (2,18), although withconflicting results (18–20).A large, international, cross-sectional
study of outpatients with diabetes re-cently demonstrated an independentassociation of low HDL-C and/or elevatedTGs with DKD after controlling for LDLcholesterol (LDL-C) levels and establishedrisk factors formicrovascular disease (21).These observations need to be confirmedin large, longitudinal cohort studies ofpatients with type 2 diabetes.In Italy, diabetes care is mainly pro-
vided by a public network of about 700 di-abetes clinics inwhich teamsof specialists
provide diagnostic confirmation of, pre-vention of, and treatment for diabetesand its complications through close follow-up and regular checkups. Since 2004 theAssociazione Medici Diabetologi (AMD)Annals Initiative, which involves approx-imately one-third of all the diabetes out-patient clinics operating within thenational health care system, has pro-moted a continuous improvement effortthrough the monitoring of a large set ofprocess and outcome indicators, withthe aim of examining strengths and lim-itations of current diabetes care (22–24).
In this study, data were analyzedfrom a large cohort of subjects withtype 2 diabetes without DKD participat-ing in the AMD Annals Initiative over a4-year follow-up period. The aim of thisstudywas to determinewhether high TGand/or low HDL-C plasma concentrationsare predictors for the development ofDKD and its components after controllingfor LDL-C levels and other well-establishedrisk factors such as glycemia and bloodpressure.
RESEARCH DESIGN AND METHODS
Design and SettingThis was a retrospective observationalstudy of a selected cohort of 15,362 pa-tients with type 2 diabetes with an esti-mated glomerular filtration rate (eGFR)$60mL/min/1.73m2, normoalbuminuria,and an LDL-C concentration #130 mg/dLat baseline, from the database of the Ital-ian Association of Clinical DiabetologistsAMD network.
Study SubjectsPatients followed up at diabetes centersparticipating in the Italian AMD initiative.The analysis was performed using a dataset of electronic medical records col-lected between 2004 and 2011. For thepurpose of the analysis, we consideredonly patients who were $40 years oldand had at least 48 months of follow-upfor data on eGFR and albuminuria. Thelast visit with complete renal data wasconsidered the 4-year evaluation. Thebaseline visit was selected consideringthe evaluation performed 48 months be-fore the last visit (range, 42–54 months).In the case of multiple records, the visitclosest to 48 months was considered asthe baseline visit. All annual visits afterthe baseline were extracted, if available.
Of the 47,177 patients identified, weexcluded those with albuminuria, eGFR
#60 mL/min/1.73m2, or a previous discor-danteGFRvalue (i.e.,,60mL/min/1.73m2)and those with missing data regardingantidiabetic treatment (SupplementaryFig. 1). Furthermore, by study design,subjects with an LDL-C concentration.130 mg/dL were also excluded. A to-tal of 15,362 subjects from 95 diabe-tes clinics homogeneously distributedthroughout the country met the inclu-sion criteria and were included in thestudy (Supplementary Fig. 1). The cen-ters involved in the study include aboutone-third of all the Italian Centers forDiabetes.
When comparing main clinical charac-teristics of subjects included and excludedfrom the study, major differences wererelated to inclusion criteria (baselineeGFR$60mL/min/1.73 m2, no albumin-uria, and LDL#130mg/dL) and exclusionconditions (most of excluded patientshad an eGFR,60 mL/min/1.73 m2 oralbuminuria at baseline). As expectedfrom the selection criteria, the twogroups were different for baselinerenal function and lipid profile. Theremaining clinical and demographiccharacteristics were similar at baseline(data not shown).
Methods and Data CollectionAs already reported (22–24), the analy-sis of the database is an attempt bythe Italian AMD Annals Initiative toidentify a set of indicators that can beused in the context of continuous qual-ity improvement. Participating centersadopted the same software systemsfor everyday management of outpa-tients, and a specially developed soft-ware package allowed us to extract theinformation we intended to analyzefrom all the clinical databases (AMDData File). Moreover, data from all par-ticipating centers were collected andcentrally analyzed anonymously (22–24).This initiative includes measuring andmonitoring HbA1c, blood pressure (LDL-C), total cholesterol and HDL-C, andTGs. The use of specific classes of drugs(insulin, statins, and two or more anti-hypertensive agents) was also evaluated.HbA1cwasmeasuredusinghigh-performanceliquid chromatography in all participat-ing centers. Since normal ranges forHbA1c varied among centers, the per-centage change with respect to theupper normal value (measured value 4upper normal limit) was estimated and
care.diabetesjournals.org Russo and Associates 2279
multiplied by 6.0 to allow comparisonsamong the centers. No standardizationwas applied to TG and HDL-C measure-ments. For TGs, 85% of the laboratoriesused the enzymatic-colorimetric methodwith glycerol-3-phosphate oxidase/phenol + aminophenazone (GPO-PAP);the remaining labs usedeither enzymatic-colorimetric GPO-PAP with the subtrac-tion of blank (glycerol) or methods usingORTHO instrumentation. Importantly, thenormal range anddecisional levels are thesame with these methods. For HDL-C, nolaboratory pretreated the samples; 60%of the laboratories used the enzymatichomogeneous direct method, and theremaining 40% used the same methodbut different detergents (e.g., polyethyl-ene glycol). Also, for HDL-C, the normalrange and decisional levels are the same.Kidney functionwas assessed by serum
creatinine and urinary albumin excretionmeasurements. Glomerular filtration rate(GFR) was estimated for each patientusing a standardized serum creatinineassay and the Chronic Kidney DiseaseEpidemiology Collaboration formula(25). Increased urinary albumin excretionwas diagnosed and defined as albumin-uria if the urinary albumin concentra-tion was .30 mg/L, the urinary albuminexcretion rate was .20 mg/min, or theurinary albumin-to-creatinine ratiowas .2.5 mg/mmol in men and .3.5mg/mmol in women.
OutcomesThe primary outcomes were 1) eGFR ,60mL/min/1.73 m2; 2) albuminuria; 3)eGFR ,60 mL/min/1.73 m2 and albu-minuria; and 4) eGFR reduced .30%.The occurrence of prespecified endpoints was evaluated on a yearly basisover the 4-year study period. Patientswere considered to have reached the studyend points if, at any annual visit during thestudy period, they met these criteria.
Statistical AnalysisData are given as means6 SDs; categor-ical variables are described as frequen-cies and percentages. The main analysisaimed to evaluate the association be-tween baseline HDL-C and TGs with re-nal outcomes during the study period.To take into account potential variabilityamong diabetes centers participating inthe study, a mixed logistic regressionmodel with diabetes clinics fitted as arandom effect was used for each renaloutcome to estimate odds ratios (ORs)
with their 95% CIs. Univariate analysiswas corrected for baseline eGFR,whereasmultivariate models adjusted for sex,age, duration of diabetes, BMI, eGFR,HbA1c, LDL-C, blood pressure, presence ofretinopathy, smoking status, and pharma-cological treatment (lipid-lowering medi-cations, statins, fibrates, antihypertensivedrugs, ACE inhibitors or angiotensin II re-ceptor antagonists, aspirin, and antidia-betic therapy). Multivariate models werefitted including a missing indicator vari-able (only for duration of diabetes, BMI,and smoking status in the case of missingvalues). Data were analyses using STATAsoftware version 14 (StataCorp, CollegeStation, TX). P values ,0.05 were consid-ered statistically significant.
RESULTS
Baseline Characteristics of StudySubjects Stratified by HDL-C and TGValuesTable 1 shows the baseline clinical char-acteristics of participants with type 2diabetes stratified by HDL-C and TG val-ues. As expected from the study design,renal function was preserved at base-line, with a mean eGFR of 87 mL/min/1.73 m2. Overall, clinical data for sub-jects with or without low HDL-C concen-trations (,40 mg/dL in males and,50 mg/dL in females) showed onlysmall but significant differences. Sub-jects with low HDL-C concentrations atbaseline had a higher BMI (30.4 vs.28.7 kg/m2), slightly worse glucose con-trol with higher HbA1c, and more HbA1cvalues above target. Subjects in the lowHDL-C group were more frequently fe-male and younger, with a shorter knowndiabetes duration. As for lipid profile,this group also had a larger percentageof subjects with high TG levels, a smallerpercentage of subjects with out-of-target LDL-C levels, and more use oflipid-lowering medications (49% vs. 44%).Also, the percentages of the group whowere smokers and who were receivingantihypertensive treatments were largerin the low HDL-C group.
Similar findings were observed whencomparing the baseline characteristicsof subjects with normal and high TG val-ues (Table 1). Subjects with high TGshad a higher BMI, worse glucose control,lower HDL-C levels, a higher percentageof patients taking lipid-lowering and an-tihypertensive medications, and a largerpercentage of smokers compared with
subjects with normal TGs. No differenceswere noted in basal use of aspirin whenstratifying the study population accordingto TG/HDL-C levels.
For antidiabetic therapy, subjectswith low HDL-C or high TG values weremore frequently treated with oral hypo-glycemic agents, with or without insulin,and less frequently treated with insulinalone or diet.
Clinical Characteristics by RenalOutcome at 4 Years of Follow-upAt the end of the 4 years of follow-up,among 15,362 study subjects, 1,962 de-veloped low eGFR values (12.8%), 1,167(7.6%) showed eGFR reduced .30%,3,570 (23.2%) developed albuminuria,and 614 (4.0%) developed both loweGFR and albuminuria (SupplementaryTable 1). As shown in Fig. 1, all renal out-comeswere significantly worse in subjectswith high TG (Fig. 1A) and/or low HDL-C(Fig. 1B) values than in subjects with base-line lipid values in the normal range.
Table 2 shows baseline characteristicsaccording to the development of DKDoutcomes. Subjects developing loweGFR within 4 years of follow-up (n =1,962) were more frequently femaleand older, with a longer diabetes durationat baseline. They also had higher baselineblood pressure and HbA1c. Baseline creat-inine levelswere higher and eGFR lower inthose who developed low eGFR at follow-up. For lipid profile, the low eGFR groupshowed higher TGs and included a largepercentage of subjects with TGs aboveand HDL-C levels below targets comparedwith the higher eGFR group, whereasLDL-C control was better in this group.
Similar findings were noted whencomparing baseline variables of patientswho developed albuminuria (n = 3,570)at follow-up versus those who remainednormoalbuminuric (Table 2), with theexception of the percentage of smokers,which was larger among those develop-ing albuminuria but not those develop-ing low eGFR.
The percentage of subjectswith retinop-athy at baseline was significantly larger insubjects developing either low eGFR (23%vs. 19%) and/or albuminuria (24% vs. 18%).
Antihypertensive drugs and aspirinwere more frequently used by subjectsdevelopingDKD,whereas between-groupdifferences in the use of lipid-loweringmedications were not statistically signifi-cant. For hypoglycemic treatment, those
2280 Diabetic Dyslipidemia Predicts DKD Diabetes Care Volume 39, December 2016
Table
1—Base
linech
aracte
risticsofstu
dypatie
nts
stratifi
edbyHDL-C
andTG
values
All
(N=15,362)
HDL-C
,40
mg/d
L(m
en)or,50
mg/d
L(w
omen
)TG
s$150
mg/d
L
No
(n=10,886)
Yes(n
=4,476)
Pvalu
eNo
(n=10,989)
Yes(n
=4,373)
Pvalu
e
Male
sex9,013
(58.7)6,780
(62.3)2,233
(49.9),0.001
6,428(58.5)
2,585(59.1)
0.425
Age
(years)64
69
646
962
69
,0.001
646
962
69
,0.001
Knownduratio
nofdiab
etes(years)
106
810
68
96
8,0.001
116
896
7,0.001
BMI(kg/m
2)29.1
64.9
28.76
4.830.4
65.1
,0.001
28.66
4.830.4
65
,0.001
Systolic
BP(m
mHg)
1396
18139
618
1376
17,0.001
1396
18139
618
0.772
Diasto
licBP(m
mHg)
806
980
69
806
90.263
806
981
69
,0.001
BP$140/85
mmHg
9,044(58.9)
6,485(59.6)
2,559(57.2)
0.1516,423
(58.4)2,621
(59.9)0.205
HbA1c ,%
(mmol/m
ol)
7.26
1.3(56
614)
7.26
1.2(55
613)
7.36
1.4(57
615)
,0.001
7.16
1.2(54
613)
7.56
1.4(58
615)
,0.001
HbA1c$7%
($53
mmol/m
ol)
8,222(53.5)
5,710(52.5)
2,512(56.1)
,0.001
5,631(51.2)
2,591(59.2)
,0.001
Totalch
olestero
l(mg/d
L)174
627
1786
26165
627
,0.001
1706
26184
627
,0.001
TGs(m
g/dL)
1306
73116
660
1646
89,0.001
956
28218
676
d
TGs$150
mg/d
L4,373
(28.5)2,253
(20.7)2,120
(47.4),0.001
0(0)
4,373(100)
d
HDL-C
(mg/d
L)52
615
586
1338
67
d55
615
456
12,0.001
HDL-C
,40
mg/d
L(m
en)or,50
mg/d
L(w
omen
)4,476
(29.1)0(0)
4,476(100)
d2,356
(21.4)2,120
(48.5),0.001
LDL-C
(mg/d
L)96
622
976
2195
622
,0.001
976
2196
623
0.463
LDL-C
$100
mg/d
L7,445
(48.5)5,375
(49.4)2,070
(46.2),0.001
5,299(48.2)
2,146(49.1)
0.253
Serum
creatinine(m
g/dL)
0.836
0.160.84
60.16
0.826
0.17,0.001
0.836
0.160.84
60.17
,0.001
eGFR
(mL/m
in/1.73
m2)
876
1387
613
866
140.002
876
1387
614
0.843
Retin
opath
y2,980
(19.4)2,144
(19.7)836
(18.7)0.263
2,199(20)
781(17.9)
0.001
Smoker
1,521(16.4)
988(14.7)
533(20.7)
,0.001
984(14.9)
537(19.9)
,0.001
Lipid-lo
werin
gtreatm
ent
7,045(45.9)
4,839(44.5)
2,206(49.3)
,0.001
4,757(43.3)
2,288(52.3)
,0.001
Treatmen
twith
statins
6,485(42.2)
4,572(42)
1,913(42.7)
0.8624,570
(41.6)1,915
(43.8)0.001
Treatmen
twith
fibrates
339(2.2)
155(1.4)
184(4.1)
,0.001
123(1.1)
216(4.9)
,0.001
Antih
yperten
sivetreatm
ent
9,654(62.8)
6,664(61.2)
2,990(66.8)
,0.001
6,808(62)
2,846(65.1)
,0.001
Treatmen
twith
ACEIs/A
RBs
8,034(52.3)
5,545(50.9)
2,489(55.6)
,0.001
5,672(51.6)
2,362(54)
0.002
Aspirin
4,437(28.9)
3,106(28.5)
1,331(29.7)
0.5863,198
(29.1)1,239
(28.3)0.557
Antid
iabetic
therap
yDiet
1,337(8.7)
1,025(9.4)
312(7)
,0.001
1,023(9.3)
314(7.2)
,0.001
Oralan
tidiab
eticdrugs
10,586(68.9)
7,439(68.3)
3,147(70.3)
0.0077,401
(67.3)3,185
(72.8),0.001
Oralan
tidiab
eticdrugs
andinsulin
1,964(12.8)
1,329(12.2)
635(14.2)
0.0021,375
(12.5)589
(13.5)0.237
Insulin
1,475(9.6)
1,093(10)
382(8.5)
0.0011,190
(10.8)285
(6.5),0.001
Data
aremean
6SD
orabsolute
frequen
cy(percen
tage).There
were
missin
gdata
atbaselin
e:knownduratio
nofdiab
etesin292
(1.9%),B
MIin
799(5.2%
),totalch
olestero
lin31
(0.2%),an
dsm
okin
gstatu
sin
6,062(39.5%
).ACEIs,A
CEinhibito
rs;ARBs,an
gioten
sinIIrecep
torblockers;
BP,b
loodpressu
re.
care.diabetesjournals.org Russo and Associates 2281
developing low eGFR were treated morefrequently with insulin, either alone or incombination with oral hypoglycemicagents.
Univariate and MultivariateAssociations of Baseline HDL-C andTG Levels and Renal OutcomesTable 3 shows univariate and multivari-ate associations of low HDL-C and highTGs with renal outcomes at follow-up.Overall, in this population of subjectswith LDL-C concentrations ,130 mg/dL,having atherogenic dyslipidemia at base-line was a significant risk factor for DKDand was associated with all the examinedrenal outcomes.
In particular, a TG concentration$150 mg/dL increased the risk of loweGFR by 26% and of a reduced eGFRby 29%; it increased the risk of albumin-uria by 19% and of developing both loweGFR and albuminuria by 35%. Theseassociations were only attenuated bymultivariate adjustment.
LowHDL-C concentrations (,40mg/dLin men, ,50 mg/dL in women) wereassociated with a 27% increased risk oflow GFR and a 28% increased risk ofreduced GFR; the risk of developing albu-minuria associated with low HDL concen-trations was 24% and that of developingboth low GFR and albuminuria was 44%.These associations were still significant
and only attenuated by multivariateadjustment.
When examined as continuous vari-ables, each 50 mg/dL increase in TG val-ues augmented the risk of low eGFR by10% and of eGFR reduction by 8%,whereas it increased the risk of albumin-uria by 6% and the risk of developingone abnormality by 13%. Each 10 mg/dLincrease in HDL-C level decreased the riskof developing low eGFR or albuminuria by9%, of reduced eGFR by 9%, and of de-veloping one abnormality by 12%. Allthese associations were only attenuatedby multivariate adjustment (Table 3).
DKD Risk Associated With High TGand Low HDL-C Levels According toSex, Age, and Common Risk FactorsAs shown in Fig. 2, low HDL-C and/orhigh TG levels significantly increasedthe risk of developing renal outcomesafter factoring for sex, age, blood pres-sure, glucose control, and LDL-C levels.The risk of developing DKD associatedwith high TG/low HDL-C values was at-tenuated in subjects with at-target val-ues of the other major risk factors, thatis, blood pressure, HbA1c, and LDL-C lev-els (Supplementary Table 2). In this well-controlled group, the risk of developingalbuminuria associated with low HDL-Clevels remained significant (P = 0.018)(Supplementary Table 2).
CONCLUSIONS
DKD is a chronic and harmful complica-tion of type 2 diabetes. The epidemiologyand natural history of DKD have changedin the past three decades, mostly as aresult of better diagnostic and treatmenttools. In particular, therapeutic progresshas led to a larger number of subjectsreaching the recommended targets forblood glucose and blood pressure. In spiteof the better control of known risk factors,the residual risk for DKD is still high; thusthe identification of other modifiable riskfactors in addition to hyperglycemia andhypertension is urgently needed.
Our data clearly indicate the mainfeatures of diabetic dyslipidemiadhighTG and/or low HDL-C levelsdas importantrisk factors for thedevelopment ofDKD. In-deed, in a large population of outpatientswith type 2 diabetes and controlled LDL-Clevels, low HDL-C and high TG levels wereindependent risk factors for the develop-ment and progression of renal disease.
Figure 1—A: DKD incidence according to baseline TG$150mg/dL. B: DKD incidence according tobaseline HDL-C (,40 mg/dL in men; ,50 mg/dL in women).
2282 Diabetic Dyslipidemia Predicts DKD Diabetes Care Volume 39, December 2016
Table
2—Base
lineclin
icalch
aracte
risticsbyrenaloutco
mewith
in4years
eGFR
Albuminuria
$60
mL/m
in/1.73
m2
(n=13,400)
,60
mL/m
in/1.73
m2
(n=1,962)
Pvalu
e*Absen
t(n
=11,792)
Present
(n=3,570)
Pvalu
e*
Male
sex8,037
(60)976
(49.7),0.001
6,734(57.1)
2,279(63.8)
,0.001
Age
(years)63
69
696
7,0.001
636
964
69
,0.001
Knownduratio
nofdiab
etes(years)
106
812
69
,0.001
106
811
68
,0.001
BMI(kg/m
2)29.1
64.9
29.66
4.8,0.001
296
4.929.5
64.8
,0.001
Systolic
BP(m
mHg)
1386
17142
619
,0.001
1386
18140
618
,0.001
Diasto
licBP(m
mHg)
806
979
69
0.58780
69
806
90.110
BP$140/85
mmHg
7,773(58)
1,271(64.8)
,0.001
6,867(58.2)
2,177(61)
,0.001
HbA1c ,%
(mmol/m
ol)
7.26
1.3(55
614)
7.36
1.2(56
613)
,0.001
7.26
1.3(55
614)
7.36
1.3(57
614)
,0.001
HbA1c$7%
($53
mmol/m
ol)
7,102(53)
1,120(57.1)
,0.001
6,248(53)
1,974(55.3)
,0.001
Totalch
olestero
l(mg/d
L)174
627
1736
270.004
1756
27171
627
,0.001
TGs(m
g/dL)
1296
73137
671
,0.001
1286
73134
673
,0.001
TGs$150
mg/d
L3,741
(27.9)632
(32.2)0.002
3,275(27.8)
1,098(30.8)
,0.001
HDL-C
(mg/d
L)52
615
526
160.012
536
1551
615
,0.001
HDL-C
,40
mg/d
L(m
en)or,50
mg/d
L(w
omen
)3,836
(28.6)640
(32.6),0.001
3,329(28.2)
1,147(32.1)
,0.001
LDL-C
(mg/d
L)97
622
956
22,0.001
976
2195
622
,0.001
LDL-C
$100
mg/d
L6,550
(48.9)895
(45.6)0.004
5,808(49.3)
1,637(45.9)
,0.001
Serum
creatinine(m
g/dL)
0.826
0.160.92
60.16
,0.001
0.836
0.160.85
60.17
,0.001
eGFR
(mL/m
in/1.73
m2)
896
1275
611
,0.001
876
1386
613
,0.001
Retin
opath
y2,530
(18.9)450
(22.9),0.001
2,133(18.1)
847(23.7)
,0.001
Smoker
1,413(17.4)
108(9.3)
0.0041,097
(15.5)424
(19.1),0.001
Lipid-lo
werin
gtreatm
ent
6,043(45.1)
1,002(51.1)
0.2745,325
(45.2)1,720
(48.2)0.130
Treatmen
twith
statins
5,585(41.7)
900(45.9)
0.8184,900
(41.6)1,585
(44.4)0.310
Treatmen
twith
fibrates
275(2.1)
64(3.3)
0.106260
(2.2)79
(2.2)0.612
Antih
yperten
sivetreatm
ent
8,137(60.7)
1,517(77.3)
,0.001
7,163(60.7)
2,491(69.8)
,0.001
Treatmen
twith
ACEIs/A
RBs
6,761(50.5)
1,273(64.9)
,0.001
5,907(50.1)
2,127(59.6)
,0.001
Aspirin
3,732(27.9)
705(35.9)
,0.001
3,336(28.3)
1,101(30.8)
,0.001
Antid
iabetic
therap
yDiet
1,228(9.2)
109(5.6)
,0.001
1,136(9.6)
201(5.6)
,0.001
Oralan
tidiab
eticdrugs
9,300(69.4)
1,286(65.5)
0.0448,174
(69.3)2,412
(67.6)0.002
Oralan
tidiab
eticdrugs
andinsulin
1,617(12.1)
347(17.7)
,0.001
1,360(11.5)
604(16.9)
,0.001
Insulin
1,255(9.4)
220(11.2)
0.1521,122
(9.5)353
(9.9)0.184
Data
aremean
6SD
orabsolute
frequen
cy(percen
tage).ACEIs,A
CEinhibito
rs;ARBs,an
gioten
sinIIrecep
torblockers;
BP,b
loodpressu
re.*P
values
areadjusted
forbaselin
eeG
FR.
care.diabetesjournals.org Russo and Associates 2283
In our cohort of .15,000 subjectswithout DKD at baseline, 32% devel-oped DKD after 4 years of follow-up.This incidence is slightly higher thanthat observed in a previous study (26)but comparable to the results of theADVANCE Study (15). In the latter study,during a median follow-up period of5 years, 32% of participants developednew or worsening microvascular diseaseand one-third (28%) experienced a renalevent. This high incidence may also de-pend on a selection bias, since subjectsparticipating in our study are routinelyfollowed by specialist outpatient clinics;thus it is possible that our patients aremore comparable to the population athigh risk for cardiovascular disease (CVD)in the ADVANCE study than to the sub-jects with diabetes not referred to the di-abetes centers. However, it is importantto note that there are relevant differencesbetween patients participating in theADVANCE Study, who had diabetes andwere at high risk for macrovascular events,and some of whom had established DKD
at baseline, and those in our cohort, includ-ing DKD-free patients routinely screenedat diabetes centers all over Italy, who werenot (because of the observational natureof our study) selected for CVD risk and/orfor therapies; thus our study is represen-tative of common clinical practice.
In keeping with the results of theADVANCE Study (15), we found that al-buminuria was the most frequent renalevent observed within the 4 years offollow-up; indeed, 23.2% of subjects inour cohort developed albuminuria, 19%developed low eGFR values or a reducedeGFR, and 4% developed both renalabnormalities.
Notably, after controlling for LDL-Clevels and numerous confounders, theincidence and progression of these renalabnormalitieswere independently associ-ated with TG and/or HDL-C levels outsidethe recommended targets at baseline.
The adjusted risk for developing anyrenal event associated with lower HDL-Clevels or higher TG levels was between19% and 44%. Our data also show that
there was no threshold in the associationbetween dyslipidemia and DKD risk,since the risk showed a linear trend withincreasing TG or decreasing HDL-C values.
Although the risk associatedwith highTGs and low HDL-C cannot be directlycompared, and since all analyses indi-cated an independent prognostic valueof both parameters, our data also suggestthat lower HDL-C levels may be morestrongly associated with DKD risk, espe-cially when albuminuria occurs; thus a TGconcentration$150mg/dL increased therisk of albuminuria by 19% and of devel-oping low eGFR or albuminuria by 35%,whereas that associated with low HDL-Clevels was 24% for albuminuria and 44%for both abnormalities.
These associations were partly atten-uated by multivariate adjustment, espe-cially in the subgroup analysis, whensubjects who were at target for bloodpressure, glucose control, and LDL-Cwere considered. This observation pointsto the major role played by classical riskfactors, which are, as recommended by
Table 3—Univariate and multivariate associations between baseline HDL-C and TGs and renal outcomes during the studyperiod
Univariate OR (95% CI)* P value Multivariate OR (95% CI)** P value
Categorical analysiseGFR ,60 mL/min/1.73 m2
TG $150 mg/dL 1.26 (1.11–1.42) ,0.001 1.20 (1.06–1.36) 0.004HDL-C ,40 mg/dL (men) or ,50 mg/dL (women) 1.27 (1.12–1.44) ,0.001 1.20 (1.06–1.36) 0.005
eGFR reduction .30% of baselineTG $150 mg/dL 1.29 (1.12–1.48) ,0.001 1.24 (1.08–1.43) 0.003HDL-C ,40 mg/dL (men) or ,50 mg/dL (women) 1.28 (1.11–1.47) 0.001 1.21 (1.05–1.39) 0.009
AlbuminuriaTG $150 mg/dL 1.19 (1.09–1.31) ,0.001 1.13 (1.03–1.25) 0.010HDL-C ,40 mg/dL (men) or ,50 mg/dL (women) 1.24 (1.13–1.36) ,0.001 1.16 (1.05–1.27) 0.002
Either eGFR ,60 mL/min/1.73 m2 or albuminuriaTG $150 mg/dL 1.35 (1.12–1.63) 0.002 1.26 (1.04–1.53) 0.020HDL-C ,40 mg/dL (men) or ,50 mg/dL (women) 1.44 (1.20–1.74) ,0.001 1.34 (1.11–1.63) 0.002
Continuous analysiseGFR ,60 mL/min/1.73 m2
TGs (by 50 mg/dL) 1.10 (1.05–1.14) ,0.001 1.08 (1.03–1.12) ,0.001HDL-C (by 10 mg/dL) 0.92 (0.89–0.96) ,0.001 0.94 (0.90–0.97) 0.002
GFR reduction .30% of baselineTGs (by 50 mg/dL) 1.08 (1.04–1.13) ,0.001 1.07 (1.02–1.11) 0.004HDL-C (by 10 mg/dL) 0.91 (0.87–0.96) ,0.001 0.93 (0.88–0.97) 0.001
AlbuminuriaTGs (by 50 mg/dL) 1.06 (1.03–1.09) ,0.001 1.04 (1.01–1.08) 0.005HDL-C (by 10 mg/dL) 0.93 (0.90–0.96) ,0.001 0.95 (0.92–0.98) 0.001
Either GFR ,60 mL/min/1.73 m2 or albuminuriaTGs (by 50 mg/dL) 1.13 (1.07–1.20) ,0.001 1.10 (1.04–1.17) 0.001HDL-C (by 10 mg/dL) 0.88 (0.83–0.94) ,0.001 0.90 (0.84–0.96) 0.002
ORs are for a single renal outcome. Duration of diabetes, BMI, and smoking habits were analyzed with the missing indicator method. Consideredcategories were 1) duration of diabetes (,5, 5–10, and.10 years); 2) BMI (27–30 and.30 kg/m2); and 3) nonsmokers. *For each outcome, analysiswas performed on a uniquemodel including TGs and HDL-C, correcting for sex, age, and baseline GFR. **Multivariate model analyzed TGs and HDL-Cadjusting for sex, age, duration of diabetes, BMI, eGFR, HbA1c, LDL-C, systolic blood pressure, smoking habits, retinopathy, and pharmacologicaltreatment (lipid-lowering medications, statins, fibrates, antihypertensive drugs, ACE inhibitors or angiotensin II receptor blockers, aspirin, andantidiabetic therapy, as reported in Table 1).
2284 Diabetic Dyslipidemia Predicts DKD Diabetes Care Volume 39, December 2016
current guidelines, the major targets forDKD prevention. On the other hand, sincethe association of diabetic dyslipidemiawith DKD risk remained significant aftercontrolling for numerous confoundersdincluding BMI, smoking habit, use ofdrugs, and blood pressure and glucosecontroldan independent role of lipidfractions on kidney function is still plausi-ble, as supported by several pieces ofexperimental evidence.Thus, DKD may share some common
features with atherosclerosis; HDL parti-cles may have a protective role in bothprocesses, including antioxidant and anti-inflammatory properties. Furthermore,recent evidence suggests that the athero-protective role of HDL-C is not solelylimited to its circulating concentrations,
but rather depends on the qualitativeproperties of different HDL particles (27).These protective properties of HDL parti-cles seem to be impaired by diabetes,as recently demonstrated in womenwith type 2 diabetes who had a dysfunc-tional HDL subpopulation distributionwhen compared with women withoutdiabetes, in spite of similar HDL-C con-centrations (28); indeed, this alteredHDL subpopulation profile was associ-ated with higher levels of inflammatorymarkers, which may contribute to thehigh CVD risk observed in women withdiabetes (29,30). In this regard, it wasrecently reported that in patients withdiabetes and nephropathy, increasedserum concentration of advanced glyca-tion end products was associated with
impairment of the antioxidative capac-ity of HDL particles (31).
On the other hand, dyslipidemia perse is not sufficient to initiate kidneydamage since individuals without diabe-tes but with elevated cholesterol or TGlevels rarely develop kidney disease;accordingly, it is plausible that the met-abolic derangement typical of diabetes(hyperglycemia, insulin resistance) facil-itates the lipotoxic effects on the micro-vascular bed and is necessary for DKD todevelop.
High TGs and low HDL-C are two clinicalcomponents of the metabolic syndromeandmaybe consequences of theunderlyinginsulin resistance. Indeed, a growing bodyof evidence supports a pathogenic role ofinsulin resistance in kidney dysfunction
Figure 2—Multivariate associations of high TG and lowHDL-C levels with renal outcomes after stratification for age, sex, and several risk factors. Dataare shown as ORs with 95% CI for eGFR ,60 mL/min/1.73 m2 (A) and for albuminuria (B). BP, blood pressure.
care.diabetesjournals.org Russo and Associates 2285
through mechanisms involving glomeru-lar hyperfiltration and increased vascularpermeability caused by hyperinsulinemia,subclinical inflammation, or podocyte ab-normalities (32,33). These findings, mostlyderiving from experimental studies, aresupported by gene-association studiesand interventional studies of the effectof insulin sensitizers on DKD progression(32).The association between dyslipide-
mia and microvascular disease is alsosupported by recent epidemiologicalstudies. In the ADVANCE Study, the onlylongitudinal study with a number of par-ticipants and follow-up duration compa-rable with those in our study, the risk ofdeveloping renal events associated withlower HDL-C levels was 19%, which is sim-ilar to our findings (15).Notably, a large, cross-sectional, mul-
ticenter study recently reported thatin a population of subjects with diabetesand controlled LDL-C levels, TG andHDL-C levels were significantly and inde-pendently associated with diabetic mi-crovascular disease, especially kidneydisease, without any difference amongdifferent geographic regions (21).Our results are in keeping with these
cross-sectional findings, demonstratingthe independent role of dyslipidemiaacross a wide set of covariates and con-founders, starting with a populationwith similar baseline characteristics.Furthermore, it is important to note thatboth a study by Sacks et al. (21) and oursenrolled patients who had controlledLDL-C levels, allowing better dissectionof the role of a high TG/low HDL-C phe-notype on DKD.The impact of atherogenic dyslipidemia
on microvascular disease is not limitedto type 2 diabetes. In children with type1 diabetes, high HDL-C levels and goodglycemic control were favorable prognos-tic factors for regression of microalbumi-nuria during long-term treatment withACE inhibitors (34). Furthermore, in across-sectional analysis of a subset of theDiabetes Control and Complications Trial(DCCT)/Epidemiology of Diabetes Inter-ventions and Complications Cohort (EDIC)Study cohort (35), albuminuria was associ-ated with specific HDL subclasses. Finally,a recent report from the Finnish DiabeticNephropathy (FinnDiane)Study (36) showedthat TGs and cholesterol content in theVLDL particles were associated with inci-dent albuminuria and its progression.
Conversely, the association of dyslipi-demia with DKD was not confirmed byother studies (18–20). The reasons forthese conflicting results may dependon several factors, including a differentgenetic background and/or gene–dietinteractions, which, although not spe-cifically evaluated in our study, may mit-igate the power of the associationbetween lipids and renal outcomes.
Also, sex may be a factor that poten-tially influences the association of DKDrisk with dyslipidemia. It has been dem-onstrated that sex differences exist inthe prevalence of DKD clinical manifes-tations (24,37): women with diabetesshow more GFR reduction, whereas al-buminuria occurs more frequently inmen. A single-center observationalstudy found that lower HDL-C levelswere associated with the progressionof DKD in men but not in women (38).When we tested this hypothesis, however,we did not find any sex difference in DKDrisk. Similarly, no difference was foundwhen the study population was stratifiedaccording to age, blood pressure values,and glucose control, nor in the subgroupof subjects with at-target LDL-C concentra-tions (,100mg/dL), furtherdemonstratingthe strength of the association betweendyslipidemia andDKD. Thiswas particularlytrue for low HDL levels that were signifi-cantly associated with albuminuria risk,evenwhenonly patients at target for bloodglucose, blood pressure, and LDL-C levelswere considered (n. 1,600).
Our study has several strengths andlimitations. The strengths of this study in-clude the duration of observation, thelarge number of patients, and the strictinclusion criteria, which allowed only sub-jectswith controlled LDL-C levels andwithrepeatedmeasurements of renal functionwithin the normal range to be included.
The limitations include the lack of cen-tralized measurements and standardiza-tion of laboratory parameters; also, theobservational nature of our study andthe lack of information on duration ofuse of hypoglycemic and hypolipidemicdrugs are other important issues to beconsidered when addressing cause-and-effect relationships betweendyslipidemiaand microvascular outcomes.
International guidelines recommendmaintaining blood glucose and bloodpressure levels within the target limits toavoid or delay DKD. Despite improvementsin blood glucose andbloodpressure control
as a result of these guidelines, many pa-tients still develop DKD, and the residualrisk for this complication remains high.
Our data clearly indicate that both highTG and low HDL-C are independent riskfactors forDKDdevelopment. These resultsmay have important therapeutic implica-tions; indeed, in the Fenofibrate Interven-tion and Event Lowering in Diabetes (FIELD)and Action to Control Cardiovascular Riskin Diabetes (ACCORD) trials, fenofibratetreatment was associated with a reductioninalbuminuria (39). Also, adose-dependenteffect of omega-3 fatty acids on DKD insubjects with hypertrygliceridemia (40)was recently reported. To date, there areno data available for treatments that in-crease HDL-C levels. Only large, long-terminterventional studies will clarify whetherlipid-lowering medications decreasing TGlevels and/or increasing HDL-C levels areeffective in reducing DKD risk among pa-tients with type 2 diabetes.
Acknowledgments.Theauthors thankDr. F.M.Sacks (Department of Nutrition, Harvard Schoolof Public Health, Boston, MA) for reading themanuscript and providing useful suggestions.The authors thank all of the centers participatingin the AMD Annals Initiative (a complete list isprovided in the Supplementary Data).Duality of Interest. No potential conflicts ofinterest relevant to this article were reported.Author Contributions. G.T.R. and P.F. re-searched data, wrote the first draft of the manu-script, and edited themanuscript. S.D.C., P.G., andR.P. researched data and contributed to thediscussion. F.V., A.P., A.C., S.G., C.G., and D.C.critically revised the manuscript and contributedto the discussion. G.T.R. is the guarantor of thiswork and, as such, had full access to all the data inthe study and takes responsibility for the integrityof the data and the accuracy of the data analysis.
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