# Abstract

 # Abstract

 

## Background Insulin resistance and lipid changes are common after antiretroviral therapy (ART) initiation. Observational studies suggest that vitamin D supplementation reduces the risk of developing diabetes and improves lipid profiles. 

## Methods This 48-week prospective, randomized, double-blind, placebo-controlled study evaluated high-dose vitamin D3 (4000 IU daily) plus calcium supplementation (1000 mg calcium carbonate daily) in HIV-infected participants initiating ART with efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Changes in insulin resistance (as estimated by homeostatic model assessment), fasting lipid profile, and components of the metabolic syndrome were assessed at baseline, 24 weeks, and 48 weeks. Stratified Wilcoxon rank sum tests and stratified normal score tests were used to evaluate differences between treatment arms, stratified by screening 25-OH vitamin D stratum (≤/>20 ng/mL). 

## Results A total of 165 participants enrolled: 79 in the vitamin D/calcium (Vit D/Cal) arm and 86 in the placebo arm. Only the placebo arm experienced a modest increase in insulin resistance at week 24 (*P* < .001). While increases in total and high-density lipoprotein cholesterol were significant in both arms at weeks 24 and 48, increases in low-density lipoprotein cholesterol at week 24 were only identified in the placebo arm (*P* = .011). Body mass index remained stable, whereas modest increases in waist circumference were observed in the placebo arm. Metabolic syndrome was present in 19 participants (12%) at baseline and 20 participants (14%) at week 48, without differences between arms. 

## Conclusions Vit D/Cal supplementation over 48 weeks did not alter the lipid profile or glucose metabolism experienced with initiation of EFV/FTC/TDF in ART-naïve persons. Vitamin D supplementation is unlikely to be an effective strategy to attenuate metabolic dysregulations with ART initiation. # RESULTS The details and disposition of the study population have been previously described \[[20](#)\]. Of the 165 eligible participants included this analysis (79 in the VitD/Cal arm, 86 in the placebo arm), 148 (90%) completed 48 weeks of study treatment. Twenty-five (15%) participants discontinued EFV/FTC/TDF prematurely (13 in VitD/Cal and 12 in placebo). 

## Baseline Demographics Baseline characteristics are shown in [Table 1](#). For the overall study population at baseline, the median age was 33 years, 90% male, 37% white non-Hispanic, 33% black non-Hispanic, with a median body mass index (BMI) of 24.4 kg/m^2^ ([Table 1](#)). ::::table-wrap

::: caption
Baseline Demographic and Laboratory Parameters
:::

______________________________________________________________________

Parameter Vitamin D/Calcium Placebo
(n = 79) (n = 86)

______________________________________________________________________

Age, y 36 (28, 47) 31 (25, 44)

Race/ethnicity

White non-Hispanic 28 (35%) 33 (38%)

Black non-Hispanic 24 (30%) 30 (35%)

Hispanic 23 (29%) 18 (21%)

Other 4 (6%) 5 (6%)

Male sex 72 (91%) 77 (90%)

BMI, kg/m^2^ 25.0 (22.5, 28.2) 24.0 (21.7, 27.2)

Presence of metabolic syndrome 7 (9%) 12 (14%)

Plasma HIV RNA, log~10~ cp/mL 4.5 (4.1, 5.1) 4.5 (4.0, 5.1)

CD4 cell count, cells/mm^3^ 339 (230, 500) 342 (232, 454)

CD4 cell count ≤ 200 cells/mm^3^ 17 (22%) 15 (17%)

Estimated daily Ca intake, mg 813 (492, 1303) 811 (365, 1227)

Estimated daily vit D intake, IU 120 (62, 215) 137 (59, 279)

Laboratory parameters

25-OH vitamin D, ng/mL 28.4 (20.9, 38.5) 26.4 (19.6, 33.0)

Insulin, ulU/mL 5.0 (2.7, 9.8) 4.4 (1.9, 8.4)

Glucose, mg/dL 85 (80, 91) 85 (79, 92)

HOMA-IR 0.97 (0.52, 2.12) 0.94 (0.46, 1.81)

Total chol, mg/dL 161 (138, 182) 156 (135, 184)

HDL-c, mg/dL 43 (34, 50) 42 (33, 49)

LDL-c, mg/dL 95 (80, 112) 89 (72, 115)



## Triglycerides, mg/dL 99 (65, 127) 96 (73, 116)

All values are presented as median values with interquartile ranges (Q1,
Q3) or number of participants with percentages.

Abbreviations: BMI, body mass index; chol, cholesterol; HDL-c,
high-density lipoprotein cholesterol; HOMA-IR, insulin resistance as
assessed by homeostatic model assessment; LDL-c, low-density lipoprotein
cholesterol.:::: 

## 25 OH Vitamin D At baseline, 25(OH)D levels appear to be balanced between the treatment arms, but they differed over the 48-week study period ([Tables 1](#)--[2](#)). Increases in 25(OH)D levels were observed in the VitD/Cal arm at 24 and 48 weeks: median concentrations increased 27.5 ng/mL (q1, Q3 = 15.0, 38.0 ng/mL) and 24.2 ng/mL (q1, Q3 = 14.6, 37.8 ng/mL) from baseline to weeks 24 and 48, respectively (*P* < .001 for both) in the VitD/Cal arm. No significant changes in the placebo arm were detected (--0.8 ng/mL [Q1, Q3 = --5.9, 4.9 ng/mL] and 0.6 ng/mL [Q1, Q3 = --6.1, 4.3 ng/mL], respectively). ::::table-wrap
::: caption
Changes in Metabolic Parameters at Weeks 24 and 48 by Treatment Arm
:::

```
                               Vitamin D/Calcium                                 Placebo                                           *P*^a^                                  Vitamin D/Calcium       Placebo                *P*^a^
```

______________________________________________________________________

Parameter Median (Q1, Q3) Change From Baseline to Week 24 Median (Q1, Q3) Change From Baseline to Week 48\
25-OH vitamin D, ng/mL 27.5^*^ (15.0, 38.0) --0.8 (--5.9, 4.9) \<.001 24.2^*^ (14.3, 35.8) 0.6 (--6.1, 4.3) \<.001
Insulin, ulU/mL 0.4 (--1.5, 3.8) 1.4^*^ (--1.1, 4.2) .24 0.5 (--1.5, 4.2) 0.9 (--1.8, 3.2) .78
Glucose, mg/dL 5^*^ (--4, 12) 5^*^ (--3, 12) .91 4^*^ (1, 8) 6^*^ (--3, 12) .73
HOMA-IR 0.17^*^ (--0.21, 0.91) 0.39^*^ (--0.11, 1.15) .21 0.13 (--0.26, 1.11) 0.26 (--1.09, 2.73) .87
Total chol, mg/dL 11^*^ (--4, 29) 18^*^ (1, 31) .22 13^*^ (--6, 28) 14^*^ (--1, 37) .55
HDL-c, mg/dL 8^*^ (0, 15) 8^*^ (2, 15) .72 8^*^ (1, 14) 8^*^ (1, 14) .44
LDL-c, mg/dL 0 (--10, 17) 8^*^ (--11, 20) .26 2 (--9, 14) 4 (--14, 27) .93
Triglycerides, mg/dL 3 (--17, 45) 4 (--18, 28) .90 3 (--14, 31) 4 (--18, 39) .87
BMI, kg/m^2^ 0.0 (--0.5, 1.1) 0.1 (--0.6, 0.9) .67 0.1 (--0.8, 1.1) 0.1 (--0.7, 1.0) .98
Waist circ, cm 0.0 (--2.5, 3.0) 0.7^*^ (--1.0, 3.7) .17 0.3 (--2.5, 3.3) 0.9^*^ (--2.0, 4.8) .38
Number of Participants (%) at Week 24 *P*^b^ Number of Participants (%) at Week 48 *P*^**b**^\
Presence of metabolic syndrome 7/71 (10%) 11/78 (14%) .55 9/66 (14%) 11/75 (15%) .97
Central obesity 19% 16% - 21% 18% -
Elevated triglycerides 22% 21% - 24% 21% -
Low HDL-c 27% 28% - 24% 28% -
Elevated BP 39% 42% - 37% 41% -
Elevated glucose 6% 5% - 6% 7% -

Statistical comparisons for the individual components of the metabolic
syndrome were not performed.

Abbreviations: BMI, body mass index; chol, cholesterol; circ,
circumference; HDL-c, high-density lipoprotein cholesterol; HOMA-IR,
insulin resistance as assessed by homeostatic model assessment; LDL-c,
low-density lipoprotein cholesterol.

^\*^Wilcoxon signed rank *P* value < .05 for within--treatment arm
change from baseline.

^a^Stratified Wilcoxon rank sum *P* value evaluating the the difference
in changes from baseline between the 2 treatment arms, stratified by
screening 25-OH vitamin D levels.

^b^Stratified normal score *P* value evaluating the difference between
the 2 treatment arms, stratified by screening 25-OH vitamin D levels.:::: 

## Lipid Profile Baseline lipid parameters appear to be balanced between the treatment arms ([Table 1](#)). Fasting total and HDL cholesterol levels increased significantly by weeks 24 and 48 for both arms, with no significant differences between the 2 arms ([Table 2](#)). In the placebo arm, LDL cholesterol increased at week 24 from baseline but not at week 48. However, triglyceride changes from baseline to week 24 or week 48 were not significant in either arm. None of the changes in lipid parameters appeared to differ by treatment arm. 

## Glucose Metabolism and Measures of Insulin Resistance Baseline fasting glucose and insulin levels, as well as HOMA-IR values, appear to be balanced between arms ([Table 1](#)). Glucose levels were increased modestly at weeks 24 and 48 in both arms ([Table 2](#)). Insulin levels increased in the placebo arm but not in the VitD/Cal arm at week 24, while the week 48 changes were not statistically significant for either arm. HOMA-IR increases were modest for both arms only at week 24. Between-arm differences were not significant for glucose, insulin, or HOMA-IR changes at either week 24 or week 48 (*P* > .05 for all). 

## Body Composition and Metabolic Syndrome Baseline waist circumference and BMI values appear to be balanced between the 2 arms ([Table 1](#)). Waist circumference increased in the placebo arm but not in the VitD/Cal arm at both weeks 24 and 48, but differences between the 2 arms were not significant ([Table 2](#)). Changes in BMI were not significant over 48 weeks for either arm. Metabolic syndrome was identified in 19 participants (12%) at baseline and 20 participants (14%) at week 48, with no significant difference between arms. For specific parameters of the metabolic syndrome, low HDL prevalence decreased from a 45% overall prevalence at baseline to 26% at week 48, and elevated TG prevalence increased from a 14% overall prevalence at baseline to 22% at week 48.


Extracted trial result:
Outcome: Metabolic syndrome (binary)
Intervention: Vitamin D plus calcium supplementation
Comparator: Placebo
Intervention events: 9
Intervention group size: 66
Comparator events: 11
Comparator group size: 75