Background Previous research has shown a correlation between high visceral fat levels and hyperuricemia incidence. The Chinese Visceral Adiposity Index (CVAI) assessed visceral fat status in the Chinese population. Our study investigates the correlation between CVAI and asymptomatic hyperuricemia in type 2 diabetes patients. Methods This cross-sectional study analyzed 1,588 hospitalized type 2 diabetes patients to investigate the association between CVAI and hyperuricemia. CVAI was included in the logistic regression analysis as both a continuous and categorical variable, and restricted cubic splines were used to assess the dose-response relationship. Additionally, subgroup analyses were performed to investigate potential interactions among variables. The predictive capability of CVAI was assessed using the receiver operating characteristic (ROC) curve based on the basic model. Results The CVAI quartile group analysis revealed a higher prevalence of hyperuricemia with increasing CVAI levels. CVAI is significantly associated with hyperuricemia, as identified through multifactorial logistic regression analysis. After adjusting for all covariates, the odds ratios for CVAI in the second, third, and fourth quartiles were significantly higher than in the lowest quartile, with values of 2.688 (95% CI [1.301–5.554], p = 0.008), 2.752 (95% CI [1.320–5.739], p = 0.007), and 4.990 (95% CI [2.392–10.409], p < 0.001), respectively. No significant interactions were observed in the subgroup analysis. Incorporating CVAI into the basic model increased the ROC curve’s area under the curve to 0.714. Conclusion This study found a positive correlation between CVAI and hyperuricemia incidence in type 2 diabetes patients. Consequently, CVAI may reliably indicate hyperuricemia in this patient population.

To characterize pathoetiologic associations of heritable thrombophilia-hypofibrinolysis with idiopathic (primary) multifocal osteonecrosis (ON) (≥3 ON anatomic sites), we prospectively studied 28 women and 12 men with primary multifocal ON compared with 27 women and 24 men with primary nonmultifocal ON (<3 sites) and 110 healthy controls without ON. The 40 cases with primary multifocal ON differed from controls for 3 familial thrombophilias: Factor V Leiden heterozygosity (6 of 40 [15%] vs 2 of 109 [2%], P=.002), G20210A prothrombin gene heterozygosity (6 of 40 [15%] vs 3 of 110 [3%], P=.011), and high (>150%) Factor VIII (8 of 40 [20%] vs 7 of 103 [7%], P=.031). These case-control familial coagulation differences paralleled those in 51 concurrently evaluated cases with primary nonmulti-focal ON, 7 of 51 (14%) of whom had Factor V Leiden heterozygosity vs 2% of controls (P=.005) and 14 of 44 (32%) of whom had high Factor VIII vs 7 of 103 (7%) of controls (P=.0002). Recognition of familial thrombophilia as a common pathoetiology of primary multifocal ON provides an opportunity for early anticoagulation (before joint collapse), allowing both prophylaxis and therapy aimed at relieving pain and slowing or stopping progression of the disease to joint collapse. [Orthopedics. 2023;46(3):164-168.].

The authors prospectively assessed long-term anticoagulation outcomes (≥3 years) for 9 patients meeting 4 inclusion criteria: pretreatment Ficat stage I or II primary hip osteonecrosis (ON), factor V Leiden or prothrombin G20210A heterozygosity, no contraindication to anticoagulation, and 90-day participation in an initial enoxaparin 60 mg/d protocol. The primary endpoint was prevention of hip collapse (Ficat stage III or IV). The secondary endpoint was pain relief. After 90 days of enoxaparin 60 mg/d, anticoagulation was continued for 8 patients: 4 receiving warfarin (international normalized ratio targeted to 2 to 2.5; 11.5, 13, 14.5, and 21 years), 1 receiving enoxaparin 120 mg/d (11.5 years), and 3 receiving novel oral anticoagulants (5, 6, and 8 years). Radiographs were obtained before treatment; at 3 to 4, 6 to 8, and 12 to 14 months; and then annually. By selection, 8 patients had factor V Leiden heterozygosity and 1 had prothrombin G202010A heterozygosity. Of their 13 hips (Ficat I or II at entry), 12 remained Ficat I or II after 12±5 years (range, 5.5–21 years) of continuous anticoagulation and follow-up; 1 hip radiographically normalized. None of the 13 hips progressed to collapse (Ficat III or IV). Six patients became symptom free after the first 3 months of receiving enoxaparin, 1 after 6 months of anticoagulation, and 1 after 10 months of anticoagulation; all 8 patients remained symptom free with anticoagulation. Anticoagulation for primary hip ON before hip collapse in patients with familial thrombophilia may change the natural history of ON because most untreated patients with ON have joint collapse and total joint replacement within 2 years of original symptoms. [ Orthopedics . 2020;43(4):e208–e214.]

In our sequential studies of 67 and 21 patients, testosterone therapy (TT) interacted with thrombophilia–hypofibrinolysis, leading to venous thromboembolism (VTE). Compared to 111 VTE controls not taking TT (VTE-no TT), the 67 and 21 cases were more likely (p < 0.05 for all) to have Factor V Leiden (FVL) heterogeneity (24% and 33% vs. 12%), the lupus anticoagulant (14% and 33% vs. 4%), and high lipoprotein(a) (33% vs. 13%, n = 21). After a first VTE and continuing TT, 11 thrombophilic cases had a second VTE despite adequate anticoagulation, 6 of whom, still anticoagulated, had a third VTE. The greatest density of thrombotic events was at three months after starting TT, with a rapid decline by 10 months. From <1 to 8 months after starting TT, 65% of VTE occurred, which may reflect TT-induced depletion of susceptible thrombophilic patients, leaving a winnowed residual group with fewer VTE events despite the continuation of TT. Before starting TT, we suggest screening for FVL, lipoprotein(a), and the lupus anticoagulant to identify patients at increased VTE risk, with an adverse risk-to-benefit ratio for TT. We suggest that TT should not be started in patients with known thrombophilia–hypofibrinolysis, and should not be continued after a first VTE. When TT is given to patients with thrombophilia–hypofibrinolysis, VTE may occur and then recur despite adequate anticoagulation.

Myotoxicity is a significant factor contributing to the poor adherence and reduced effectiveness in the treatment of statins. Genetic variations and high drug plasma exposure are considered as critique causes for statin-induced myopathy (SIM). This study aims to explore the sequential influences of rosuvastatin (RST) pharmacokinetic and myopathy-related single-nucleotide polymorphisms (SNPs) on the plasma exposure to RST and its metabolites: rosuvastatin lactone (RSTL) and N-desmethyl rosuvastatin (DM-RST), and further on RST-induced myopathy. A total of 758 Chinese patients with coronary artery disease were enrolled and followed up SIM incidents for 2 years. The plasma concentrations of RST and its metabolites were determined through a validated ultra-performance liquid chromatography mass spectrometry method. Nine SNPs in six genes were genotyped by using the Sequenom MassArray iPlex platform. Results revealed that ABCG2 rs2231142 variations were highly associated with the plasma concentrations of RST, RSTL, and DM-RST (Padj < 0.01, FDR < 0.05). CYP2C9 rs1057910 significantly affected the DM-RST concentration (Padj < 0.01, FDR < 0.05). SLCO1B1 rs4149056 variant allele was significantly associated with high SIM risk (OR: 1.741, 95% CI: 1.180–2.568, P = 0.0052, FDR = 0.0468). Glycine amidinotransferase (GATM) rs9806699 was marginally associated with SIM incidents (OR: 0.617, 95% CI: 0.406–0.939, P = 0.0240, FDR = 0.0960). The plasma concentrations of RST and its metabolites were not significantly different between the SIM (n = 51) and control groups (n = 707) (all P > 0.05). In conclusion, SLCO1B1 and GATM genetic variants are potential biomarkers for predicting RST-induced myopathy, and their effects on SIM are unrelated to the high plasma exposure of RST and its metabolites.

We assessed contributions of thrombophilia to premature cardiovascular disease (CVD) events (≤ age 45) in 153 patients. Test results of thrombophilia–hypofibrinolysis were obtained in 153 patients with CVD ≤ age 45, 110 healthy normal controls, and 110 patients who had venous thromboembolism (VTE) without CVD. Of the 153 patients with CVD, 121 (79%) had sustained myocardial infarction, 70 (46%) had coronary artery stenting, and 53 (35%) had coronary artery bypass grafts. The first CVD events occurred at ages >20 to 35 in 47 patients and at ages >35 to 45 in 106 patients. At study entry, median low-density lipoprotein cholesterol was 126 mg/dL, 56 (37%) smoked, 56 (37%) had hypertension, and 56 (37%) were diabetic. Cases differed from normal controls for high factor VIII (10 [22%] of 45 vs 7 of 103 [7%], P = .007), high homocysteine (32 [21%] of 151 vs 5 [5%] of 107, P = .0002), low free protein S (5 [11%] of 44 vs 2 [2%] of 96, P = .032), high anticardiolipin antibodies (ACLA) IgM (11 [9%] of 129 vs 2 [2%] of 109, P = .024), high lipoprotein (a) [Lp(a)] (46 [30%] of 151 vs 21 [19%] of 110, P = .038), and the lupus anticoagulant (4 [11%] of 37 vs 2 [2%] of 110, P = .035). There were no differences ( P > .05) between cases and VTE controls except free protein S and Lp(a). Free protein S was more often low in VTE controls (24 [28%] of 85 vs 5 [11%] of 44, P = .03) and Lp(a) was more often high in cases (46 [30%] of 151, VTE controls 12 [17%] of 71, P = .032). In 153 patients with premature CVD ≤ age 45, thrombophilia was pervasive (high factor VIII, homocysteine, ACLA IgM, low free protein S, high Lp(a), and lupus anticoagulant), evidencing thrombotic contribution to premature CVD. Moreover, thrombophilia in patients with premature CVD was comparable to VTE controls, emphasizing the pervasive nature of thrombophilia in premature CVD.

Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO) have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated cholesterol lowering therapy, we assessed efficacy and safety of ALI and EVO.

In 153 patients who sustained premature cardiovascular disease (CVD) events ≤ age 45, we evaluated the contribution of thrombosis to atherosclerosis-atherothrombosis. Measures of thrombophilia-hypofibrinolysis were obtained in 153 patients with CVD ≤ age 45 compared to 110 healthy normal

We compared thrombophilia and hypofibrinolysis in 6 men with Klinefelter syndrome (KS), without previously known familial thrombophilia, who had sustained deep venous thrombosis (DVT)-pulmonary emboli (PE) or mesenteric artery thrombosis on testosterone replacement therapy (TRT). After the diagnosis of KS, TRT had been started in the 6 men at ages 11, 12, 13, 13, 19, and 48 years. After starting TRT, DVT-PE or mesenteric artery thrombosis was developed in 6 months, 1, 11, 11, 12, and 49 years. Of the 6 men, 4 had high (>150%) factor VIII (177%, 192%, 263%, and 293%), 3 had high (>150%) factor XI (165%, 181%, and 193%), 1 was heterozygous for the factor V Leiden mutation, and 1 was heterozygous for the G20210A prothrombin gene mutation. None of the 6 men had a precipitating event before their DVT-PE. We speculate that the previously known increased rate of DVT-PE and other thrombi in KS reflects an interaction between prothrombotic, long-term TRT with previously undiagnosed familial thrombophilia. Thrombophilia screening in men with KS before starting TRT would identify a cohort at increased risk for subsequent DVT-PE, providing an optimally informed estimate of the risk/benefit ratio of TRT.

We assessed time of thrombotic events (venous thromboembolism (VTE)) after starting testosterone therapy (TT) in 21 men who sustained 23 VTE. The density of thrombotic events was greatest at 3 months after starting TT, with a rapid decline in events by 10 months. The 21 cases with VTE on TT differed from 110 patient controls with unprovoked VTE, not taking TT (VTE-no TT) for Factor V Leiden heterozygosity (FVL) (33 per cent vs 13 per cent, P=0.037), for high lipoprotein (a) (Lp(a)) (55 per cent vs 17 per cent, P=0.012), and for the lupus anticoagulant (33 per cent vs 4 per cent, P=0.003). These differences between cases and VTE-no TT controls were independent of age and gender. TT can interact with underlying thrombophilia–hypofibrinolysis promoting VTE. We suggest that TT should not be started in subjects with known thrombophilia. Coagulation screening, particularly for the FVL , Lp(a), and the lupus anticoagulant should be considered before starting TT, to identify men at high VTE risk who have an adverse risk/benefit ratio for TT.

Lowering of LDL cholesterol (LDLC) has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha). PCSK9 inhibitors have approved indications as adjunct to diet and maximally tolerated lipid lowering therapy (MTLLT) for patients with heterozygous familial

Mutations in the T786C endothelial nitric oxide synthase gene (eNOS) are associated with osteonecrosis and Prinzmetal's angina. Nitric oxide is necessary for bone health and ameliorates Prinzmetal's angina. This study compared mutations of T786C eNOS in 146 patients with primary osteonecrosis, 114 patients with Prinzmetal's angina, and 83 normal control subjects. Patients with osteonecrosis had more mutant eNOS alleles than control subjects (42% vs 22%, respectively; P<.0001) but had the same number of mutant alleles as patients with Prinzmetal's angina (42% vs 41%, respectively; P=.7), who in turn had more mutant eNOS alleles than control subjects (41% vs 22%, respectively; P=.0001). Of 146 patients with primary osteonecrosis, 65 (45%) had none of the 5 thrombophilias (Factor V Leiden heterozygosity, high levels of Factors VIII and XI, anticardiolipin antibody immunoglobulin M, and homocysteine) that otherwise distinguished patients with osteonecrosis from control subjects (P<.05). No associations were found between eNOS hetero-homozygosity and the 5 major thrombophilias in primary osteonecrosis. Of the 65 patients who had osteonecrosis but no major thrombophilias, for 41 (28% of the total sample of 146), eNOS hetero-homozygosity was the only abnormality. Normalization of nitric oxide levels with l-arginine 9 g/d or l-citrulline 800 mg/d, both of which relieve vasospastic angina in Prinzmetal's angina, which has the same eNOS genotype as primary osteonecrosis, may slow or stop the progression of osteonecrosis. Placebo-controlled trials of patients with primary osteonecrosis who are hetero-homozygous for the T786C eNOS mutation and have no major thrombophilias are needed to assess the safety and efficacy of this treatment. [Orthopedics. 2017; 40(5):e898-e903.].

Efficacy-safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO), have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in 69 patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated LDLC therapy, we assessed efficacy and safety of ALI and EVO.

In 35 patients with 116 severe premature cardiovascular disease (CVD) events (median age: 48 years), 14 having worsening CVD despite maximal intervention, we evaluated thrombophilia and speculated that anticoagulation might arrest–reverse progressive thrombophilic–atherothrombotic CVD. Thrombophilia–hypofibrinolysis in the 35 patients was compared to 110 patients with venous thromboembolism (VTE) without CVD and to 110 healthy normal controls. Efficacy–safety of anticoagulation was prospectively assessed in 14 of the 35 patients whose CVD worsened over 2 years despite maximal medical–surgical intervention. At entry on maximally tolerated lipid-lowering therapy, median low-density lipoprotein was 88 mg/dL. Measures of thrombophilia–hypofibrinolysis in the 35 cases differed from 110 VTE controls only for the lupus anticoagulant, present in 6 (21%) of 28 cases versus 4 (4%) of 91 VTE controls (P = .01), and for high anticardiolipin antibodies (ACLAs) immunoglobulin G, 5 (14%) of 35 cases versus 4 of 108 VTE controls (4%), P = .04. The 14 patients who were anticoagulated differed from 110 VTE controls only for the lupus anticoagulant, 38% versus 4%, P = .001, and for high lipoprotein (a), 46% versus 17%, P = .028, respectively. The 14 patients with atherothrombosis having inexorably worsening CAD despite maximal medical–surgical therapy were anticoagulated for 6.5 years (median), with clinical CVD progression arrested in 12 (86%), and all 12 became asymptomatic. In the 35 patients with premature CVD, thrombophilia was pervasive, comparable to or more severe than in VTE controls without CVD. When CVD progressively worsens despite maximal intervention, thrombophilia and atherosclerosis (atherothrombosis) are commonly concurrent, and the downhill course of CVD may be arrested–stabilized by anticoagulation.

INTRODUCTION:The prevalence of metabolic syndrome (MetS) is rapidly increasing in the United States and, because of its strong association with male hypogonadism, has become a significant topic of interest in the sexual medicine community. At the center of this conversation is the efficacy and safety of testosterone replacement therapy (TRT) as a therapeutic option for HG and MetS. AIM:To provide a review of the current literature pertaining to TRT and MetS. METHODS:A thorough literature review was performed to review the relation between TRT and MetS using the PubMed online database from 1976 through 2016 with the keywords testosterone, hypogonadism, metabolic syndrome, and testosterone therapy. MAIN OUTCOME MEASURES:Outcomes pertaining to MetS including weight, waist circumference, body mass index, blood glucose control, cholesterol parameters, blood pressure, and quality of life. RESULTS:From the plethora of contrasting literature on the efficacy and safety of TRT, it is increasingly clear that more well-designed studies are needed to clarify the efficacy and safety of TRT. Although most of the current literature shows that TRT has the potential to significantly lower the studied outcome variables associated with MetS, several studies provide more mixed results. CONCLUSION:TRT has the potential to alleviate some of the morbidity associated with hypogonadism and MetS. Larger multicenter well-designed studies are needed to better describe and quantify the relation between MetS and TRT. Anaissie J, Roberts NH, Wang P, et al. Testosterone Replacement Therapy and Components of the Metabolic Syndrome. Sex Med Rev 2017;5:200-210.

In their study of statin-associated muscle symptoms (SAMS) in 120 patients with previous self-described SAMS, published in this issue of Atherosclerosis, Taylor et al. [[1]Taylor B. Lorson L. White M. Thompson P.D. Low vitamin D does not predict statin-associated muscle symptoms but is associated with transient increases in muscle damage and pain.Atherosclerosis. 2016; 256: 100-104Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] carried out an 8-week, randomized, double-blind cross-over trial of simvastatin 20 mg/day and placebo, with measurement of serum vitamin D at each phase of the trial. Of the 120 patients, 43 (36%) had muscle symptoms on simvastastin but not on placebo, reflecting the small proportion of patients with self-described SAMS, demonstrating SAMS under placebo controlled-double blind conditions [[1]Taylor B. Lorson L. White M. Thompson P.D. Low vitamin D does not predict statin-associated muscle symptoms but is associated with transient increases in muscle damage and pain.Atherosclerosis. 2016; 256: 100-104Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Serum vitamin D at entry, vitamin D deficiency or insufficiency, and changes in vitamin D on simvastatin therapy did not predict SAMS [[1]Taylor B. Lorson L. White M. Thompson P.D. Low vitamin D does not predict statin-associated muscle symptoms but is associated with transient increases in muscle damage and pain.Atherosclerosis. 2016; 256: 100-104Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. However, both entry and on-simvastatin serum vitamin D were inversely related to the change in creatine kinase (CK) on statin therapy, independent of SAMS [[1]Taylor B. Lorson L. White M. Thompson P.D. Low vitamin D does not predict statin-associated muscle symptoms but is associated with transient increases in muscle damage and pain.Atherosclerosis. 2016; 256: 100-104Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. This suggested that low levels of serum vitamin D are related to muscle pain and damage, which might then be exacerbated by statin therapy. From these observations, the authors stated [[1]Taylor B. Lorson L. White M. Thompson P.D. Low vitamin D does not predict statin-associated muscle symptoms but is associated with transient increases in muscle damage and pain.Atherosclerosis. 2016; 256: 100-104Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] "… these results cannot dismiss low vitamin D as a factor in SAMS and suggest that low vitamin D may indeed be a potential mechanism contributing to SAMS." This speculation provides a bridge to broadly uniform, clinical studies [2Ahmed W. Khan N. Glueck C.J. et al.Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients.Transl. Res. 2009; 153: 11-16Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 3Glueck C.J. Budhani S.B. Masineni S.S. et al.Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance.Curr. Med. Res. Opin. 2011; 27: 1683-1690Crossref PubMed Scopus (69) Google Scholar, 4Khayznikov M. Kumar A. Wang P. et al.Statin intolerance and vitamin D.Suppl. N. Am. J. Med. Sci. 2015; 7: 339-340PubMed Google Scholar, 5Jetty V. Glueck C.J. Wang P. et al.Safety of 50,000-100,000 Units of vitamin d3/week in vitamin d-deficient, hypercholesterolemic patients with reversible statin intolerance.N. Am. J. Med. Sci. 2016; 8: 156-162Crossref PubMed Scopus (15) Google Scholar, 6Kang J.H. Nguyen Q.N. Mutka J. et al.Rechallenging statin therapy in veterans with statin-induced myopathy post vitamin D replenishment.J. Pharm. Pract. 2016; (pii: 0897190016674407. [Epub ahead of print])PubMed Google Scholar] reporting that vitamin D supplementation, particularly when documented to elevate previously low serum vitamin D into the normal range, effectively reduces SAMS on statin re-challenge in most (≥85%) patients previously unable to tolerate statins. Given recent emphasis on the value of statin-mediated reduction of LDL cholesterol [7Chou R. Dana T. Blazina I. et al.Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US preventive services task force.JAMA. 2016; 316: 2008-2024Crossref PubMed Scopus (361) Google Scholar, 8Rodriguez F. Harrington R.A. Cholesterol, cardiovascular risk, statins, PCSK9 inhibitors, and the future of LDL-C lowering.JAMA. 2016; 316: 1967-1968Crossref PubMed Scopus (16) Google Scholar], and reports that SAMS may occur in up to 10% of patients given statins [9Bitzur R. Cohen H. Kamari Y. et al.Intolerance to statins: mechanisms and management.Diabetes Care. 2013; 36: S325-S330Crossref PubMed Scopus (114) Google Scholar, 10Thompson P.D. Panza G. Zaleski A. et al.Statin-associated side effects.J. Am. Coll. Cardiol. 2016; 67: 2395-2410Crossref PubMed Scopus (377) Google Scholar], SAMS is an important impediment to statin-mediated reduction of coronary vascular disease. As recently observed by Thompson et al. [[10]Thompson P.D. Panza G. Zaleski A. et al.Statin-associated side effects.J. Am. Coll. Cardiol. 2016; 67: 2395-2410Crossref PubMed Scopus (377) Google Scholar] "… patients who take less than 80% of their stain dose have a 45% relative increase in total mortality compared with more adherent patients, an increase greater than that observed with poor adherence to other cardiac drugs including antihypertensive and B-adrenergic blocking agents." To optimally answer whether vitamin D supplementation in SAMS patients with low serum vitamin D will resolve their symptoms and allow them to take therapeutic statin doses, we need a double blind, placebo-controlled, crossover trial with rigorously defined criteria [[11]Parker B.A. Capizzi J.A. Grimaldi A.S. et al.Effect of statins on skeletal muscle function.Circulation. 2013; 127: 96-103Crossref PubMed Scopus (349) Google Scholar] for SAMS, with a single statin, and supplemental vitamin D to normalize serum vitamin D (50,000 to 100,000 IU/week). Without such a trial, the clinical success of non-blinded vitamin D supplementation, as demonstrated in Fig. 1, necessarily involves an unknown degree of placebo effect. Michalska-Kasiczak et al. [[12]Michalska-Kasiczak M. Sahebkar A. Mikhailidis D.P. et al.Analysis of vitamin D levels in patients with and without statin-associated myalgia - a systematic review and meta-analysis of 7 studies with 2420 patients.Int. J. Cardiol. 2015; 178: 111-116Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar], in a meta-analysis of 2420 patients, reported that plasma vitamin D levels were lower in patients with SAMS compared to patients without SAMS (weighted mean difference in plasma vitamin D −9.41 ng/ml; 95% confidence interval: −10.17 to −8.64; p < 0.00001). We [[2]Ahmed W. Khan N. Glueck C.J. et al.Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients.Transl. Res. 2009; 153: 11-16Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar] initially reported a prospective cohort study of 38 patients with SAMS and mean ± SD vitamin D 20 ± 7.3 ng/ml at entry. Supplementation with Rx vitamin D (50,000 IU/week for 12 weeks) increased serum vitamin D to 48 ± 18, with resolution of myalgia [[2]Ahmed W. Khan N. Glueck C.J. et al.Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients.Transl. Res. 2009; 153: 11-16Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar] in 92% of the patients. Subsequently [[3]Glueck C.J. Budhani S.B. Masineni S.S. et al.Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance.Curr. Med. Res. Opin. 2011; 27: 1683-1690Crossref PubMed Scopus (69) Google Scholar], in 150 patients with SAMS and low entry median vitamin D (21 ng/ml), giving vitamin D supplementation, 50,000 IU twice/week for 3 weeks, then once/week, we reported that 131 (87%) were able to successfully restart statin therapy and have remained symptom free for 24 months. Khaznikov et al. [[4]Khayznikov M. Kumar A. Wang P. et al.Statin intolerance and vitamin D.Suppl. N. Am. J. Med. Sci. 2015; 7: 339-340PubMed Google Scholar], in a study of 134 patients with SAMS, provided vitamin D supplementation 50,000–100,000 IU/week to 134 patients with SAMS and low serum vitamin D at entry (Fig. 1). At 6, 12, and 24 months, median serum vitamin D normalized, low density lipoprotein cholesterol was reduced to target (<100 mg/dl), and 88%, 91%, and 95% of patients were free of muscle symptoms (Fig. 1). Jetty et al. [[5]Jetty V. Glueck C.J. Wang P. et al.Safety of 50,000-100,000 Units of vitamin d3/week in vitamin d-deficient, hypercholesterolemic patients with reversible statin intolerance.N. Am. J. Med. Sci. 2016; 8: 156-162Crossref PubMed Scopus (15) Google Scholar] examined safety and efficacy of vitamin D supplementation (50,000–100,000 IU/week) in 282 statin-intolerant hypercholesterolemic patients for 6 months and in 112 of these 282 for 12 months. Median serum calcium and glomerular filtration rate (eGFR) were unchanged from entry (p > 0.05), and revealed no trends in change (p > 0.05) at 6 and 12 months. Serum vitamin D rose from pre-treatment (21 ng/ml) to 46 ng/dl at 6 months and was 51 ng/ml at 12 months. Serum vitamin D became high (>100 ng/ml) but not toxic (>150 ng/ml) at 6 months in 4 patients (1.4%), and in 1 patient (0.9%) at 12 months. Of 183 patients with SAMS at entry, 136 on re-challenge with statins at 6 months were symptom-free (74%). At 12-month follow-up of 82 patients with SAMS at entry, 74 (90%) were symptom-free on statins [[5]Jetty V. Glueck C.J. Wang P. et al.Safety of 50,000-100,000 Units of vitamin d3/week in vitamin d-deficient, hypercholesterolemic patients with reversible statin intolerance.N. Am. J. Med. Sci. 2016; 8: 156-162Crossref PubMed Scopus (15) Google Scholar]. Kang et al. [[6]Kang J.H. Nguyen Q.N. Mutka J. et al.Rechallenging statin therapy in veterans with statin-induced myopathy post vitamin D replenishment.J. Pharm. Pract. 2016; (pii: 0897190016674407. [Epub ahead of print])PubMed Google Scholar] have recently reported a retrospective small study in 27 VA patients with SAMS who had low serum vitamin D (<30 ng/ml), and received vitamin D supplementation, 50,000 IU/week for 8–12 weeks, then 800–1000 IU/day maintenance. Statins were restarted ∼6 months after starting vitamin D supplementation. All 27 patients were able to maintain their statin therapy for 12 months, and 11 (41%) tolerated their previously failed statins. Kang et al. [[6]Kang J.H. Nguyen Q.N. Mutka J. et al.Rechallenging statin therapy in veterans with statin-induced myopathy post vitamin D replenishment.J. Pharm. Pract. 2016; (pii: 0897190016674407. [Epub ahead of print])PubMed Google Scholar] concluded that "replenishing low vitamin D in patients with statin-induced myopathy appears to be an effective strategy in improving medication adherence." Low serum vitamin D levels could lead to development of both SAMS and non-specific muscle pain subsequently amplified by statins [[1]Taylor B. Lorson L. White M. Thompson P.D. Low vitamin D does not predict statin-associated muscle symptoms but is associated with transient increases in muscle damage and pain.Atherosclerosis. 2016; 256: 100-104Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], and ameliorated by vitamin D supplementation [2Ahmed W. Khan N. Glueck C.J. et al.Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients.Transl. Res. 2009; 153: 11-16Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 3Glueck C.J. Budhani S.B. Masineni S.S. et al.Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance.Curr. Med. Res. Opin. 2011; 27: 1683-1690Crossref PubMed Scopus (69) Google Scholar, 4Khayznikov M. Kumar A. Wang P. et al.Statin intolerance and vitamin D.Suppl. N. Am. J. Med. Sci. 2015; 7: 339-340PubMed Google Scholar, 5Jetty V. Glueck C.J. Wang P. et al.Safety of 50,000-100,000 Units of vitamin d3/week in vitamin d-deficient, hypercholesterolemic patients with reversible statin intolerance.N. Am. J. Med. Sci. 2016; 8: 156-162Crossref PubMed Scopus (15) Google Scholar, 6Kang J.H. Nguyen Q.N. Mutka J. et al.Rechallenging statin therapy in veterans with statin-induced myopathy post vitamin D replenishment.J. Pharm. Pract. 2016; (pii: 0897190016674407. [Epub ahead of print])PubMed Google Scholar] to normalize serum vitamin D. Given the major clinical importance of SAMS [10Thompson P.D. Panza G. Zaleski A. et al.Statin-associated side effects.J. Am. Coll. Cardiol. 2016; 67: 2395-2410Crossref PubMed Scopus (377) Google Scholar, 13Thompson P.D. What to believe and do about statin-associated adverse effects.JAMA. 2016; 316: 1969-1970Crossref PubMed Scopus (20) Google Scholar], we need a large, double-blind, placebo-controlled crossover trial of vitamin D supplementation in patients with SAMS to elucidate the effectiveness of vitamin D supplementation in ameliorating SAMS. The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript. Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and painAtherosclerosisVol. 256PreviewLow vitamin D (VITD) may contribute to statin-associated muscle symptoms (SAMS). We examined the influence of baseline and change in VITD in patients with verified SAMS. Full-Text PDF

BACKGROUND:Serum 25(OH) vitamin D levels are inversely associated with cardiovascular disease (CVD) mortality, mediated in part by independent positive relationships with high-density lipoprotein cholesterol (HDLC) and inverse relationships with low-density lipoprotein cholesterol (LDLC), triglyceride, and homocysteine.AIMS:In this study, we assessed relationships between fasting serum vitamin D and lipids, lipoprotein cholesterols, and homocysteine.MATERIALS AND METHODS:We studied 1534 patients sequentially referred to our center from 2007 to 2016. Fasting serum total 25(OH) vitamin D, plasma cholesterol, triglyceride, HDLC, LDLC, and homocysteine were measured. Stepwise regression models were used with total cholesterol, triglyceride, HDLC, LDLC, and homocysteine as dependent variables and explanatory variables age, race, gender, body mass index (BMI), and serum vitamin D levels. Relationships between quintiles of serum vitamin D and triglycerides, HDLC, LDLC, and homocysteine were assessed after covariance adjusting for age, race, gender, and BMI.RESULTS:Fasting serum vitamin D was positively correlated with age, HDLC, and White race, and was inversely correlated with BMI, total and LDL cholesterol, triglyceride, and fasting serum homocysteine (P ≤ 0.0001 for all). Serum vitamin D was a significant independent inverse explanatory variable for total cholesterol, triglyceride, and LDL cholesterol, and accounted for the largest amount of variance in serum total cholesterol (partial R (2) =3.6%), triglyceride (partial R (2) =3.1%), and LDLC (partial R (2) =2.9%) (P < 0.0001 for all). Serum vitamin D was a significant positive explanatory variable for HDLC (partial R (2) = 1.4%, P < 0.0001), and a significant inverse explanatory variable for homocysteine (partial R (2) = 6.0-12.6%).CONCLUSIONS:In hyperlipidemic patients, serum vitamin D was a significant independent inverse determinant of total cholesterol, LDLC, triglyceride, and homocysteine, and a significant independent positive determinant of HDLC. Thus, serum vitamin D might be protective against CVD.

BACKGROUND:Low serum vitamin D can cause myalgia, myositis, myopathy, and myonecrosis. Statin-induced myalgia is a major and common cause of statin intolerance. Low serum vitamin D and statins, additively or synergistically, cause myalgia, myositis, myopathy, and/or myonecrosis. Statin-induced myalgia in vitamin D deficient patients can often be resolved by vitamin D supplementation, normalizing serum vitamin D levels.AIMS:In 74 men and 72 women (age 59 ± 14 years) intolerant to ≥2 statins because of myalgia, myositis, myopathy, or myonecrosis and found to have low (<32 ng/mL) serum vitamin D, we prospectively assessed whether vitamin D supplementation (vitamin D2: 50,000-100,000 units/week) to normalize serum vitamin D would allow successful rechallenge therapy with statins.MATERIALS AND METHODS:Follow-up evaluation on vitamin D supplementation was done on 134 patients at 6 months (median 5.3), 103 patients at 12 months (median 12.2), and 82 patients at 24 months (median 24).RESULTS:Median entry serum vitamin D (22 ng/mL, 23 ng/mL, and 23 ng/mL) rose at 6 months, 12 months, and 24 months follow-up to 53 ng/mL, 53 ng/mL, and 55 ng/mL, respectively, (P < .0001 for all) on vitamin D therapy (50,000-100,000 units/week). On vitamin D supplementation, serum vitamin D normalized at 6 months, 12 months, and 24 months follow-up in 90%, 86%, and 91% of the patients, respectively. On rechallenge with statins while on vitamin D supplementation, median low-density lipoprotein cholesterol (LDLC) fell from the study entry (167 mg/dL, 164 mg/dL, and 158 mg/dL) to 90 mg/dL, 91 mg/dL, and 84 mg/dL, respectively, (P < .0001 for all). On follow-up at median 6 months, 12 months, and 24 months on statins and vitamin D, 88%, 91%, and 95% of the previously statin-intolerant patients, respectively, were free of myalgia, myositis, myopathy, and/or myonecrosis.CONCLUSIONS:Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis associated with low serum vitamin D can be safely resolved by vitamin D supplementation (50,000-100,000 units /week) in most cases (88-95%).