Niacin 500 mg [Discontinued] by Bronson Laboratories

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies show that intake of calcium supplements or dietary calcium modestly reduces blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as salt-sensitive people and patients with low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221). Also, a meta-analysis of clinical research shows that calcium intake during pregnancy reduces systolic blood pressure in offspring by 1-2 mmHg (38852). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplement sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia in high risk pregnancies, especially if calcium intakes are low. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces pregnancy-related hypertension and pre-eclampsia (973,1833,8828,39043,39319,39426,96480). Calcium appears to reduce the risk of pre-eclampsia by about 50% when compared with placebo. One meta-analysis of 19 controlled trials involving over 29,000 pregnancies found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (96480). Calcium appears to have the greatest effect in individuals at high-risk of pre-eclampsia or with low calcium levels, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,96480,99714). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely. Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium supplementation 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low, in order to prevent pre-eclampsia (97347).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium does not seem to be beneficial for breast cancer prevention. Details: Although some population research disagrees (15631,39041,95811,107237), most research shows that increased calcium intake is not associated with a reduced risk of breast cancer (15631,16715,98895,107236,107237). Subgroup analyses of population research suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237). Another subgroup analysis in a large meta-analysis of population research also suggests that dietary intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most other research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: The most recent and robust meta-analysis of clinical research shows that calcium supplementation with or without vitamin D is NOT associated with reduced fractures in older adults without osteoporosis (95822). A large-scale study in postmenopausal females aged 50-79 years suggests calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the Women's Health Initiative study found that, in older females with the lowest genetic susceptibility to low bone mineral density (BMD), taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). The most recent meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if oral calcium is beneficial for type 2 diabetes prevention. Details: Some population research has found that a higher intake of calcium from diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473). However, population research is often limited by confounding variables. For example, one analysis found that any beneficial effect might be influenced by concomitant magnesium intake (96473). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis. This study is limited because it was not determined whether increased serum calcium was due to increased calcium intake or another factor such as parathyroid function (95815).
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Hypercholesterolemia. It is unclear if oral calcium is beneficial for hypercholesterolemia. Details: Some evidence shows that taking calcium carbonate 400 mg three times daily reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% after 6 weeks of treatment when used in combination with a low-fat diet (American Heart Association Step 1) (2557). In contrast, a study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years might INCREASE total cholesterol levels by about 12 mg/dL when compared with placebo. This same study showed an association between calcium supplementation and an increase in total cholesterol levels and carotid intimal thickness in postmenopausal females, but not premenopausal females (97350). A recent meta-analysis of randomized controlled trials which included both healthy patients and patients with dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is more effective in patients with dyslipidemia at baseline. It is unclear if this effect is due to calcium, vitamin D, or the combination (107227). However, other research shows that taking a specific supplement containing calcium 600 mg plus vitamin D 200 IU (Caltrate 600 D, Wyeth Consumer Healthcare Inc.) twice daily in combination with calorie restriction does not reduce total or LDL cholesterol levels when compared with placebo (15601).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

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LIKELY EFFECTIVE

• Dyslipidemia. Niacin prescription products, in doses of 500 mg or greater, are FDA-approved for primary hyperlipidemia and mixed dyslipidemia. Niacin dietary supplements are generally available in lower doses and have not been shown to improve lipid levels. Details: Prescription niacin is not routinely recommended as second-line therapy for patients who primarily need to decrease low-density lipoprotein (LDL) cholesterol. This is due to results from clinical trials showing no effect on cardiovascular related events or mortality (93346,93354,96208,96211,97308,97477,97336). However, niacin might be considered for patients with mixed hyperlipidemia or patients who need to increase high-density lipoprotein (HDL) cholesterol and lower triglycerides. Niacin might also be effective for isolated hypoalphalipoproteinemia (4817). The most pronounced increases in HDL and decreases in triglycerides occur at 1-1.5 grams daily, and the greatest LDL reduction occurs at 2-3 grams daily. Niacin reduces LDL cholesterol by up to 25%, compared with up to a 55% reduction with statins. High-dose niacin can also decrease triglycerides by 20% to 50%, increase HDL by 13% to 35%, decrease apolipoprotein B levels by 2% to 20%, and decrease lipoprotein(a) levels by 23% (4818,4886,4887,4888,4889,4890,12033,25567,93347,96213). The effects of higher dose extended-release niacin on LDL cholesterol and triglycerides appear to be greater in females than males (25565). Experts recommend maximizing statins first because they have the best evidence for improving cardiovascular outcomes (97477,97336,97337). However, if patients cannot reach their LDL goal with a statin alone or if they cannot tolerate a statin, niacin might be combined with other cholesterol-lowering drugs when diet and single-drug therapy are not adequately effective (8545,25566,93351,94191,97337). Adding low-dose niacin, 50 mg daily, to statin therapy has no additional benefit on lipid levels (8546). Population research in adults without dyslipidemia has also found that higher dietary intake of niacin for 3-10 years is associated with a 29% lower risk of developing dyslipidemia when compared with low dietary niacin intake (110493).
• Pellagra. Oral niacin is FDA-approved for the prevention and treatment of pellagra. Details: Population research has found that low consumption of niacin is associated with an increased risk of developing pellagra (25903). Taking niacin 500-1000 mg daily can resolve symptoms of pellagra within a week of treatment initiation (25904). However, niacinamide is sometimes preferred for this indication because it lacks the vasodilating effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• HIV/AIDS-related dyslipidemia. Oral niacin seems to improve lipid levels in patients with dyslipidemia due to HIV/AIDs. Details: Small clinical trials in HIV patients with dyslipidemia associated with antiretroviral therapy shows that taking extended-release niacin (Niaspan, Abbott Laboratories) titrated up to 2 grams daily for 14-48 weeks improves total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels when compared to baseline (25570,25902). Other preliminary clinical research in this population shows that taking extended-release niacin (Niaspan, Abbott Laboratories) titrated to 2 grams daily for up to 2 years improves HDL cholesterol levels, but not total cholesterol or triglyceride levels, when compared with no treatment (25569).
• Metabolic syndrome. Oral niacin seems to improve lipid levels in patients with metabolic syndrome. Details: Clinical research shows that taking niacin (Niaspan, Abbott Laboratories) 2 grams daily orally for 16 weeks reduces triglyceride levels by 39 mg/dL and increases high-density lipoprotein (HDL) cholesterol by 5 mg/dL when compared to baseline in patients with metabolic syndrome. These improvements are significant when compared with placebo and are further increased when niacin is taken along with prescription omega-3 ethyl esters (Lovaza, GlaxoSmithKline Pharmaceuticals) 4 grams daily orally (93353). However, niacin does not seem to improve postprandial glucose levels in patients with metabolic syndrome (97333).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral niacin does not seem to reduce cardiovascular-related events in patients with or without CVD. Details: Overall, niacin is not recommended for primary or secondary prevention of CVD. Most clinical trials and meta-analyses conducted prior to 2011 showed a reduction in cardiovascular-related events, cardiovascular-related mortality, and all-cause mortality in patients taking niacin alone or in combination with a statin or clofibrate for primary or secondary prevention of CVD (4847,7388,25095,25911,25912,93349). However, recent meta-analyses of these studies and additional moderate-to-high quality research conducted in over 39,000 patients show no effect of niacin on cardiovascular-related events, cardiovascular-related mortality, or overall mortality (93346,93354,96208,96211,97308). Additionally, one meta-analysis shows that patients taking niacin are twice as likely to report side effects when compared with placebo (96211).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if oral niacin is beneficial for reducing Alzheimer disease risk. Details: Observational research has found that consuming higher amounts of niacin (17-45 mg daily) from food and supplements is associated with a slower cognitive decline and a lower risk of developing Alzheimer disease when compared with people who consume less niacin (14 mg daily) (12077). It is not known if the risk of Alzheimer disease is reduced by taking a stand-alone niacin supplement.
• Atherosclerosis. It is unclear if oral niacin prevents atherosclerosis progression. Details: Preliminary clinical studies show that taking niacin orally, in combination with colestipol for up to 2 years, might modestly reduce progression of atherosclerosis as measured by coronary lesions and carotid arterial intima-media thickness in high-risk males with existing coronary atherosclerosis (25906,25909,25910). However, niacin does not seem to be better than statins. One clinical study in adults with atherosclerosis and peripheral arterial disease shows that taking extended-release niacin 1500 mg, simvastatin 40 mg, and ezetimibe 10 mg daily for 2 years does not reduce atherosclerosis of the superficial femoral artery when compared with simvastatin alone (96208). Niacin has also not been shown to prevent cardiovascular events or mortality (93346,93354,96208,96211,97308).
• Athletic performance. It is unclear if oral niacin improves athletic performance. Details: Preliminary clinical research in untrained adult males shows that taking niacin 1000 mg orally once before a cycling test does not improve power, respiratory exchange ratio, or time to exhaustion when compared with placebo. In addition, these measures were significantly worse when compared with taking caffeine 5 mg/kg orally as a single dose (107942). Clinical research in untrained males also shows that taking a supplement containing niacin 40 mg, caffeine 400 mg, capsicum extract 66.7 mg, and black pepper extract 10 mg prior to exercising does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral niacin for ADHD, there is insufficient reliable information about the clinical effects of niacin for this condition.
• Cancer. It is unclear if dietary niacin is beneficial for cancer. Details: Population research in adults with cancer has found that high dietary niacin intake is associated with 49% and 27% lower risk of cancer-related mortality and all-cause mortality when compared with low dietary niacin intake. The same study also found that taking niacin supplements is associated with a lower risk of cancer-related mortality, but not all-cause mortality when compared with not taking niacin supplements (110496).
• Cataracts. It is unclear if oral niacin is beneficial for preventing cataracts. Details: Population research has found that high dietary intake of niacin is associated with a reduced risk of nuclear cataracts (6378). However, there is no reliable evidence that niacin supplements reduce the risk of cataracts.
• Cholera. It is unclear if oral niacin is beneficial for cholera. Details: One small clinical study in adults with severe cholera shows that taking 1-2 grams niacin orally reduces fluid loss in the stool by 31% to 47% in the first 16 hours when compared with control. The 2 gram dose seemed to result in a greater reduction in fluid loss than the 1 gram dose (4868).
• Erectile dysfunction (ED). It is unclear if oral niacin is beneficial in patients with ED and dyslipidemia. Details: Clinical research in patients with erectile dysfunction and dyslipidemia shows that taking extended-release niacin (Niaspan, Abbott Laboratories) titrated to 1.5 grams nightly for a total of 12 weeks significantly improves penetration frequency and the maintenance of an erection after penetration when compared to baseline (25913). The validity of this finding is limited by the lack of a comparator group.
• Glaucoma. It is unclear if oral niacin is beneficial for preventing or treating glaucoma. Details: Population research has found that higher dietary intake of niacin is associated with a lower odds of having glaucoma. However, this association was not consistently present when adjusting for confounders. The effects of niacin supplementation on glaucoma have not been evaluated (107942).
• Hyperphosphatemia. It is unclear if oral niacin is beneficial for preventing high levels of phosphorus in the blood. Details: Preliminary clinical research in patients on maintenance dialysis who are no longer using phosphate binders shows that taking niacin 375-750 mg daily for 8 weeks reduces serum phosphorus levels by 2.1 mg/dL, increases calcium levels by 0.4 mg/dL, and decreases serum alkaline phosphatase when compared with baseline (25914). However, clinical research in hemodialysis patients with inadequate phosphate control despite using standard phosphate-binding therapy shows that taking niacin at the maximum tolerated dose, up to 1000 mg daily, for 12 weeks, does not decrease serum phosphate levels when compared with placebo (93341). It is possible that this latter study was too small to observe between-group differences in changes in serum phosphate levels.
• Hypertension. It is unclear if dietary niacin is beneficial for preventing hypertension. Details: Observational research in Chinese adults found a J-shaped association between dietary niacin intake and development of hypertension, with the lowest risk occurring in those with a daily dietary niacin intake of 14.3-16.7 mg (104934).
• Meniere disease. Although there is interest in using oral niacin for Meniere disease, there is insufficient reliable information about the clinical effects of niacin for this condition.
• Migraine headache. It is unclear if dietary niacin is beneficial for preventing migraine headaches. Details: Population research in adults has found that high dietary intake of niacin is associated with a 28% lower likelihood of having migraine headaches when compared with low dietary intake of niacin (110495). However, the effect of niacin supplementation on migraines has not been studied.
• Motion sickness. Although there is interest in using oral niacin for motion sickness, there is insufficient reliable information about the clinical effects of niacin for this purpose.
• Parkinson disease. It is unclear if oral niacin is beneficial for improving Parkinson disease symptoms. Details: Low-quality clinical research in adults with Parkinson disease shows that taking slow-release niacin 250 mg orally daily for 12 months improves Parkinson disease motor scores and fatigue scores by 17% and 26%, respectively, when compared with baseline (107944). However, higher quality clinical research shows that taking niacin 250 mg orally daily for 6 months does not improve Parkinson disease motor scores when compared with placebo (107943).
• Retinal vein occlusion. It is unclear if oral niacin is beneficial for improving retinal vein occlusion symptoms. Details: A small case series in patients with chronic retinal vein occlusion shows that taking niacin titrated to 500 mg three times daily for 1 year is associated with reduced central macular thickness and improved visual acuity in over 50% of patients when compared with a control group. The addition of prednisolone eye drops does not alter the outcomes of those taking niacin (96212). The validity of this finding is limited due to the retrospective nature of this study.
• Sickle cell disease. It is unclear if oral niacin is beneficial for improving lipid levels in patients with sickle cell disease. Details: A small clinical study in patients with sickle cell disease shows that taking extended-release niacin titrated to 1.5 grams daily for 12 weeks does not improve vascular function or increase high-density lipoprotein (HDL) or apolipoprotein A-I cholesterol levels when compared with placebo (96209).
• Schizophrenia. Although there is interest in using oral niacin for schizophrenia, there is insufficient reliable information about the clinical effects of niacin for this condition.
• Vertigo. Although there is interest in using oral niacin for vertigo, there is insufficient reliable information about the clinical effects of niacin for this condition. More evidence is needed to rate niacin for these uses.

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LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

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LIKELY SAFE ...when niacin is taken in food or as a supplement in amounts below the tolerable upper intake level (UL) of 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243). ...when prescription products are used orally and appropriately in doses of up to 2 grams daily (12033). CHILDREN:

LIKELY SAFE ...when used orally in amounts that do not exceed the tolerable upper intake level (UL). The ULs of niacin for children are: 1-3 years of age, 10 mg daily; 4-8 years of age, 15 mg daily; 9-13 years of age, 20 mg daily; 14-18 years of age, 30 mg daily (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL). The UL of niacin during pregnancy and lactation is 30 mg daily for 14-18 years of age and 35 mg daily for 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacin during pregnancy or lactation; avoid using.

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

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ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Concomitant use of alcohol and niacin might increase the risk of flushing and hepatotoxicity.  Details Alcohol can exacerbate the flushing and pruritus associated with niacin (4458,11689). Large doses of niacin might also exacerbate liver dysfunction associated with chronic alcohol use. A case report describes delirium and lactic acidosis in a patient taking niacin 3 grams daily who ingested 1 liter of wine (14510). Advise patients to avoid large amounts of alcohol while taking niacin.

ALLOPURINOL (Zyloprim) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as allopurinol.  Details Large doses of niacin can reduce urinary excretion of uric acid, potentially resulting in hyperuricemia (4860,4863,12033). Doses of uricosurics such as allopurinol might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, niacin may have additive effects when used with anticoagulant or antiplatelet drugs.  Details Several cases of clotting factor synthesis deficiency and coagulopathy have been reported in patients taking sustained-release niacin (25915). Also, thrombocytopenia has been reported in patients treated with niacin or niacin plus lovastatin (25916).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Niacin can increase blood glucose levels and may diminish the effects of antidiabetes drugs.  Details Niacin impairs glucose tolerance in a dose-dependent manner, probably by causing or aggravating insulin resistance and increasing hepatic production of glucose (4860,4863,11692,11693). In diabetes patients, niacin 4.5 grams daily for 5 weeks can increase plasma glucose by an average of 16% and glycated hemoglobin (HbA1c) by 21% (4860). However, lower doses of 1.5 grams daily or less appear to have minimal effects on blood glucose (12033). In some patients, glucose levels increase when niacin is started, but then return to baseline when a stable dose is reached (12033,93344). Up to 35% of patients with diabetes may need adjustments in hypoglycemic therapy when niacin is added (4458,4860,4863,11689,12033).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, niacin may increase the risk of hypotension when used with antihypertensive drugs.  Details The vasodilating effects of niacin can cause hypotension (4863,12033,93341). Furthermore, some clinical evidence suggests that a one-hour infusion of niacin can reduce systolic, diastolic, and mean blood pressure in hypertensive patients. This effect is not observed in normotensive patients (25917).

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Likely •  Level of Evidence = B Large doses of aspirin might alter the clearance of niacin.  Details Aspirin is often used with niacin to reduce niacin-induced flushing (4458,11689). Doses of 80-975 mg aspirin have been used, but 325 mg appears to be optimal (4458,4852,4853,11689). Aspirin also seems to reduce the clearance of niacin by competing for glycine conjugation. Taking aspirin 1 gram seems to reduce niacin clearance by 45% (14524). This is probably a dose-related effect and not clinically significant with the more common aspirin dose of 325 mg (11689,14524).

BILE ACID SEQUESTRANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Bile acid sequestrants can bind niacin and decrease absorption. Separate administration by 4-6 hours to avoid an interaction.  Details In vitro studies show that colestipol (Colestid) binds about 98% of available niacin and cholestyramine (Questran) binds 10% to 30% (14511).

GEMFIBROZIL (Lopid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and gemfibrozil might increase the risk of myopathy in some patients.  Details A case of myopathy from concomitant use of niacin and gemfibrozil has been reported (25920). Niacin alone has also been associated with cases of myopathy (26100,26111). Using gemfibrozil with niacin might further increase the risk of developing myopathy.

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and hepatotoxic drugs might increase the risk of hepatotoxicity.  Details Niacin has been associated with cases of liver toxicity, especially when used in pharmacologic doses (4863,11689,11691,25929,25930,25931). Sustained-release niacin preparations appear to be associated with a higher risk of hepatotoxicity than immediate-release niacin (11691,25930,25931,93342).

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and statins might increase the risk of myopathy and rhabdomyolysis in some patients.  Details Some case reports have raised concerns that niacin might increase the risk of myopathy and rhabdomyolysis when combined with statins (14508,25918). However, a significantly increased risk of myopathy has not been demonstrated in clinical trials, including those using an FDA-approved combination of lovastatin and niacin (Advicor) (7388,11689,12033,14509).

PROBENECID (Benemid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as probenecid.  Details Large doses of niacin reduce urinary excretion of uric acid, potentially causing hyperuricemia (4863,12033). Doses of uricosurics such as probenecid might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).

SULFINPYRAZONE (Anturane) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, niacin might antagonize the therapeutic effects of uricosurics such as sulfinpyrazone.  Details Large doses of niacin reduce urinary excretion of uric acid, potentially causing hyperuricemia (4863,12033). Doses of uricosurics such as sulfinpyrazone might need to be increased to maintain control of gout in patients who start taking niacin (4458). People who have frequent attacks of gout despite uricosuric therapy should avoid niacin (4863).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, niacin might antagonize the therapeutic effects of thyroid hormones.  Details Clinical research and case reports suggests that taking niacin can reduce serum levels of thyroxine-binding globulin by up to 25% and moderately reduce levels of thyroxine (T4) (25916,25925,25926,25928). Patients taking thyroid hormone for hypothyroidism might need dose adjustments when using niacin.

TRANSDERMAL NICOTINE (Nicoderm) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of niacin and transdermal nicotine might increase the risk of flushing and dizziness.  Details Niacin and nicotine can both cause flushing and dizziness (496,96211).

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General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

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General ...Orally, niacin is well tolerated in the amounts found in foods. It is also generally well tolerated in prescription doses when monitored by a healthcare provider.
Most Common Adverse Effects:
Orally: Flushing, gastrointestinal complaints (abdominal pain, constipation, diarrhea, heartburn, nausea, vomiting), and elevated liver enzymes.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity, myopathy, thrombocytopenia, and vision changes.

Cardiovascular ...Orally, flushing is a common dose-related adverse reaction to niacin. A large meta-analysis of clinical studies shows that up to 70% of patients may experience flushing (96211). Although flushing can occur with doses of niacin as low as 30 mg daily, it is more common with the larger doses used for treatment of dyslipidemia. The flushing reaction is due to prostaglandin-induced blood vessel dilation and can also include symptoms of burning, tingling, urticaria, erythema, pain, and itching of the face, arms, and chest. There may also be increased intracranial blood flow and headache (4889,26089,93341,104933). Onset is highly variable and ranges from within 30 minutes to as long as 6 weeks after the initial dose (6243). Flushing can be minimized via various strategies, including taking doses with meals, slow dose titration, using extended release formulations, pretreating with non-steroidal anti-inflammatory drugs, taking regular-release niacin with meals, or taking the sustained-release product at bedtime (4852,4853,4854,4857,4858,25922,26073,26084). Flushing often diminishes with continued use but can recur when niacin is restarted after missed doses (4863,6243,26081). The vasodilating effects of niacin can also cause hypotension, dizziness, tachycardia, arrhythmias, syncope, and vasovagal attacks, especially in patients who are already taking antihypertensive drugs (4863,12033,93341,110494).
High doses of niacin can raise homocysteine levels. A 17% increase has been reported with 1 gram daily and a 55% increased has been reported with 3 grams daily. Elevated homocysteine levels are an independent risk factor for cardiovascular disease (490); however, the clinical significance of this effect is unknown. A large-scale study (AIM-HIGH) found that patients receiving extended-release niacin (Niaspan) 1500-2000 mg daily with a statin had an over two-fold increased risk of ischemic stroke (1.6%) when compared with those receiving only simvastatin (0.7%). However, when the risk was adjusted for confounding factors, niacin was not found to be associated with increased stroke risk (17627,93354). A meta-analysis of three clinical trials conducted in approximately 29,000 patients showed a higher risk of mortality in patients taking niacin in addition to a statin when compared with a statin alone. However, with a p-value of 0.05 and confidence interval including 1, the validity of this finding remains unclear (97308).

Endocrine ...Orally, niacin can impair glucose tolerance in a dose-dependent manner. Dosages of 3-4 grams daily appear to increase blood glucose in patients with or without diabetes, while dosages of 1.5 grams daily or less have minimal effects (12033). Niacin is thought to impair glucose tolerance by increasing insulin resistance or increasing hepatic output of glucose (4863,11692,11693). In patients with diabetes, niacin 4.5 grams daily for 5 weeks has been associated with an average 16% increase in plasma glucose and 21% increase in glycated hemoglobin (HbA1C) (4860). Up to 35% of patients with diabetes may need to increase the dose or number of hypoglycemic agents when niacin is started (4458,4860,4863,11689,12033). Occasionally, severe hyperglycemia requiring hospitalization can occur (11693). In patients with impaired fasting glucose levels, niacin may also increase fasting blood glucose, and adding colesevelam might attenuate this effect (93343).
Although patients without diabetes seem to only experience small and clinically insignificant increases in glucose (4458), niacin might increase their risk of developing diabetes. A meta-analysis of clinical research involving over 26,000 patients shows that using niacin over 5 years is associated with increased prevalence of new onset type 2 diabetes at a rate of 1 additional case of diabetes for every 43 patients treated with niacin (96207). This finding is limited because the individual trials were not designed to assess diabetes risk and the analysis could not be adjusted for confounding factors like obesity. One small clinical study shows that taking extended-release niacin with ezetimibe/simvastatin does not increase the risk of a new diagnosis of diabetes or need for antidiabetic medication when compared with ezetimibe/simvastatin alone after 16 months (93344). This may indicate that the increased risk of developing diabetes is associated with niacin use for more than 16 months.
Niacin therapy has also been linked with hypothyroidism and its associated alterations in thyroid hormone and binding globulin tests (such as decreased total serum thyroxine, increased triiodothyronine, decreased thyroxine-binding globulin levels, and increased triiodothyronine uptake) (25916,25925,25926,25928).

Gastrointestinal ...Orally, large doses of niacin can cause gastrointestinal disturbances including nausea, vomiting, bloating, heartburn, abdominal pain, anorexia, diarrhea, constipation, and activation of peptic ulcers (4458,4863,12033,26083,93341,96211). These effects may be reduced by taking the drug with meals or antacid, and usually disappear within two weeks of continued therapy (4851,26094). Gastrointestinal effects may be more common with time-release preparations of niacin (11691).

Hematologic ...Orally, sustained-release niacin has been associated with cases of reversible coagulopathy, mild eosinophilia, and decreased platelet counts (4818,25915,26097,93340). Also, there have been reports of patients who developed leukopenia while taking niacin for the treatment of hypercholesterolemia (25916).

Hepatic ...Orally, niacin is associated with elevated liver function tests and jaundice, especially with doses of 3 grams/day or more, and when doses are rapidly increased (4458,4863,6243). The risk of hepatotoxicity appears to be higher with slow-release and extended-release products (4855,4856,4863,6243,11691,12026,12033,93342). Niacin should be discontinued if liver function tests rise to three times the upper limit of normal (4863). There are rare cases of severe hepatotoxicity with fulminant hepatitis and encephalopathy due to niacin (4863,6243,11691). Also, there is at least one case of niacin-induced coagulopathy resulting from liver injury without liver enzyme changes (93340).

Musculoskeletal ...Orally, niacin has been associated with elevated creatine kinase levels (4818,4888). Also, several cases of niacin-induced myopathy have been reported (26100,26111). Concomitant administration of niacin and HMG-CoA reductase inhibitors may increase the risk of myopathy and rhabdomyolysis (14508,25918,26111); patients should be monitored closely.

Neurologic/CNS ...Orally, high-dose niacin has been associated with cases of neuropsychiatric adverse events such as extreme pain and psychosis. Two 65-year-old males taking niacin orally for 5 months for the treatment of dyslipidemias developed severe dental and gingival pain. The pain was relieved by the discontinuation of niacin. The pain was thought to be due to inflammation and pain referral to the teeth (4862). In one case report, a 52-year-old male with no history of psychiatric illness who initially complained of hot flushes when taking niacin 500 mg daily, presented with an acute psychotic episode involving mania after niacin was increased to 1000 mg daily (93350).

Ocular/Otic ...Orally, chronic use of large amounts of niacin has been associated with dry eyes, toxic amblyopia, blurred vision, eyelid swelling, eyelid discoloration, loss of eyebrows and eyelashes, proptosis, keratitis, macular edema, and cystic maculopathy, which appear to be dose-dependent and reversible (4863,6243,26112).

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