Matti J. Tikkanen

Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.

CONTEXT A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus. OBJECTIVE To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. DATA SOURCES We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators. STUDY SELECTION We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year. DATA EXTRACTION Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I(2) statistic. RESULTS In 5 statin trials with 32,752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. CONCLUSION In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.

Effect of statins on C-reactive protein in patients with coronary artery disease

patients who had SCLC-LEMS with a matched group of patients who had SCLC only. Survival data were available for 15 SCLC-LEMS patients seen in a neuromuscular clinic since 1987. All had biopsyproven SCLC, typical clinical and electromyographic features of LEMS, and raised titres of anti-P/Q-type voltagegated calcium channel antibodies detectable by RIA. Hospital records were available for SCLC patients who had no neurological illness and who had participated in randomised SCLC treatment trials between 1988 and 1997 at the Middlesex and University College Hospitals, London, UK. We matched each of the 15 SCLC-LEMS patients with five or six SCLC-only patients (n=81) for sex, age at SCLC diagnosis, tumour extent (limited or extensive), and treatment (chemotherapy of radiotherapy). Computer matching was done by medical staff masked to the SCLCLEMS patients’ survival data. Three SCLC-LEMS patients had extensive disease at tumour diagnosis; four did not receive specific tumour treatment because they died soon after diagnosis. With one exception, symptoms of LEMS predated the diagnosis of SCLC (range 0·3–4·7 years). At the time of the study, four SCLC-LEMS patients were alive with no evidence of tumour recurrence after a median of 6 years (range 1·5–8·5) since tumour detection and treatment. Kaplan-Meier survival estimates (figure) show a significantly shorter median survival time from the diagnosis of SCLC in SCLC-only patients (10 months) than in the SCLC-LEMS patients (17·3 months, p=0·048, Log-rank test). Factors contributing to this better survival rate in SCLC-LEMS might be a slower rate of growth in tumours that provoke LEMS, or lead-time bias, in that once LEMS is diagnosed, the vigilance for associated lung cancer may be increased. In SCLC-LEMS, however, tumour macrophage infiltration is greater and MHC class I antigen expression less in patients with SCLC only, which implies more tumour-cell destruction in LEMS. Moreover, the time between onset of LEMS and clinical presentation of the tumour can be longer than would be predicted from the estimated ratio of tumour growth on the basis of radiographic analysis of non-LEMS patients. These observations and our survival data support the view that the autoimmune response in LEMS retards tumour growth. Therefore, the recognition of LEMS in any patients with SCLC could have important implications for long-term outcome after antitumour therapy.

Dietary soy-derived isoflavone phytoestrogens: Could they have a role in coronary heart disease prevention?

Soy protein-containing foods are a rich source of isoflavone phytoestrogens, such as genistein and daidzein. There is great interest in these substances, as lower rates of chronic diseases, including coronary heart disease, have been associated with high dietary intake of soy-containing foods. Soy phytoestrogens bind weakly to estrogen receptors, and some bind more strongly to estrogen receptor-beta compared with estrogen receptor-alpha. A meta-analysis has indicated that isoflavone phytoestrogens lowered plasma cholesterol concentrations in subjects with initially elevated levels, but had little effect in subjects with normal cholesterol concentrations. These substances reportedly may also have beneficial effects on arterial endothelial function. In addition to these potentially antiatherogenic effects, many laboratories are investigating other possible mechanisms, including antioxidative and antiproliferative properties of these substances. We have shown that dietary supplementation with soy-derived isoflavones reduced the in vitro oxidation susceptibility of low-density lipoprotein (LDL). To further explore this phenomenon, we incorporated genistein and daidzein into LDL molecules in vitro with the aid of an artificial transfer system. However, it was necessary to convert the isoflavone molecules to fat-soluble derivatives, fatty acid esters (analogous to esterified endogenous estrogens, which are known to occur in vivo), to achieve significant incorporation. The LDLs containing esterified isoflavones were shown to be less susceptible to oxidation in vitro than native LDL. We also employed U937 cell cultures for investigating the effects of isoflavone-containing LDLs on cell proliferation. Some of these LDLs exhibited antiproliferative effects in cultured U937 cells. In summary, lipophilic phytoestrogen derivatives could be incorporated into LDLs, increasing their oxidation resistance and antiproliferative efficacy ex vivo, both of which are, in theory, antiatherogenic effects. Further studies are needed to assess to what extent analogous effects could be produced in vivo and whether such substances have a role in hormone replacement and coronary heart disease prevention in postmenopausal women.

Regulation of hepatic lipase and serum lipoproteins by sex steroids

The influence of sex steroids on the serum lipoprotein pattern was recognized more than 30 years ago, and it still remains among the areas of major interest. This is because of the compatible sex difference in plasma lipoprotein pattern and in coronary heart disease risk. Recent discoveries of the role of hepatic lipase in lipoprotein metabolism have elucidated mechanisms behind sex steroid-induced changes in lipoproteins. These steroids regulate the activity of hepatic lipase, an enzyme bound to the endothelial cells of liver sinusoids. Hepatic lipase has a central role in the removal of phospholipids and triglycerides from subfractions of high-density lipoprotein (HDL2) particles, but it may also function in the lipolysis of triglyceride-rich particles. Some older and more recent developments in this area will be reviewed.

The effect of Simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle*

It has been hypothesized that treating hypercholesterolemic patients with statins will lead not only to a reduction in cholesterol, but also to inhibited synthesis of other compounds which derive from the synthetic pathway of cholesterol. In theory, this could further lead to ubiquinone deficiency in muscle cell mitochondria, disturbing normal cellular respiration and causing adverse effects such as rhabdomyolysis. Furthermore, ubiquinone is one of the lipophilic antioxidants in low-density lipoprotein (LDL), and therefore it has also been hypothesized that statin treatment will reduce the antioxidant capacity of LDL. We investigated the effect of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentrations of high-energy phosphates and ubiquinone by performing biopsies in 19 hypercholesterolemic patients. Parallel assays were performed in untreated control subjects. The muscle high-energy phosphate and ubiquinone concentrations assayed after simvastatin treatment were similar to those observed at baseline and did not differ from the values obtained in control subjects at the beginning and end of follow-up. These results do not support the hypothesis of diminished isoprenoid synthesis or energy generation in muscle cells during simvastatin treatment. Furthermore, the results of analysis of antioxidant concentrations in LDL before and after simvastatin treatment indicate that the antioxidant capacity of LDL is maintained in simvastatin-treated patients.

Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans

Statins, which are commonly used drugs for hypercholesterolemia, inhibit 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, the rate‐limiting enzyme in cholesterol synthesis. Important nonsterol compounds, such as ubiquinone, are also derived from the same synthetic pathway. Therefore it has been hypothesized that statin treatment causes ubiquinone deficiency in muscle cells, which could interfere with cellular respiration causing severe adverse effects. In this study we observed decreased serum levels but an enhancement in muscle tissue ubiquinone levels in patients with hypercholesterolemia after 4 weeks of simvastatin treatment. These results indicate that ubiquinone supply is not reduced during short‐term statin treatment in the muscle tissue of subjects in whom myopathy did not develop.

Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians.

We determined the common polymorphism of apolipoprotein E (E2, E3, and E4), apolipoprotein B Xba I polymorphism, and apolipoprotein C-III Sst I polymorphism in almost all Finnish centenarians alive in 1991 (n = 179/185). Plasma lipid and lipoprotein levels in different apolipoprotein genotypes were also measured. In comparison with younger Finnish populations studied previously, the frequency of the apolipoprotein E epsilon 2 allele was almost twice as high (7.0% versus 4.1%; P < .05) and that of the epsilon 4 allele only approximately one third as high (8.4% versus 22.7%; P < .001) in the centenarians. Plasma cholesterol and high-density lipoprotein cholesterol levels tended to be lowest in the group with the epsilon 2 allele (4.33 mmol/L and 1.41 mmol/L, respectively), intermediate in those with the epsilon 3 allele (4.57 mmol/L and 1.48 mmol/L, respectively), and highest in those with the epsilon 4 allele (4.82 mmol/L and 1.60 mmol/L, respectively). The frequencies of the apolipoprotein B X1 and X2 alleles (Xba I restriction site absent or present, respectively) among the centenarians and among the young Finns were not significantly different, whereas the apolipoprotein C-III S2 allele (Sst I restriction site present) occurred more often in the centenarians (frequency, 12.9%) than in the youngest reference population (frequency, 8.8%; P < .05). Centenarians with the apolipoprotein B X2X2 genotype and apolipoprotein E4 phenotype had a higher mean plasma cholesterol level than those with the X1X1 genotype and E2 phenotype (5.24 versus 3.43 mmol/L; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein E4 homozygosity predisposes to serum cholesterol elevation during high fat diet

The hypothesis that apolipoprotein E (apo E)-isoform-related differences in plasma and LDL cholesterol concentrations are due to differential responses to dietary lipids was explored in 110 North Karelian subjects who had previously participated in dietary intervention studies. This was accomplished by collecting fresh blood samples for apo E phenotyping and by re-analysis of the original plasma lipid data according to apo E phenotypes. During high fat, high cholesterol baseline (p = 0.003) and switchback diets (p = 0.002), plasma cholesterol correlated inversely with the sum of subscript numbers (e.g., apo E3/4 = 7). Thus, subjects with the apo E4/4 phenotype had the highest (7.63 +/- 1.32 mmol/l), and subjects with the apo E3/2 phenotype had the lowest baseline levels of plasma cholesterol (5.85 +/- 1.48 mmol/l). This association became weaker during a low fat, low cholesterol diet intervention (p = 0.069). Greater reductions in plasma cholesterol occurred in subjects homozygous for the apo epsilon 4 allele (-1.84 mmol/l) as compared to subjects with other genotypes (-1.13 mmol/l) (p = 0.0097). Moreover, these subjects responded to the switchback diet by greater increases in plasma cholesterol (1.52 mmol/l) than others (0.92 mmol/l, p = 0.0141). The results suggest that the effect of apo epsilon genotype on plasma cholesterol is modulated by dietary fat and cholesterol intake.

Different effects of two progestins on plasma high density lipoprotein (HDL2) and postheparin plasma hepatic lipase activity.

Two progestins with different androgenic activity were compared for their effects on plasma high density lipoproteins and postheparin plasma lipase activities in premenopausal women. Levonorgestrel, a nortestosterone-derived steroid with androgenic activity reduced plasma HDL cholesterol by 17% (P less than 0.05) and HDL2 cholesterol by 30% (P less than 0.05), without changing the HDL3 cholesterol concentration. At the same time the postheparin plasma hepatic lipase activity was increased by 56% (P less than 0.01) whereas the lipoprotein lipase was not changed. None of these effects was reproduced during administration of medroxyprogesterone acetate, a progestin with low androgenic activity. The results suggest, first, that the decrease of HDL cholesterol observed during treatment with progestins is related to the androgenic activity of the steroid used, and, second, that the change in HDL (HDL2) is caused by androgen-induced increase of hepatic lipase activity.

Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors.

Serum ubiquinone levels were studied during long- and short-term treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in 17 men with primary non-familial hypercholesterolaemia. The serum ubiquinone levels were determined after the patients had received simvastatin (20–40 mg per day) for 4.7 years, after a 4 week treatment pause and again after they had resumed treatment with lovastatin (20–40 mg per day) for 12 weeks.During the treatment pause the average serum ubiquinone levels increased by 32%; resumption of treatment caused a reduction of 25%. The changes in the levels of ubiquinone and serum total cholesterol as well as those of ubiquinone and low-density lipoprotein cholesterol were closely parallel.This suggested that changes in serum ubiquinone reflected changes in cholesterol-containing serum lipoproteins which could serve as carrier vehicles for ubiquinone. After long-term simvastain treatment and after short-term lovastatin treatment, average serum ubiquinone levels (1.16 and 1.22 mg·l-1, respectively) were similar to that observed in a group of apparently healthy middle-aged men (1.16 mg·l-1).