Anton J. M. de Craen

Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials

BACKGROUND Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. METHODS We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. FINDINGS We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. INTERPRETATION Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. FUNDING None.

Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies.

BACKGROUND Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated to what extent metabolic syndrome and its individual components were related to risk for these two diseases in elderly populations. METHODS We related metabolic syndrome (defined on the basis of criteria from the Third Report of the National Cholesterol Education Program) and its five individual components to the risk of events of incident cardiovascular disease and type 2 diabetes in 4812 non-diabetic individuals aged 70-82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). We corroborated these data in a second prospective study (the British Regional Heart Study [BRHS]) of 2737 non-diabetic men aged 60-79 years. FINDINGS In PROSPER, 772 cases of incident cardiovascular disease and 287 of diabetes occurred over 3.2 years. Metabolic syndrome was not associated with increased risk of cardiovascular disease in those without baseline disease (hazard ratio 1.07 [95% CI 0.86-1.32]) but was associated with increased risk of diabetes (4.41 [3.33-5.84]) as was each of its components, particularly fasting glucose (18.4 [13.9-24.5]). Results were similar in participants with existing cardiovascular disease. In BRHS, 440 cases of incident cardiovascular disease and 105 of diabetes occurred over 7 years. Metabolic syndrome was modestly associated with incident cardiovascular disease (relative risk 1.27 [1.04-1.56]) despite strong association with diabetes (7.47 [4.90-11.46]). In both studies, body-mass index or waist circumference, triglyceride, and glucose cutoff points were not associated with risk of cardiovascular disease, but all five components were associated with risk of new-onset diabetes. INTERPRETATION Metabolic syndrome and its components are associated with type 2 diabetes but have weak or no association with vascular risk in elderly populations, suggesting that attempts to define criteria that simultaneously predict risk for both cardiovascular disease and diabetes are unhelpful. Clinical focus should remain on establishing optimum risk algorithms for each disease.

Identification of seven loci affecting mean telomere length and their association with disease

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10−8). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5–35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Whole-genome sequence variation, population structure and demographic history of the Dutch population

Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage (∼13×) and trio design enabled extensive characterization of structural variation, including midsize events (30–500 bp) previously poorly catalogued and de novo mutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies.

Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis.

OBJECTIVES This study was designed to determine whether statins reduce all-cause mortality in elderly patients with coronary heart disease. BACKGROUND Statins continue to be underutilized in elderly patients because evidence has not consistently shown that they reduce mortality. METHODS We searched 5 electronic databases, the Internet, and conference proceedings to identify relevant trials. In addition, we obtained unpublished data for the elderly patient subgroups from 4 trials and for the secondary prevention subgroup from the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial. Inclusion criteria were randomized allocation to statin or placebo, documented coronary heart disease, > or =50 elderly patients (defined as age > or =65 years), and > or =6 months of follow-up. Data were analyzed with hierarchical Bayesian modeling. RESULTS We included 9 trials encompassing 19,569 patients with an age range of 65 to 82 years. Pooled rates of all-cause mortality were 15.6% with statins and 18.7% with placebo. We estimated a relative risk reduction of 22% over 5 years (relative risk [RR] 0.78; 95% credible interval [CI] 0.65 to 0.89). Furthermore, statins reduced coronary heart disease mortality by 30% (RR 0.70; 95% CI 0.53 to 0.83), nonfatal myocardial infarction by 26% (RR 0.74; 95% CI 0.60 to 0.89), need for revascularization by 30% (RR 0.70; 95% CI 0.53 to 0.83), and stroke by 25% (RR 0.75; 95% CI 0.56 to 0.94). The posterior median estimate of the number needed to treat to save 1 life was 28 (95% CI 15 to 56). CONCLUSIONS Statins reduce all-cause mortality in elderly patients and the magnitude of this effect is substantially larger than had been previously estimated.

Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study.

Objectives To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease. Design The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up. Setting General population of the city of Leiden, the Netherlands. Participants Population based sample of participants aged 85 years (215 women and 87 men) with no history of cardiovascular disease; no other exclusion criteria. Main measurements Cause specific mortality was registered during follow-up. All classic risk factors included in the Framingham risk score (sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and electrocardiogram based left ventricular hypertrophy), as well as plasma concentrations of the new biomarkers homocysteine, folic acid, C reactive protein, and interleukin 6, were assessed at baseline. Results During follow-up, 108 of the 302 participants died; 32% (35/108) of deaths were from cardiovascular causes. Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score (area under receiver operating characteristic curve 0.53, 95% confidence interval 0.42 to 0.63) or in a newly calibrated model (0.53, 0.43 to 0.64). Of the new biomarkers studied, homocysteine had most predictive power (0.65, 0.55 to 0.75). Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power. Conclusions In very old people from the general population with no history of cardiovascular disease, concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. These preliminary findings warrant validation in a separate cohort.

Handgrip strength as a predictor of functional, psychological and social health. A prospective population-based study among the oldest old

BACKGROUND muscle wasting is associated with a detrimental outcome in older people. Muscle strength measurements could be useful as part of a clinical evaluation of oldest old patients to determine who are most at risk of accelerated decline in the near future. OBJECTIVE this study aimed to assess if handgrip strength predicts changes in functional, psychological and social health among oldest old. DESIGN the Leiden 85-plus Study is a prospective population-based follow-up study. SUBJECTS five-hundred fifty-five, all aged 85 years at baseline, participated in the study. METHODS handgrip strength was measured with a handgrip strength dynamometer. Functional, psychological and social health were assessed annually. Baseline data on chronic diseases were obtained from the treating physician, pharmacist, electrocardiogram and blood sample analysis. RESULTS at age 85, lower handgrip strength was correlated with poorer scores in functional, psychological and social health domains (all, P < 0.001). Lower baseline handgrip strength predicted an accelerated decline in activities of daily living (ADL) and cognition (both, P <or= 0.001), but not in social health (P > 0.30). CONCLUSION poor handgrip strength predicts accelerated dependency in ADL and cognitive decline in oldest old. Measuring handgrip strength could be a useful instrument in geriatric practice to identify those oldest old patients at risk for this accelerated decline.

Evidence of genetic enrichment for exceptional survival using a family approach : the Leiden Longevity study

We conducted a sib pair study in very old subjects for the purpose of mapping longevity loci. In the present analysis, we explore whether our recruitment strategy has resulted in a population enriched for a heritable component for exceptional longevity. Our study includes families with at least two long-living siblings (men aged 89 years or above; women aged 91 years or above). Data were collected on date of birth and, if applicable, date of death of parents, brothers and sisters, offspring, and spouses of the long-living participants. Standardised mortality ratios (SMRs) compared with the general Dutch population, were calculated. The SMR for all siblings of the long-living participants was 0.66 (95% CI 0.60–0.73). A similar survival benefit was also observed in the parents (SMR=0.76, 95% CI 0.66–0.87) and in the offspring of the long-living subjects (SMR=0.65, 95% CI 0.51–0.80). The SMR of the spouses of the long-living subjects was 0.95 (95% CI 0.82–1.12). The familial clustering of extended survival is unlikely to be caused by ascertainment bias, because in all analyses the long-living participants were excluded. Moreover, it is also unlikely to be caused by environmental factors, because the spouses of the long-living participants had a mortality risk comparable with the general Dutch population, whereas they share the same environment. We conclude that our sample is genetically enriched for extreme survival.

Handgrip strength and mortality in the oldest old population: the Leiden 85-plus study

Background: Poor muscular strength has been shown to be associated with increased morbidity and mortality in diverse samples of middle-aged and elderly people. However, the oldest old population (i.e., over 85 years) is underrepresented in such studies. Our objective was to assess the association between muscular strength and mortality in the oldest old population. Methods: We included 555 participants (65% women) from the Leiden 85-plus study, a prospective population-based study of all 85-year-old inhabitants of Leiden, Netherlands. We measured the handgrip strength of participants at baseline and again at age 89 years. We collected baseline data on comorbidities, functional status, levels of physical activity, and adjusted for potential confounders. During the follow-up period, we collected data on mortality. Results: During a follow-up period of 9.5 years (range 8.5–10.5 years), 444 (80%) participants died. Risk for all-cause mortality was elevated among participants in the lowest tertile of handgrip strength at age 85 years (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.00–1.82, p = 0.047) and the lowest two tertiles of handgrip strength at age 89 years (HR 2.04, CI 1.24–3.35, p = 0.005 and HR 1.73, CI 1.11–2.70, p = 0.016). We also observed significantly increased mortality among participants in the tertile with the highest relative loss of handgrip strength over four years (HR 1.72, CI 1.07–2.77, p = 0.026). Interpretation: Handgrip strength, a surrogate measurement of overall muscular strength, is a predictor of all-cause mortality in the oldest old population and may serve as a convenient tool for prognostication of mortality risk among elderly people.

Systemic Markers of Inflammation and Cognitive Decline in Old Age

OBJECTIVES: To investigate whether higher circulating levels of C‐reactive protein (CRP), interleukin‐6 (IL‐6), and α1‐antichymotrypsin (ACT) are associated with worse cognitive function and decline in old age.