Prediabetes as a risk factor for all-cause and cause-specific mortality: a prospective analysis of 115,919 adults without diabetes in Mexico City.

BACKGROUND: Prediabetes has been associated with increased all-cause and cardiovascular mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations. METHODS: We analyzed data from 115,919 adults without diabetes (diagnosed or undiagnosed) aged 35-84 years who participated in the Mexico City Prospective Study between 1998 and 2004. Participants were followed until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c 5.7% to 6.4%) and the International Expert Committee (IEC, HbA1c 6.0-6.4%) definitions. Cox regression adjusted for confounders was used to estimate all-cause and cause-specific mortality rate ratios (RR) at ages 35-74 years associated with prediabetes. FINDINGS: During 2,085,392 person-years of follow-up (median in survivors 19 years), there were 6,810 deaths at ages 35-74, including 1,742 from cardiovascular disease, 892 from renal disease and 108 from acute diabetic crises. Of 110,405 participants aged 35-74 years at recruitment, 28,852 (26%) had ADA-defined prediabetes and 7,203 (7%) had IEC-defined prediabetes. Compared with those without prediabetes, individuals with prediabetes had higher risk of all-cause mortality at ages 35-74 years (RR 1.13, 95% CI 1.07-1.19 for ADA-defined prediabetes and RR 1.28, 1.18-1.39 for IEC-defined prediabetes), as well as increased risk of cardiovascular mortality (RR 1.22 [1.10-1.35] and 1.42 [1.22-1.65], respectively), renal mortality (RR 1.35 [1.08-1.68] and 1.69 [1.24-2.31], respectively), and death from an acute diabetic crisis (RR 2.63 [1.76-3.94] and 3.43 [2.09-5.62], respectively). RRs were larger at younger than at older ages, and similar for men compared to women. The absolute excess risk associated with ADA and IEC-defined prediabetes at ages 35-74 accounted for6% and 3% of cardiovascular deaths respectively, 10% and 5% of renal deaths respectively, and 31% and 14% of acute diabetic deaths respectively. INTERPRETATION: Prediabetes is a significant risk factor for all-cause, cardiovascular, renal, and acute diabetic deaths in Mexican adults. Identification and timely management of individuals with prediabetes for targeted risk reduction could contribute to reducing premature mortality from cardiometabolic causes in this population. FUNDING: Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, UK Medical Research Council. Instituto Nacional de Geriatría (Mexico City).

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases.

The etiology of prostate cancer, the second most common cancer in men globally, has a strong heritable component. While rare coding germline variants in several genes have been identified as risk factors from candidate gene and linkage studies, the exome-wide spectrum of causal rare variants remains to be fully explored. To more comprehensively address their contribution, we analysed data from 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline exome/genome sequencing and one cohort with imputed array data from a population enriched in low-frequency deleterious variants. Our gene-level collapsing analysis revealed that rare damaging variants in SAMHD1 as well as genes in the DNA damage response pathway ( BRCA2 , ATM and CHEK2 ) are associated with the risk of overall prostate cancer. We also found that rare damaging variants in AOX1 and BRCA2 were associated with increased severity of prostate cancer in a case-only analysis of aggressive versus non-aggressive prostate cancer. At the single-variant level, we found rare non-synonymous variants in three genes ( HOXB13 , CHEK2 , BIK ) significantly associated with increased risk of overall prostate cancer and in four genes ( ANO7 , SPDL1 , AR , TERT ) with decreased risk. Altogether, this study provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

Genotyping, sequencing and analysis of 140,000 adults from Mexico City.

The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.

Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

Educational and social inequalities and cause-specific mortality in Mexico City: a prospective study.

BACKGROUND: Social inequalities in adult mortality have been reported across diverse populations, but there is no large-scale prospective evidence from Mexico. We aimed to quantify social, including educational, inequalities in mortality among adults in Mexico City. METHODS: The Mexico City Prospective Study recruited 150 000 adults aged 35 years and older from two districts of Mexico City between 1998 and 2004. Participants were followed up until Jan 1, 2021 for cause-specific mortality. Cox regression analysis yielded rate ratios (RRs) for death at ages 35-74 years associated with education and examined, in exploratory analyses, the mediating effects of lifestyle and related risk factors. FINDINGS: Among 143 478 participants aged 35-74 years, there was a strong inverse association of education with premature death. Compared with participants with tertiary education, after adjustment for age and sex, those with no education had about twice the mortality rate (RR 1·84; 95% CI 1·71-1·98), equivalent to approximately 6 years lower life expectancy, with an RR of 1·78 (1·67-1·90) among participants with incomplete primary, 1·62 (1·53-1·72) with complete primary, and 1·34 (1·25-1·42) with secondary education. Education was most strongly associated with death from renal disease and acute diabetic crises (RR 3·65; 95% CI 3·05-4·38 for no education vs tertiary education) and from infectious diseases (2·67; 2·00-3·56), but there was an apparent higher rate of death from all specific causes studied with lower education, with the exception of cancer for which there was little association. Lifestyle factors (ie, smoking, alcohol drinking, and leisure time physical activity) and related physiological correlates (ie, adiposity, diabetes, and blood pressure) accounted for about four-fifths of the association of education with premature mortality. INTERPRETATION: In this Mexican population there were marked educational inequalities in premature adult mortality, which appeared to largely be accounted for by lifestyle and related risk factors. Effective interventions to reduce these risk factors could reduce inequalities and have a major impact on premature mortality. FUNDING: Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, and the UK Medical Research Council Population Health Research Unit.

Diabetes and infectious disease mortality in Mexico City.

INTRODUCTION: Although higher risks of infectious diseases among individuals with diabetes have long been recognized, the magnitude of these risks is poorly described, particularly in lower income settings. This study sought to assess the risk of death from infection associated with diabetes in Mexico. RESEARCH DESIGN AND METHODS: Between 1998 and 2004, a total of 159 755 adults ≥35 years were recruited from Mexico City and followed up until January 2021 for cause-specific mortality. Cox regression yielded adjusted rate ratios (RR) for death due to infection associated with previously diagnosed and undiagnosed (HbA1c ≥6.5%) diabetes and, among participants with previously diagnosed diabetes, with duration of diabetes and with HbA1c. RESULTS: Among 130 997 participants aged 35-74 and without other prior chronic diseases at recruitment, 12.3% had previously diagnosed diabetes, with a mean (SD) HbA1c of 9.1% (2.5%), and 4.9% had undiagnosed diabetes. During 2.1 million person-years of follow-up, 2030 deaths due to infectious causes were recorded at ages 35-74. Previously diagnosed diabetes was associated with an RR for death from infection of 4.48 (95% CI 4.05-4.95), compared with participants without diabetes, with notably strong associations with death from urinary tract (9.68 (7.07-13.3)) and skin, bone and connective tissue (9.19 (5.92-14.3)) infections and septicemia (8.37 (5.97-11.7)). In those with previously diagnosed diabetes, longer diabetes duration (1.03 (1.02-1.05) per 1 year) and higher HbA1c (1.12 (1.08-1.15) per 1.0%) were independently associated with higher risk of death due to infection. Even among participants with undiagnosed diabetes, the risk of death due to infection was nearly treble the risk of those without diabetes (2.69 (2.31-3.13)). CONCLUSIONS: In this study of Mexican adults, diabetes was common, frequently poorly controlled, and associated with much higher risks of death due to infection than observed previously, accounting for approximately one-third of all premature mortality due to infection.

Body Composition and Risk of Vascular-Metabolic Mortality Risk in 113 000 Mexican Men and Women Without Prior Chronic Disease.

Background Body-mass index is the sum of fat mass index (FMI) and lean mass index (LMI), which vary by age, sex, and impact on disease outcomes. We investigated the separate and joint relevance of FMI and LMI with vascular-metabolic causes of death in Mexican adults. Methods and Results A total of 113 025 adults aged 35 to 74 years and free from diabetes or other chronic diseases when recruited into the Mexico City Prospective Study were followed for 19 years. Cox models estimated sex-specific death rate ratios from vascular-metabolic causes after adjustment for confounders and exclusion of the first 5 years of follow-up. To account for the strong correlation between FMI and LMI, additional models estimated rate ratios associated with "residual FMI" and "residual LMI" (ie, the residuals from linear regression analyses of FMI on LMI, or vice versa). In both sexes, higher FMI and LMI were associated with higher risks of vascular-metabolic mortality. For a given (ie, fixed) level of LMI, the rate ratio (95% CI) for vascular-metabolic mortality per 1 kg/m2 higher residual FMI strengthened and was higher in women (1.52 [1.38-1.68]) than in men (1.19 [1.13-1.25]). By contrast, for a given level of FMI, higher residual LMI was inversely associated with vascular-metabolic mortality (rate ratio per 1 kg/m2 0.67 [0.56-0.80] in women and 0.94 [0.90-0.98] in men). Conclusions In this study, higher residual FMI was more strongly associated with vascular-metabolic mortality in women than in men. Conversely, higher residual LMI was inversely associated with vascular-metabolic mortality, particularly in women.

Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes.

We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes (P = 5.7 × 10-10) and had lower glycosylated hemoglobin (ß = -0.14 SD units, P = 1.1 × 10-24). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype (P = 6.0 × 10-4). Separately, we identified a Finnish-enriched MAP3K15 protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes (P < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating MAP3K15 variants in the UKB, supporting this gene as a therapeutic target for diabetes.

Adiposity and NMR-measured lipid and metabolic biomarkers among 30,000 Mexican adults.

BACKGROUND: Adiposity is a major cause of morbidity and mortality in part due to effects on blood lipids. Nuclear magnetic resonance (NMR) spectroscopy provides direct information on >130 biomarkers mostly related to blood lipid particles. METHODS: Among 28,934 Mexican adults without chronic disease and not taking lipid-lowering therapy, we examine the cross-sectional relevance of body-mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and hip circumference (HC) to NMR-measured metabolic biomarkers. Confounder-adjusted associations between each adiposity measure and NMR biomarkers are estimated before and after mutual adjustment for other adiposity measures. RESULTS: Markers of general (ie, BMI), abdominal (ie, WC and WHR) and gluteo-femoral (ie, HC) adiposity all display similar and strong associations across the NMR-platform of biomarkers, particularly for biomarkers that increase cardiometabolic risk. Higher adiposity associates with higher levels of Apolipoprotein-B (about 0.35, 0.30, 0.35, and 0.25 SD higher Apolipoprotein-B per 2-SD higher BMI, WHR, WC, and HC, respectively), higher levels of very low-density lipoprotein particles (and the cholesterol, triglycerides, and phospholipids within these lipoproteins), higher levels of all fatty acids (particularly mono-unsaturated fatty acids) and multiple changes in other metabolic biomarkers including higher levels of branched-chain amino acids and the inflammation biomarker glycoprotein acetyls. Associations for general and abdominal adiposity are fairly independent of each other but, given general and abdominal adiposity, higher gluteo-femoral adiposity is associated with a strongly favourable cardiometabolic lipid profile. CONCLUSIONS: Our results provide insight to the lipidic and metabolomic signatures of different adiposity markers in a previously understudied population where adiposity is common but lipid-lowering therapy is not.

Obesity increases the risk of multiple diseases, in part due to alterations in how the body breaks down carbohydrates and fats, which is reflected in molecules that circulate in blood. In obesity, disease risk may vary depending on whether fat accumulates in the body overall (i.e. total adiposity), in the middle of the body (i.e. abdominal adiposity) or around the hips (i.e. gluteo-femoral adiposity). Here, we show that in a population of Mexican adults higher total and abdominal adiposity relate adversely, while higher gluteo-femoral adiposity relates favourably, to numerous molecules in blood that are linked to type 2 diabetes and heart disease. These findings provide insight on the processes that link the accumulation of fat across the body with disease risk in a population where obesity rates are high.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin ßE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

Ethnicity and other COVID-19 death risk factors in Mexico.

Introduction: Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may develop coronavirus disease 2019 (COVID-19). Risk factors associated with death vary among countries with different ethnic backgrounds. We aimed to describe the factors associated with death in Mexicans with confirmed COVID-19. Material and methods: We analysed the Mexican Ministry of Health's official database on people tested for SARS-CoV-2 infection by real-time reverse transcriptase-polymerase chain reaction (rtRT-PCR) of nasopharyngeal fluids. Bivariate analyses were performed to select characteristics potentially associated with death, to integrate a Cox-proportional hazards model. Results: As of May 18, 2020, a total of 177,133 persons (90,586 men and 86,551 women) in Mexico received rtRT-PCR testing for SARS-CoV-2. There were 5332 deaths among the 51,633 rtRT-PCR-confirmed cases (10.33%, 95% CI: 10.07-10.59%). The median time (interquartile range, IQR) from symptoms onset to death was 9 days (5-13 days), and from hospital admission to death 4 days (2-8 days). The analysis by age groups revealed that the significant risk of death started gradually at the age of 40 years. Independent death risk factors were obesity, hypertension, male sex, indigenous ethnicity, diabetes, chronic kidney disease, immunosuppression, chronic obstructive pulmonary disease, age > 40 years, and the need for invasive mechanical ventilation (IMV). Only 1959 (3.8%) cases received IMV, of whom 1893 were admitted to the intensive care unit (96.6% of those who received IMV). Conclusions: In Mexico, highly prevalent chronic diseases are risk factors for death among persons with COVID-19. Indigenous ethnicity is a poorly studied factor that needs more investigation.

Abdominal and gluteo-femoral markers of adiposity and risk of vascular-metabolic mortality in a prospective study of 150 000 Mexican adults.

AIMS: Results of previous studies of abdominal adiposity and risk of vascular-metabolic mortality in Hispanic populations have been conflicting. We report results from a large prospective study of Mexican adults with high levels of abdominal adiposity. METHODS AND RESULTS: A total of 159 755 adults aged ≥35 years from Mexico City were enrolled in a prospective study and followed for 16 years. Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) associated with three markers of abdominal adiposity (waist circumference, waist-hip ratio, and waist-height ratio) and one marker of gluteo-femoral adiposity (hip circumference) for cause-specific mortality before age 75 years. To reduce reverse causality, deaths in the first 5 years of follow-up and participants with diabetes or other prior chronic disease were excluded. Among 113 163 participants without prior disease and aged 35-74 years at recruitment, all adiposity markers were positively associated with vascular-metabolic mortality. Comparing the top versus bottom tenth of the sex-specific distributions, the vascular-metabolic mortality RRs at ages 40-74 years were 2.32 [95% confidence interval (CI) 1.84-2.94] for waist circumference, 2.22 (1.71-2.88) for the waist-hip ratio, 2.63 (2.06-3.36) for the waist-height ratio, and 1.58 (1.29-1.93) for hip circumference. The RRs corresponding to each standard deviation (SD) higher usual levels of these adiposity markers were 1.34 (95% CI 1.27-1.41), 1.31 (1.23-1.39), 1.38 (1.31-1.45), and 1.18 (1.13-1.24), respectively. For the markers of abdominal adiposity, the RRs did not change much after further adjustment for other adiposity markers, but for hip circumference the association was reversed; given body mass index and waist circumference, the RR for vascular-metabolic mortality for each one SD higher usual hip circumference was 0.80 (0.75-0.86). CONCLUSIONS: In this study of Mexican adults, abdominal adiposity (and in particular the waist-height ratio) was strongly and positively associated with vascular-metabolic mortality. For a given amount of general and abdominal adiposity, however, higher hip circumference was associated with lower vascular-metabolic mortality.

Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.

Association of Kidney Function With NMR-Quantified Lipids, Lipoproteins, and Metabolic Measures in Mexican Adults.

CONTEXT: Chronic kidney disease (CKD) and diabetes are associated with dyslipidemia, metabolic abnormalities, and atherosclerotic risk. Nuclear magnetic resonance (NMR) spectroscopy provides much more detail on lipoproteins than traditional assays. METHODS: In about 38 000 participants from the Mexico City Prospective Study, aged 35 to 84 years and not using lipid-lowering medication, NMR spectroscopy quantified plasma concentrations of lipoprotein particles, their lipidic compositions, and other metabolic measures. Linear regression related low estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2) to each NMR measure after adjustment for confounders and for multiplicity. Analyses were done separately for those with and without diabetes. RESULTS: Among the 38 081 participants (mean age 52 years, 64% women), low eGFR was present for 4.8% (306/6403) of those with diabetes and 1.2% (365/31 678) of those without diabetes. Among both those with and without diabetes, low eGFR was significantly associated with higher levels of 58 NMR measures, including apolipoprotein B (Apo-B), the particle numbers of most Apo-B containing lipoproteins, the cholesterol and triglycerides carried in these lipoproteins, several fatty acids, total cholines and phosphatidylcholine, citrate, glutamine, phenylalanine, ß-OH-butyrate, and the inflammatory measure glycoprotein-A, and significantly lower levels of 13 NMR measures, including medium and small high-density lipoprotein particle measures, very low-density lipoprotein particle size, the ratio of saturated:total fatty acids, valine, tyrosine, and aceto-acetate. CONCLUSIONS: In this Mexican population with high levels of adiposity and diabetes, low kidney function was associated with widespread alterations in lipidic and metabolic profiles, both in those with and without diabetes. These alterations may help explain the higher atherosclerotic risk experienced by people with CKD.

Low-intensity daily smoking and cause-specific mortality in Mexico: prospective study of 150 000 adults.

BACKGROUND: Research is needed to determine the relevance of low-intensity daily smoking to mortality in countries such as Mexico, where such smoking habits are common. METHODS: Prospective study of 159 755 Mexican adults recruited from 1998-2004 and followed for cause-specific mortality to 1 January 2018. Participants were categorized according to baseline self-reported smoking status. Confounder-adjusted mortality rate ratios (RRs) at ages 35-89 were estimated using Cox regression, after excluding those with previous chronic disease (to avoid reverse causality). RESULTS: Among 42 416 men and 86 735 women aged 35-89 and without previous disease, 18 985 men (45%) and 18 072 women (21%) reported current smoking and 8866 men (21%) and 53 912 women (62%) reported never smoking. Smoking less than daily was common: 33% of male current smokers and 39% of female current smokers. During follow-up, the all-cause mortality RRs associated with the baseline smoking categories of <10 cigarettes per day (average during follow-up 4 per day) or ≥10 cigarettes per day (average during follow-up 10 per day), compared with never smoking, were 1.17 (95% confidence interval 1.10-1.25) and 1.54 (1.42-1.67), respectively. RRs were similar irrespective of age or sex. The diseases most strongly associated with daily smoking were respiratory cancers, chronic obstructive pulmonary disease and gastrointestinal and vascular diseases. Ex-daily smokers had substantially lower mortality rates than those who were current daily smokers at recruitment. CONCLUSIONS: In this Mexican population, low-intensity daily smoking was associated with increased mortality. Of those smoking 10 cigarettes per day on average, about one-third were killed by their habit. Quitting substantially reduced these risks.

Changes in the Diagnosis and Management of Diabetes in Mexico City Between 1998-2004 and 2015-2019.

OBJECTIVE: To investigate the trends in diabetes prevalence, diagnosis, and management among Mexican adults who were participants in a long-term prospective study. RESEARCH DESIGN AND METHODS: From 1998 to 2004, 159,755 adults from Mexico City were recruited to a prospective study, and from 2015 to 2019, 10,144 survivors were resurveyed. Diabetes was defined as self-reported diagnosis, glucose-lowering medication use, or HbA1c ≥6.5%. Controlled diabetes was defined as HbA1c <7%. Prevalence estimates were uniformly standardized for age, sex, and residential district. Cox models explored the relevance of controlled and inadequately controlled diabetes to cause-specific mortality. RESULTS: During 1998-2004 and 2015-2019, 99,623 and 8,986 participants were aged 45-84 years. Diabetes prevalence had increased from 26% in 1998-2004 to 35% by 2015-2019. Of those with diabetes, the proportion previously diagnosed had increased from 76% to 89%, and glucose-lowering medication use among them had increased from 80% to 94%. Median HbA1c among those with diabetes had decreased from 8.2% to 7.3%, and the proportion of participants with controlled diabetes had increased from 16% to 37%. Use of blood pressure-lowering medication among those with previously diagnosed diabetes had increased from 35% to 51%, and their use of lipid-lowering therapy had increased from 1% to 14%. The excess mortality risk associated with diabetes accounted for 34% of deaths at ages 35-74 years, of which 5% were attributable to controlled and 29% to inadequately controlled diabetes. CONCLUSIONS: Inadequately controlled diabetes is a leading cause of premature adult death in Mexico. Improvements in diabetes management have increased diagnosis and control, but substantial opportunities remain to improve treatment, particularly with lipid-lowering therapy.

Association of Blood Pressure With Cause-Specific Mortality in Mexican Adults.

Importance: Elevated blood pressure is a major cause of premature death, but there is little direct evidence demonstrating this association in studies of Hispanic populations. Objective: To assess the association between blood pressure and cause-specific mortality in a large cohort of Mexican adults with a high prevalence of uncontrolled diabetes. Design, Setting, and Participants: A total of 159 755 adults aged 35 years or older from 2 districts in Mexico City were recruited to this cohort study between April 1998 and September 2004 and followed up until January 2018. The present analyses focused on 133 613 participants who were aged 35 to 74 years and had no history of chronic disease besides diabetes. Exposure: Blood pressure. Main Outcomes and Measures: Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) for deaths of participants occurring between ages 35 and 74 years. Results: Of the 133 613 participants (43 263 [32.4%] men; mean [SD] age, 50 [11] years), 16 911 (12.7%) had self-reported previously diagnosed diabetes (including 8435 [6.3%] with uncontrolled diabetes, defined as hemoglobin A1c ≥9%) and 6548 (4.9%) had undiagnosed diabetes. Systolic blood pressure (SBP) was associated with vascular mortality between ages 35 to 74 years, with each 20 mm Hg lower usual SBP associated with 35% lower vascular mortality (RR, 0.65; 95% CI, 0.61-0.68), including 48% lower stroke mortality (RR, 0.52; 95% CI, 0.47-0.59) and 32% lower ischemic heart disease mortality (RR, 0.68; 95% CI, 0.63-0.74). These RRs were broadly similar in those with and without diabetes. Compared with those without diabetes and SBP less than 135 mm Hg at recruitment, the vascular mortality RR was 2.8 (95% CI, 2.4-3.3) for those without diabetes and SBP of 155 mm Hg or greater, 4.7 (95% CI, 4.1-5.4) for those with uncontrolled diabetes and SBP less than 135 mm Hg, and 8.9 (95% CI, 7.2-11.1) for those with uncontrolled diabetes and SBP of 155 mm Hg or greater. Lower SBP was also associated with decreased kidney-related mortality (RR per 20 mm Hg lower usual SBP, 0.69; 95% CI, 0.64-0.74), decreased mortality from infection (RR, 0.81; 95% CI, 0.71-0.91), and decreased mortality from hepatobiliary disease (RR, 0.87; 95% CI, 0.78-0.98), but not decreased neoplastic or respiratory mortality. SBP was more informative for vascular mortality than other blood pressure measures (eg, compared with SBP, diastolic blood pressure was only two-thirds as informative). Conclusions and Relevance: Blood pressure was most strongly associated with vascular and kidney-related mortality in this Mexican population, with particularly high absolute excess mortality rates among individuals with diabetes. The findings reinforce the need for more widespread use of blood pressure-lowering medication in Mexico, particularly among those with diabetes.