Browsing by Author "Nirantharakumar, K."

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Metabolically healthy obese and incident cardiovascular disease events among 3.5 million men and women
(Elsevier Biomedical, 2017) Caleyachetty, R.; Thomas, G.N.; Toulis, K.A.; Mohammed, N.; Gokhale, K.M.; Balachandran, K.; Nirantharakumar, K.
BACKGROUND: Previous studies have been unclear about the cardiovascular risks for metabolically healthy obese individuals. OBJECTIVES: This study examined the associations among metabolically healthy obese individuals and 4 different presentations of incidentcardiovascular disease in a contemporary population. METHODS: We used linked electronic health records (1995 to 2015) in The Health Improvement Network (THIN) to assemble a cohort of 3.5million individuals, 18 years of age or older and initially free of cardiovascular disease. We created body size phenotypes defined by body mass index categories (underweight, normal weight, overweight, and obesity) and 3 metabolic abnormalities (diabetes, hypertension, and hyperlipidemia). The primary endpoints were the first record of 1 of 4 cardiovascular presentations (coronary heart disease [CHD], cerebrovascular disease, heart failure, and peripheral vascular disease). RESULTS: During a mean follow-up of 5.4 years, obese individuals with no metabolic abnormalities had a higher risk of CHD (multivariate-adjusted hazard ratio [HR]: 1.49; 95% confidence interval [CI]: 1.45 to 1.54), cerebrovascular disease (HR: 1.07; 95% CI: 1.04 to 1.11), and heart failure (HR: 1.96; 95% CI: 1.86 to 2.06) compared with normal weight individuals with 0 metabolic abnormalities. Risk of CHD, cerebrovascular disease, and heart failure in normal weight, overweight, and obese individuals increased with increasing number of metabolic abnormalities. CONCLUSIONS: Metabolically healthy obese individuals had a higher risk of coronary heart disease, cerebrovascular disease, and heart failure than normal weight metabolically healthy individuals. Even individuals who are normal weight can have metabolic abnormalities and similar risks for cardiovascular disease events.
Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database
(Public Library of Science, 2018) Kumarendran, B.; O'Reilly, M.W.; Manolopoulos, K.N.; Toulis, K.A.; Gokhale, K.M.; Sitch, A.J.; Wijeyaratne, C.N.; Coomarasamy, A.; Arlt, W.; Nirantharakumar, K.
BACKGROUND: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver. METHODS AND FINDINGS: We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86-2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16-4.53, p = 0.017 for 3-3.49 nmol/L and HR = 2.40, 95% CI 1.24-4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44-9.25, p < 0.001 for 20-29.99 nmol/L and HR = 4.98, 95% CI 2.45-10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens. CONCLUSIONS: We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered.
Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort
(Blackwell Scientific Publications, 2019) O'Reilly, M. W.; Glisic, M.; Kumarendran, B.; Subramanian, A.; Manolopoulos, K. N.; Tahrani, A. A.; Keerthy, D.; Muka, T.; Toulis, K. A.; Hanif, W.; Thomas, G. N.; Franco, O. H.; Arlt, W.; Nirantharakumar, K.
OBJECTIVE: Previous studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex-specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study. DESIGN: A retrospective cohort study in a UK primary care database. PATIENTS: We included men and women with available serum testosterone and sex hormone-binding globulin (SHBG) results. MEASUREMENTS: We categorized serum concentrations according to clinically relevant cut-off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs). RESULTS: Serum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone <7 nmol/L (aIRR 2.71, 95% CI 2.34-3.14, P < 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55-2.52, P < 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG <40 and <50 nmol/L, respectively. CONCLUSIONS/INTERPRETATION: In this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively.