General Practice and Primary Care - Research Publications

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    Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin-treated Type 2 diabetes mellitus
    Khunti, K ; Berkovic, MC ; Ludvik, B ; Moberg, E ; Lekdorf, JB ; Gydesen, H ; Pedersen-Bjergaard, U (WILEY, 2018-09)
    AIM: To determine participant knowledge and reporting of hypoglycaemia in the non-interventional Hypoglycaemia Assessment Tool (HAT) study. METHODS: HAT was conducted in 24 countries over a 6-month retrospective/4-week prospective period in 27 585 adults with Type 1 or insulin-treated Type 2 diabetes mellitus. Participants recorded whether hypoglycaemia was based on blood glucose levels, symptoms or both. RESULTS: Hypoglycaemia rates were consistently higher in the prospective compared with the retrospective period. Most respondents (96.8% Type 1 diabetes; 85.6% Type 2 diabetes) knew the American Diabetes Association/European Association for the Study of Diabetes hypoglycaemia definition, but there were regional differences in the use of blood glucose measurements and/or symptoms to define events. Confirmed symptomatic hypoglycaemia rates were highest in Northern Europe/Canada for Type 1 diabetes (63.9 events/year) and in Eastern Europe for Type 2 diabetes (19.4 events/year), and lowest in South East Asia (Type 1 diabetes: 6.0 events/year; Type 2 diabetes: 3.2 events/year). Unconfirmed symptomatic hypoglycaemia rates were highest in Eastern Europe for Type 1 diabetes (5.6 events/year) and South East Asia for Type 2 diabetes (4.7 events/year), and lowest for both in Russia (Type 1 diabetes: 2.1 events/year; Type 2 diabetes: 0.4 events/year). Participants in Latin America reported the highest rates of severe hypoglycaemia (Type 1 diabetes: 10.8 events/year; Type 2 diabetes 3.7 events/year) and severe hypoglycaemia requiring hospitalization (Type 1 diabetes: 0.56 events/year; Type 2 diabetes: 0.44 events/year). The lowest rates of severe hypoglycaemia were reported in South East Asia (Type 1 diabetes: 2.0 events/year) and Northern Europe/Canada (Type 2 diabetes: 1.3 events/year), and the lowest rates of severe hypoglycaemia requiring hospitalization were in Russia (Type 1 diabetes: 0.15 events/year; Type 2 diabetes: 0.09 events/year). The blood glucose cut-off used to define hypoglycaemia varied between regions (Type 1 diabetes: 3.1-3.6 mmol/l; Type 2 diabetes: 3.5-3.8 mmol/l). CONCLUSIONS: Under-reporting of hypoglycaemia rates in retrospective recall and regional variations in participant definitions of hypoglycaemia may contribute to the global differences in reported rates. Discrepancies between participant definitions and guidelines may highlight a need to redefine hypoglycaemia criteria. (Clinical Trials Registry No: NCT01696266).
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    Global burden of hypoglycaemia-related mortality in 109 countries, from 2000 to 2014: an analysis of death certificates
    Zaccardi, F ; Dhalwani, NN ; Webb, DR ; Davies, MJ ; Khunti, K (SPRINGER, 2018-07)
    AIMS/HYPOTHESIS: In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality. METHODS: We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes [i.e. the sum of hypoglycaemia- and diabetes-related deaths]) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time. RESULTS: Data for proportions were extracted from 109 countries (31 had data from all years analysed [2000-2014] available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed [2000-2014] available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person-years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis showed an overall 60% increase in hypoglycaemia-related deaths until 2010 and stable rate trends onwards; rising rates were particularly evident for Brazil, Chile and the USA. CONCLUSIONS/INTERPRETATION: Most countries in South America, Central America and the Caribbean showed the highest proportions of diabetes-related deaths attributable to hypoglycaemia and the highest rates of hypoglycaemia-related deaths. Between 2000 and 2014, rising trends were observed in Brazil, Chile and the USA for both rates and proportions of hypoglycaemia-related death, and in Argentina and Japan for proportions only. Further studies are required to unravel the contribution of clinical and socioeconomic factors, difference in diabetes prevalence and heterogeneity of death certification in determining lower rates and proportions of hypoglycaemia-related deaths in high-income countries in Europe, North America and Asia. DATA AVAILABILITY: Data used for these analyses are available at https://doi.org/10.17632/ndp52fbz8r.1.
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    Identification of barriers to insulin therapy and approaches to overcoming them
    Russell-Jones, D ; Pouwer, F ; Khunti, K (WILEY, 2018-03)
    Poor glycaemic control in type 2 diabetes (T2D) is a global problem despite the availability of numerous glucose-lowering therapies and clear guidelines for T2D management. Tackling clinical or therapeutic inertia, where the person with diabetes and/or their healthcare providers do not intensify treatment regimens despite this being appropriate, is key to improving patients' long-term outcomes. This gap between best practice and current level of care is most pronounced when considering insulin regimens, with studies showing that insulin initiation/intensification is frequently and inappropriately delayed for several years. Patient- and physician-related factors both contribute to this resistance at the stages of insulin initiation, titration and intensification, impeding achievement of optimal glycaemic control. The present review evaluates the evidence and reasons for this delay, together with available methods for facilitation of insulin initiation or intensification.
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    Patterns of glycaemic control in patients with type 2 diabetes mellitus initiating second-line therapy after metformin monotherapy: Retrospective data for 10256 individuals from the United Kingdom and Germany
    Khunti, K ; Godec, TR ; Medina, J ; Garcia-Alvarez, L ; Hiller, J ; Gomes, MB ; Cid-Ruzafa, J ; Charbonnel, B ; Fenici, P ; Hammar, N ; Hashigami, K ; Kosiborod, M ; Nicolucci, A ; Shestakova, MV ; Ji, L ; Pocock, S (WILEY, 2018-02)
    AIM: To investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second-line glucose-lowering therapies. MATERIALS AND METHODS: This cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second-line glucose-lowering therapy (switch from or add-on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre-specified patient characteristics on 6-month HbA1c changes were assessed using analysis of covariance. RESULTS: Patients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add-on therapy. Mean (SE) unadjusted 6-month HbA1c change was -1.27% (0.02). When adjusted for baseline HbA1c, 6-month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, -0.45% per unit increase in HbA1c; HbA1c ≥9%, -0.87% per unit increase in HbA1c). Adjusted mean 6-month HbA1c reductions showed slight treatment differences (range, 0.92-1.09%; P < .001). Greater reductions in HbA1c were associated with second-line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P < .001]) and advanced age (≥70 years, 1.13%; <70 years, 1.02% [P < .001]). CONCLUSIONS: Many patients with T2DM have very high HbA1c levels when initiating second-line therapy, indicating the need for earlier treatment intensification. Patient-specific factors merit consideration when making treatment decisions.
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    Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: A systematic review
    Khunti, K ; Gomes, MB ; Pocock, S ; Shestakova, MV ; Pintat, S ; Fenici, P ; Hammar, N ; Medina, J (WILEY, 2018-02)
    AIMS: Therapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner according to evidence-based clinical guidelines, is a key reason for uncontrolled hyperglycaemia in patients with type 2 diabetes. The aims of this systematic review were to identify how therapeutic inertia in the management of hyperglycaemia was measured and to assess its extent over the past decade. MATERIALS AND METHODS: Systematic searches for articles published from January 1, 2004 to August 1, 2016 were conducted in MEDLINE and Embase. Two researchers independently screened all of the titles and abstracts, and the full texts of publications deemed relevant. Data were extracted by a single researcher using a standardized data extraction form. RESULTS: The final selection for the review included 53 articles. Measurements used to assess therapeutic inertia varied across studies, making comparisons difficult. Data from low- to middle-income countries were scarce. In most studies, the median time to treatment intensification after a glycated haemoglobin (HbA1c) measurement above target was more than 1 year (range 0.3 to >7.2 years). Therapeutic inertia increased as the number of antidiabetic drugs rose and decreased with increasing HbA1c levels. Data were mainly available from Western countries. Diversity of inertia measures precluded meta-analysis. CONCLUSIONS: Therapeutic inertia in the management of hyperglycaemia in patients with type 2 diabetes is a major concern. This is well documented in Western countries, but corresponding data are urgently needed in low- and middle-income countries, in view of their high prevalence of type 2 diabetes.
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    Sedentary Time and MRI-Derived Measures of Adiposity in Active Versus Inactive Individuals
    Henson, J ; Edwardson, CL ; Morgan, B ; Horsfield, MA ; Khunti, K ; Davies, MJ ; Yates, T (WILEY, 2018-01)
    OBJECTIVE: The aim of this study was to examine cross-sectional associations between objectively measured sedentary time and magnetic resonance imaging (MRI)-assessed adiposity in a population at high risk for type 2 diabetes (T2DM) and to determine whether associations are modified by the recommended levels of moderate-to-vigorous physical activity (MVPA). METHODS: Sedentary time and MVPA were measured objectively by using accelerometers. Linear regression models examined the association of sedentary time with liver, visceral, subcutaneous, and total abdominal fat (quantified by using MRI). Interaction terms determined whether results were consistent across activity categories (active [> 150 min/wk of MVPA] vs. inactive [< 150 min/wk of MVPA]). RESULTS: One hundred and twenty-four participants (age = 64.0 ± 7.1 years; male = 65.3%; BMI = 31.8 ± 5.6 kg/m2 ) were included. Following adjustment, each 60 minutes of sedentary time was associated with 1.74 L higher total abdominal fat, 0.62 L higher visceral fat, 1.14 L higher subcutaneous fat, and 1.86% higher liver fat. When results were stratified by MVPA (active vs. inactive), sedentary time was associated with greater liver, visceral, and total abdominal fat in the inactive group only. CONCLUSIONS: These findings suggest that sedentary time is associated with higher levels of inter- and intraorgan fat, but associations with liver, visceral, and total abdominal fat were stronger in those who do not reach the current exercise recommendations for health.
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    Polycystic ovary syndrome: An underestimated problem in primary care
    Mani, H ; Levy, MJ ; Khunti, K (WILEY, 2018-04)
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    Association of hypoglycaemia and risk of cardiac arrhythmia in patients with diabetes mellitus: A systematic review and meta-analysis
    Fitzpatrick, C ; Chatterjee, S ; Seidu, S ; Bodicoat, DH ; Ng, GA ; Davies, MJ ; Khunti, K (WILEY, 2018-09)
    AIMS: Hypoglycaemia is associated with increased cardiovascular risk among individuals with diabetes mellitus. It has been hypothesized that hypoglycaemia may trigger autonomic changes leading to increased cardiac arrhythmia risk. We conducted a systematic review and meta-analysis to explore this association. MATERIALS AND METHODS: Ovid Medline, Embase, Scopus, Web of Science and Cochrane were searched from inception to October 10, 2017. We included studies of adults with diabetes (Type 1 or Type 2) that compared acute electrocardiogram (ECG) changes during episodes of hypoglycaemia and euglycaemia. RESULTS: Our search resulted in 4625 citations, among which 20 studies met the predefined inclusion criteria. Finally, 12 studies were included in the descriptive analysis and 15 in the meta-analysis. Overall hypoglycaemia was associated with a reduction in heart rate variability and an increase in arrhythmia occurrence. QTc interval length was more significantly prolonged during hypoglycaemia compared to euglycaemia (pooled mean difference [95% confidence intervals] [0.64 (0.27-1.01], P = ·001). Subgroup analysis based on diabetes type showed that QTc prolongation occurred in individuals with Type 1 and Type 2 diabetes; however, the change between euglycaemia reached statistical significance only among individuals with Type 1 diabetes. CONCLUSION: Our findings suggest that hypoglycaemia results in ECG alterations that are associated with increased risk of cardiac arrhythmia, which is associated with increased cardiovascular events and mortality. More clinical studies are needed to determine the cardiac risks of hypoglycaemia in individuals with diabetes, especially in Type 2 diabetes.
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    What have we learnt from "real world" data, observational studies and meta-analyses
    Chatterjee, S ; Davies, MJ ; Khunti, K (WILEY, 2018-02)
    The incretin therapies glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-IV (DPP-IV) inhibitors are now well-established as second and third-line therapies and in combination with insulin for the treatment of type 2 diabetes. Over the last decade, there is accumulating evidence of their efficacy and safety from both large multicentre randomized clinical trials (RCT) and observational studies. Cardiovascular outcome trials have confirmed that several of these agents are also non-inferior to placebo with the GLP-1 RA liraglutide and semaglutide recently found to be superior in terms of major adverse cardiovascular events. Observational studies and post-marketing surveillance provide real world evidence of safety and effectiveness of these agents and have provided reassurance that signals for pancreatitis and pancreatic cancer seen in clinical trials are not of major concern in large patient populations. Well-designed real world studies complement RCTs and systematic reviews but appropriate data and methodologies, which are constantly improving, are necessary to answer appropriate clinical questions relating to the use of incretin therapies.
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    Moderate increases in daily step count are associated with reduced IL6 and CRP in women with PCOS
    Webb, MA ; Mani, H ; Robertson, SJ ; Waller, HL ; Webb, DR ; Edwardson, CL ; Bodicoat, DH ; Yates, T ; Khunti, K ; Davies, MJ (BIOSCIENTIFICA LTD, 2018-12)
    Aims Physical activity has been proposed to be an effective non-pharmacological method of reducing systemic inflammation and therefore may prove particularly efficacious for women with polycystic ovary syndrome (PCOS) who have been shown to have high levels of inflammation and an increased risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Therefore, the aim of the present study was to assess whether modest changes in daily step count could significantly reduce levels of inflammatory markers in women with PCOS. Subjects and Methods Sixty-five women with PCOS were assessed at baseline and again at 6 months. All had been provided with an accelerometer and encouraged to increase activity levels. Multivariate linear regression analyses (adjusted for age, ethnicity, baseline step count, change in BMI and change in accelerometer wear-time) were used to assess changes in daily step count against clinical and research biomarkers of inflammation, CVD and T2DM. Results Mean step count/day at baseline was 6337 (±270). An increase in step count (by 1000 steps) was associated with a 13% reduction in IL6 (β: -0.81 ng/L; 95% CI, -1.37, -0.25, P = 0.005) and a 13% reduction in CRP (β: -0.68 mg/L; 95% CI, -1.30, -0.06, P = 0.033). Additionally, there was a modest decrease in BMI (β: 0.20 kg/m2; 95% CI, -0.38, -0.01, P = 0.038). Clinical markers of T2DM and CVD were not affected by increased step count. Conclusions Modest increases in step count/day can reduce levels of inflammatory markers in women with PCOS, which may reduce the future risk of T2DM and CVD.