The Effect of HIV on the Association of Hyperglycaemia and Active Tuberculosis in Zambia, a Case-Control Study.

OBJECTIVES: To determine if HIV modifies the association between hyperglycaemia and active tuberculosis in Lusaka, Zambia. METHODS: A case-control study among newly-diagnosed adult tuberculosis cases and population controls in three areas of Lusaka. Hyperglycaemia is determined by random blood glucose (RBG) concentration measured at the time of recruitment; active tuberculosis disease by clinical diagnosis, and HIV status by serological result. Multivariable logistic regression is used to explore the primary association and effect modification by HIV. RESULTS: The prevalence of RBG concentration ≥ 11.1 mmol/L among 3843 tuberculosis cases was 1.4% and among 6977 controls was 1.5%. Overall, the adjusted odds ratio of active tuberculosis was 1.60 (95% CI 0.91-2.82) comparing those with RBG concentration ≥ 11.1- < 11.1 mmol/L. The corresponding adjusted odds ratio among those with and without HIV was 5.47 (95% CI 1.29-23.21) and 1.17 (95% CI 0.61-2.27) respectively; p-value for effect modification by HIV = 0.042. On subgroup analysis, the adjusted odds ratio of smear/Xpert-positive tuberculosis was 2.97 (95% CI 1.49-5.90) comparing RBG concentration ≥ 11.1- < 11.1 mmol/L. CONCLUSIONS: Overall, no evidence of association between hyperglycaemia and active tuberculosis was found, though among those with HIV and/or smear/Xpert-positive tuberculosis there was evidence of association. Differentiation of hyperglycaemia caused by diabetes mellitus and stress-induced hyperglycaemia secondary to tuberculosis infection is important for a better understanding of these findings.

Reducing non-communicable diseases among Palestinian populations in Gaza: A participatory comparative and cost-effectiveness modeling assessment.

We sought to assess the effectiveness and cost-effectiveness of potential new public health and healthcare NCD risk reduction efforts among Palestinians in Gaza. We created a microsimulation model using: (i) a cross-sectional household survey of NCD risk factors among 4,576 Palestinian adults aged ≥40 years old in Gaza; (ii) a modified Delphi process among local public health experts to identify potentially feasible new interventions; and (iii) reviews of intervention cost and effectiveness, modified to the Gazan and refugee contexts. The survey revealed 28.6% tobacco smoking, a 40.4% prevalence of hypertension diagnosis (with a 95.6% medication treatment rate), a 25.6% prevalence of diabetes diagnosis (with 95.3% on treatment), a 21.9% prevalence of dyslipidemia (with 79.6% on a statin), and a 9.8% prevalence of asthma or chronic obstructive pulmonary disease (without known treatment). A calibrated model estimated a loss of 9,516 DALYs per 10,000 population over the 10-year policy horizon. The interventions having an incremental cost-effectiveness ratio (ICER) less than three times the GDP per capita of Palestine per DALY averted (<$10,992 per DALY averted)(<$10,992 per DALY averted) included bans on tobacco smoking in indoor and public places [$34 per incremental DALY averted (95% CI: $17, $50)], treatment of asthma using low dose inhaled beclometasone and short-acting beta-agonists [$140 per DALY averted (95% CI: $77, $207)], treatment of breast cancer stages I and II [$730 per DALY averted (95% CI: $372, $1,100)], implementing a mass media campaign for healthier nutrition [$737 per DALY averted (95% CI: $403, $1,100)], treatment of colorectal cancer stages I and II [$7,657 per DALY averted (95% CI: $3,721, $11,639)], and (screening with mammography [$17,054 per DALY averted (95% CI: $8,693, $25,359)]). Despite high levels of NCD risk factors among Palestinians in Gaza, we estimated that several interventions would be expected to reduce the loss of DALYs within common cost-effectiveness thresholds.

The hypertension cascade of care in the midst of conflict: the case of the Gaza Strip.

Although hypertension constitutes a substantial burden in conflict-affected areas, little is known about its prevalence, control, and management in Gaza. This study aims to estimate the prevalence and correlates of hypertension, its diagnosis and control among adults in Gaza. We conducted a representative, cross-sectional, anonymous, household survey of 4576 persons older than 40 years in Gaza in mid-2020. Data were collected through face-to-face interviews, anthropometric, and blood pressure measurements. Hypertension was defined in anyone with an average systolic blood pressure ≥140 mmHg or average diastolic blood pressure ≥90 mmHg from two consecutive readings or a hypertension diagnosis. The mean age of participants was 56.9 ± 10.5 years, 54.0% were female and 68.5% were Palestinian refugees. The prevalence of hypertension was 56.5%, of whom 71.5% had been diagnosed. Hypertension was significantly higher among older participants, refugees, ex-smokers, those who were overweight or obese, and had other co-morbidities including mental illnesses. Two-thirds (68.3%) of those with hypertension were on treatment with one in three (35.6%) having their hypertension controlled. Having controlled hypertension was significantly higher in females, those receiving all medications for high blood pressure and those who never or rarely added salt to food. Investing in comprehensive but cost-effective initiatives that strengthen the prevention, early detection and timely treatment of hypertension in conflict settings is critical. It is essential to better understand the underlying barriers behind the lack of control and develop multi-sectoral programs to address these barriers.

Management of type 1 diabetes in low- and middle-income countries: Comparative health system assessments in Kyrgyzstan, Mali, Peru and Tanzania.

AIMS: To describe and compare the health system responses for type 1 diabetes in Kyrgyzstan, Mali, Peru and Tanzania. METHODS: The Rapid Assessment Protocol for Insulin Access, a multi-level assessment of the health system, was implemented in Kyrgyzstan, Mali, Peru and Tanzania using document reviews, site visits and interviews to assess the delivery of care and access to insulin. RESULTS: Despite the existence of noncommunicable or diabetes strategies and Universal Health Coverage policies including diabetes-related supplies, this has not necessarily translated into access to insulin or diabetes care for all. Insulin and related supplies were often unavailable and unaffordable. Across the four countries test strips and insulin, when paid for by the individual, represented respectively 48-82% and 25-36% of total costs. Care was mainly delivered at tertiary-level hospitals by specialists. Only Kyrgyzstan had data collection systems integrated into the Ministry of Health structure. In addition, issues with healthcare worker training and education and empowerment of people with diabetes were present in these health systems. CONCLUSIONS: People with type 1 diabetes in these countries face different barriers, including the cost of insulin and care. Given the renewed attention to diabetes on the global health agenda tailored health system responses for type 1 diabetes are needed. Insulin should be prioritized as it is the foundation of type 1 diabetes care, but other elements of care and support need to be fostered by different actors.

The role of non-governmental organizations in strengthening healthcare systems in low- and middle-income countries: Lessons from Santé Diabète in Mali.

Non-governmental organizations play a vital part in the achievement of the Sustainable Development Goals as defined by the United Nations. These Goals also include targets related to noncommunicable diseases. However, non-governmental organizations have played a limited role in this area despite such diseases causing the bulk of morbidity and mortality worldwide. Through their activities, non-governmental organizations should aim to strengthen health systems, yet they often only support these for a single disease. Mali, like many other low- and middle-income countries, is facing an increasing burden of diabetes and a health system not adapted to address this challenge. Santé Diabète, a non-governmental organization based in Mali since 2003, has been working specifically on diabetes, and has developed a wide range of activities to improve the national health system. This paper describes changes in the diabetes environment in Mali between 2004 and 2018 based on two health system assessments carried out using a Rapid Assessment Protocol. Over this period, the health system was strengthened with regard to financing and access to medical products. Leadership and governance, service delivery and health workforce were all improved but still partially rely on sustained support from Santé Diabète. The key lesson from this study is that to be effective in changing the management of noncommunicable diseases in a low- and middle-income country, non-governmental organizations need to play a variety of roles, many of which may change over time.

REPRINT OF: CLASSIFICATION OF DIABETES MELLITUS.

Executive Summary This document updates the 1999 World Health Organization (WHO) classification of diabetes. It prioritizes clinical care and guides health professionals in choosing appropriate treatments at the time of diabetes diagnosis, and provides practical guidance to clinicians in assigning a type of diabetes to individuals at the time of diagnosis. It is a compromise between clinical and aetiological classification because there remain gaps in knowledge of the aetiology and pathophysiology of diabetes. While acknowledging the progress that is being made towards a more precise categorization of diabetes subtypes, the aim of this document is to recommend a classification that is feasible to implement in different settings throughout the world. The revised classification is presented in Table 1. Unlike the previous classification, this classification does not recognize subtypes of type 1 diabetes and type 2 diabetes and includes new types of diabetes ("hybrid types of diabetes" and "unclassified diabetes").

Regression to the Mean Contributes to the Apparent Improvement in Glycemia 3.8 Years After Screening: The ELSA-Brasil Study.

OBJECTIVE: Glycemic regression is common in real-world settings, but the contribution of regression to the mean (RTM) has been little investigated. We aimed to estimate glycemic regression before and after adjusting for RTM in a free-living cohort of adults with newly ascertained diabetes and intermediate hyperglycemia (IH). RESEARCH DESIGN AND METHODS: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a cohort study of 15,105 adults screened between 2008 and 2010 with standardized oral glucose tolerance test and HbA1c, repeated after 3.84 ± 0.42 years. After excluding those receiving medical treatment for diabetes, we calculated partial or complete regression before and after adjusting baseline values for RTM. RESULTS: Regarding newly ascertained diabetes, partial or complete regression was seen in 49.4% (95% CI 45.2-53.7); after adjustment for RTM, in 20.2% (95% CI 12.1-28.3). Regarding IH, regression to normal levels was seen in 39.5% (95% CI 37.9-41.3) or in 23.7% (95% CI 22.6-24.3), depending on use of the World Health Organization (WHO) or the American Diabetes Association (ADA) definition, respectively; after adjustment, corresponding frequencies were 26.1% (95% CI 22.4-28.1) and 19.4% (95% CI 18.4-20.5). Adjustment for RTM reduced the number of cases detected at screening: 526 to 94 cases of diabetes, 3,118 to 1,986 cases of WHO-defined IH, and 6,182 to 5,711 cases of ADA-defined IH. Weight loss ≥2.6% was associated with greater regression from diabetes (relative risk 1.52, 95% CI 1.26-1.84) and IH (relative risk 1.30, 95% CI 1.17-1.45). CONCLUSIONS: In this quasi-real-world setting, regression from diabetes at ∼4 years was common, less so for IH. Regression was frequently explained by RTM but, in part, also related to improved weight loss and homeostasis over the follow-up.

Estimates of insulin needs and dispensation given wastage, alternative glycemic targets, and non-insulin therapies in US populations with type 2 diabetes mellitus: A microsimulation study.

AIMS: Registries and health plans estimate insulin need for population health metrics. We sought to identify how such estimates affect population- and individual-level estimates of over- and under-treatment. METHODS: We developed a microsimulation comparing estimated insulin need to dispensation using the National Health and Nutrition Examination Survey (NHANES, 2005-2016, N= 2832) and Medical Expenditure Panel Survey (MEPS, 2005-2016, N = 29,615). RESULTS: From NHANES, ~21.6% of people with type 2 diabetes would require insulin to achieve a HbA1c target of 7% after maximum titration of two non-insulins (60.7 IU/person/day, or 84,629,833 vials of 1000 IU in the US). From MEPS, we observed 57.4 IU/person/day of insulin dispensed (81,585,842 vials). About 29% of people were dispensed at least two standard deviations less than their estimated need, and 22% at least two standard deviations more than estimated need. Population-level need estimates reduced 39.4% if liberalizing HbA1c targets to 8% for people ≥75 years old. CONCLUSIONS: Estimated insulin needs of people with type 2 diabetes in the U.S. are consistent with their dispensed insulin at the population level, but are sensitive to HbA1c targets for older adults, and conceal under- and over-treated subpopulations.

Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion, Mitochondrial Protein Expression, and Glucose Uptake in Muscle Through Adipomuscular Arterioles.

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and diabetes.

JNK2 in myeloid cells impairs insulin's vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction.

Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2-/- bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo.NEW & NOTEWORTHY We demonstrate that in the earliest phase of weight gain, changes in perivascular adipose tissue in muscle impair insulin-stimulated muscle perfusion. The hallmark of these changes is infiltration by inflammatory cells. Deletion of JNK2 from the bone marrow restores the function of perivascular adipose tissue to enhance insulin's vasodilator effects in muscle, showing that the bone marrow contributes to regulation of muscle perfusion.

Combining Multiple Treatment Comparisons with Personalized Patient Preferences: A Randomized Trial of an Interactive Platform for Statin Treatment Selection.

BACKGROUND: Patients and clinicians are often required to make tradeoffs between the relative benefits and harms of multiple treatment options. Combining network meta-analysis results with user preferences can be useful when choosing among several treatment alternatives. OBJECTIVE: Using cholesterol-lowering statin drugs as a case study, we aimed to determine whether an interactive web-based platform that combines network meta-analysis findings with patient preferences had an effect on the decision-making process in a general population sample. METHOD: This was a pilot parallel randomized controlled trial. We used Amazon's Mechanical Turk to recruit adults residing in the United States. A total of 349 participants were randomly allocated to view either the interactive tool (intervention) or a series of bar charts (control). The primary endpoint was decisional conflict, and secondary endpoints included decision self-efficacy, preparation for decision making, and the overall ranking of statins. RESULTS: A total of 258 participants completed the trial and were included in the analysis. On the primary outcome, participants randomized to the interactive tool had significantly lower levels of decisional conflict than those in the control group (difference, -8.53; 95% confidence interval [CI], -12.96 to -4.11 on a 100-point scale; P = 0.001). They also appeared to have higher levels of preparation for decision making (difference, 4.19; 95% CI, -0.24 to 8.63 on a 100-point scale; P = 0.031). No difference was found for decision self-efficacy, although groups were statistically significantly different in how they ranked different statins. CONCLUSION: The findings of our proof-of-concept evaluation suggest that an interactive web-based tool combining published clinical evidence with individual preferences can reduce decisional conflict and better prepare individuals for decision making.

Intermediate hyperglycaemia to predict progression to type 2 diabetes (ELSA-Brasil): an occupational cohort study in Brazil.

BACKGROUND: The burden of diabetes is increasing worldwide and diabetes can be prevented with intervention in people with impaired glucose tolerance (IGT). Intermediate hyperglycaemia defined without an oral glucose tolerance test as impaired fasting glucose (IFG) and high HbA1c are also used to characterise risk. We aimed to assess the prognostic properties of five definitions of intermediate hyperglycaemia (also known as prediabetes) on the basis of their ability to predict who will progress to diabetes. METHODS: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is an occupational cohort study of active or retired civil servants, aged 35-74 years, recruited from public universities and research institutes in six state capital cities in Brazil. We excluded participants who provided insufficient information to ascertain diabetes status, those without information on relevant covariates, and those with diabetes. We classified type 2 diabetes on the basis of self-report, medication use, measures of fasting plasma glucose (FPG), 2 h plasma glucose, and HbA1c. We used five laboratory definitions of intermediate hyperglycaemia: IGT (2 h plasma glucose ≥7·8 mmol/L [≥140 mg/dL]); IFG based on American Diabetes Association (ADA) criteria (FPG ≥5·5 mmol/L [≥100 mg/dL]); IFG based on WHO criteria (FPG ≥6·1 mmol/L [≥110 mg/dL]); HbA1c based on ADA criteria (HbA1c ≥39 mmol/mol [5·7%]); and HbA1c based on International Expert Committee criteria, IEC-HbA1c, (HbA1c ≥42 mmol/mol [6·0%]). We estimated risk of each definition using Cox regression and overall predictability (area under the receiver operating characteristic curve [AUC]) using logistic regression. FINDINGS: We recruited 15 105 participants from Aug 18, 2008, to Dec 20, 2010, and followed up for a mean of 3·7 (SD 0·63) years. Diabetes incidence rate was 2·0 per 100 person-years (95% CI 1·8-2·1). Among the 11 199 eligible participants, 6563 (59%) presented with some form of intermediate hyperglycaemia. ADA-IFG (4870/11 199 [43·5%), IEC-HbA1c (1005 [9·0%]), and ADA-HbA1c (2299 [20·5%]) poorly predicted diabetes (3·5-3·6 per 100 person-years). WHO-IFG (1140 [10·2%]) and IGT (2245 [20·0%]) predicted greater conversion (7·5 per 100 person-years and 5·8 per 100 person-years, respectively). All definitions presented either low sensitivity or specificity. Combinations of tests improved prognostic properties, with the combination of IGT or WHO-IFG showing the best, but still insufficient, predictability (sensitivity 67·7%, 95% CI 64·5-70·1; specificity 77·9%, 77·1-78·7). The AUC for the three underlying glycaemic tests was 65·0% (95% CI 63·0-66·9) for HbA1c, 74·6% (72·7-76·4) for FPG, and 77·1% (75·4-78·8) for 2 h plasma glucose, whereas the AUC for a score composed of clinical information was 71·6% (69·8-73·3). When this score was combined with results of an oral glucose tolerance test, the AUC reached 82·4% (80·9-83·9). INTERPRETATION: IFG based on WHO criteria and IGT predict diabetes progression better than do the other three definitions of intermediate hyperglycaemia, but their sensitivity is low. IFG based on ADA criteria has better sensitivity than the others, but classifies almost half of adults as having intermediate hyperglycaemia and poorly predicts diabetes. Combining glycaemic results with clinical information improves prognostic properties of those at risk. FUNDING: The Brazilian Ministry of Health (Science and Technology Department), the Brazilian Ministry of Science, Technology and Innovation (Financiadora de Estudos e Projetos and Conselho Nacional de Desenvolvimento Científico e Tecnológico), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES).

Personalizing Second-Line Type 2 Diabetes Treatment Selection: Combining Network Meta-analysis, Individualized Risk, and Patient Preferences for Unified Decision Support.

BACKGROUND: Personalizing medical treatment often requires practitioners to compare multiple treatment options, assess a patient's unique risk and benefit from each option, and elicit a patient's preferences around treatment. We integrated these 3 considerations into a decision-modeling framework for the selection of second-line glycemic therapy for type 2 diabetes. METHODS: Based on multicriteria decision analysis, we developed a unified treatment decision support tool accounting for 3 factors: patient preferences, disease outcomes, and medication efficacy and safety profiles. By standardizing and multiplying these 3 factors, we calculated the ranking score for each medication. This approach was applied to determining second-line glycemic therapy by integrating 1) treatment efficacy and side-effect data from a network meta-analysis of 301 randomized trials ( N = 219,277), 2) validated risk equations for type 2 diabetes complications, and 3) patient preferences around treatment (e.g., to avoid daily glucose testing). Data from participants with type 2 diabetes in the U.S. National Health and Nutrition Examination Survey (NHANES 2003-2014, N = 1107) were used to explore variations in treatment recommendations and associated quality-adjusted life-years given different patient features. RESULTS: Patients at the highest microvascular disease risk had glucagon-like peptide 1 agonists or basal insulin recommended as top choices, whereas those wanting to avoid an injected medication or daily glucose testing had sodium-glucose linked transporter 2 or dipeptidyl peptidase 4 inhibitors commonly recommended, and those with major cost concerns had sulfonylureas commonly recommended. By converting from the most common sulfonylurea treatment to the model-recommended treatment, NHANES participants were expected to save an average of 0.036 quality-adjusted life-years per person (about a half month) from 10 years of treatment. CONCLUSIONS: Models can help integrate meta-analytic treatment effect estimates with individualized risk calculations and preferences, to aid personalized treatment selection.

Estimation of global insulin use for type 2 diabetes, 2018-30: a microsimulation analysis.

BACKGROUND: The amount of insulin needed to effectively treat type 2 diabetes worldwide is unknown. It also remains unclear how alternative treatment algorithms would affect insulin use and disability-adjusted life-years (DALYs) averted by insulin use, given that current access to insulin (availability and affordability) in many areas is low. The aim of this study was to compare alternative projections for and consequences of insulin use worldwide under varying treatment algorithms and degrees of insulin access. METHODS: We developed a microsimulation of type 2 diabetes burden from 2018 to 2030 across 221 countries using data from the International Diabetes Federation for prevalence projections and from 14 cohort studies representing more than 60% of the global type 2 diabetes population for HbA1c, treatment, and bodyweight data. We estimated the number of people with type 2 diabetes expected to use insulin, international units (IU) required, and DALYs averted per year under alternative treatment algorithms targeting HbA1c from 6·5% to 8%, lower microvascular risk, or higher HbA1c for those aged 75 years and older. FINDINGS: The number of people with type 2 diabetes worldwide was estimated to increase from 405·6 million (95% CI 315·3 million-533·7 million) in 2018 to 510·8 million (395·9 million-674·3 million) in 2030. On this basis, insulin use is estimated to increase from 516·1 million 1000 IU vials (95% CI 409·0 million-658·6 million) per year in 2018 to 633·7 million (500·5 million-806·7 million) per year in 2030. Without improved insulin access, 7·4% (95% CI 5·8-9·4) of people with type 2 diabetes in 2030 would use insulin, increasing to 15·5% (12·0-20·3) if insulin were widely accessible and prescribed to achieve an HbA1c of 7% (53 mmol/mol) or lower. If HbA1c of 7% or lower was universally achieved, insulin would avert 331 101 DALYs per year by 2030 (95% CI 256 601-437 053). DALYs averted would increase by 14·9% with access to newer oral antihyperglycaemic drugs. DALYs averted would increase by 44·2% if an HbA1c of 8% (64 mmol/mol) were used as a target among people aged 75 years and older because of reduced hypoglycaemia. INTERPRETATION: The insulin required to treat type 2 diabetes is expected to increase by more than 20% from 2018 to 2030. More DALYs might be averted if HbA1c targets are higher for older adults. FUNDING: The Leona M and Harry B Helmsley Charitable Trust.