HbA1c trajectories over 3 years in people with type 2 diabetes starting second-line glucose-lowering therapy: The prospective global DISCOVER study.

AIM: To identify distinct HbA1c trajectories in people with type 2 diabetes (T2D) starting second-line glucose-lowering therapy. MATERIALS AND METHODS: DISCOVER was a 3-year observational study of individuals with T2D beginning second-line glucose-lowering therapy. Data were collected at initiation of second-line treatment (baseline) and at 6, 12, 24 and 36 months. Latent class growth modelling was used to identify groups with distinct HbA1c trajectories. RESULTS: After exclusions, 9295 participants were assessed. Four distinct HbA1c trajectories were identified. Mean HbA1c levels decreased between baseline and 6 months in all groups; 72.4% of participants showed stable good levels of glycaemic control over the remainder of follow-up, 18.0% showed stable moderate levels of glycaemic control and 2.9% showed stable poor levels of glycaemic control. Only 6.7% of participants showed highly improved glycaemic control at month 6 and stable control over the rest of follow-up. For all groups, dual oral therapy use decreased over time, compensated for by the increasing use of other treatment regimens. Use of injectable agents increased over time in groups with moderate and poor glycaemic control. Logistic regression models suggested that participants from high-income countries were more probable to be in the stable good trajectory group. CONCLUSIONS: Most people receiving second-line glucose-lowering treatment in this global cohort achieved stable good or highly improved long-term glycaemic control. One-fifth of participants showed moderate or poor glycaemic control during follow-up. Further large-scale studies are required to characterize possible factors associated with patterns of glycaemic control to inform personalized diabetes treatment.

Treatment patterns and glycated haemoglobin levels over 36 months in individuals with type 2 diabetes initiating second-line glucose-lowering therapy: The global DISCOVER study.

AIMS: To describe glucose-lowering treatment regimens and glycated haemoglobin (HbA1c) trajectories in individuals with type 2 diabetes (T2D) over 36 months of follow-up from the start of second-line therapy. MATERIALS AND METHODS: This data analysis from the 3-year, observational DISCOVER study programme included 14 687 participants from 37 countries with T2D initiating second-line glucose-lowering therapy. Treatment and HbA1c data were collected at baseline (start of second-line therapy) and at 6, 12, 24 and 36 months. Treatment regimen changes over follow-up were analysed using the McNemar test, with carry-forward imputation for intermediate missing values. RESULTS: A total of 11 592 participants had treatment data at baseline and 36 months, and 11 882 had HbA1c data at baseline. At baseline and 36 months, respectively, rates of oral monotherapy use were 12.1% and 12.4% (P = 0.22), rates of dual oral therapy use were 63.4% and 47.6% (P < 0.0001), rates of ≥ triple oral therapy use were 17.5% and 25.4% (P < 0.0001), and rates of injectable treatment use were 7.0% and 13.7% (P < 0.0001). Use of injectable drugs was most common among participants with an HbA1c level ≥64 mmol/mol (≥8.0%). Overall, 42.9% of participants changed treatment during follow-up. Mean HbA1c levels at baseline and 6 months were 67 mmol/mol (8.3%) and 55 mmol/mol (7.2%), respectively, remaining stable thereafter. CONCLUSIONS: Dual oral therapy was the most common treatment regimen at the start of second-line treatment, and over half of the participants remained on the same treatment during follow-up.

HLA Genotypes and Type 1 Diabetes and Its Relationship to Reported Race/Skin Color in Their Relatives: A Brazilian Multicenter Study.

We aimed to investigate the relationship between HLA alleles in patients with type 1 diabetes from an admixed population and the reported race/skin color of their relatives. This cross-sectional, multicenter study was conducted in public clinics in nine Brazilian cities and included 662 patients with type 1 diabetes and their relatives. Demographic data for patients and information on the race/skin color and birthplace of their relatives were obtained. Typing of the HLA-DRB1, -DQA1, and -DQB1 genes was performed. Most studied patients reported having a White relative (95.17%), and the most frequently observed allele among them was DRB1*03:01. Increased odds of presenting this allele were found only in those patients who reported having all White relatives. Considering that most of the patients reported having a White relative and that the most frequent observed allele was DRB1*03:01 (probably a European-derived allele), regardless of the race/skin color of their relatives, we conclude that the type 1 diabetes genotype comes probably from European, Caucasian ethnicity. However, future studies with other ancestry markers are needed to fill the knowledge gap regarding the genetic origin of the type 1 diabetes genotype in admixed populations such as the Brazilian.

Factors associated with weight loss in people with overweight or obesity living with type 2 diabetes mellitus: Insights from the global DISCOVER study.

AIMS: To estimate real-world change in weight over 3 years and the factors influencing it in participants who are overweight and live with type 2 diabetes. MATERIALS AND METHODS: DISCOVER is a multinational prospective observational study that enrolled participants with type 2 diabetes between December 2014 and June 2016 at the time of initiation of a second-line glucose-lowering medication (GLM). Demographic, anthropometric, and quality-of-life data were collected at baseline, and after 6, 12, 24 and 36 months of follow-up. Using a hierarchical, repeated-measures linear regression model, we examined factors associated with weight change over time. RESULTS: Of 10 675 participants with type 2 diabetes who were overweight/obese (mean age 57.1 ± 11.1 years, 46% women), 21% lost ≥5% weight over 3 years, which was associated with modestly improved physical and mental health. Advancing age, female sex, and higher baseline weight were associated with weight loss. Most importantly, the type of GLM prescribed at previous visit had the strongest impact on weight change over time independent of participant factors, with use of a sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist associated with 1.0% weight loss versus a 0.6% weight gain with sulphonylureas, thiazolidinediones, meglitinides or insulin. CONCLUSION: In this large contemporary prospective study, approximately one in five participants with early-stage type 2 diabetes and overweight/obesity lost ≥5% weight over 3 years. The type of GLM has the most impact on weight loss over time, highlighting the need for a careful selection of agents that takes baseline weight into consideration.

Socioeconomic Factors Associated With Glycemic Measurement and Poor HbA1c Control in People With Type 2 Diabetes: The Global DISCOVER Study.

DISCOVER is a 3-year observational study program of 15,983 people with type 2 diabetes initiating second-line glucose-lowering therapy in 38 countries. We investigated the association between socioeconomic status and both the availability of a baseline glycated hemoglobin (HbA1c) measurement and poor glycemic control (HbA1c level ≥ 9.0%) in participants enrolled in DISCOVER. Factors associated with a lack of baseline HbA1c measurement or an HbA1c level ≥ 9.0% were assessed using three-level hierarchical logistic models. Overall, 19.1% of participants did not have a baseline HbA1c measurement recorded. Lower-middle country income (vs. high) and primary/no formal education (vs. university education) were independently associated with a reduced likelihood of having a baseline HbA1c measurement (odds ratio [95% confidence interval]: 0.11 [0.03-0.49] and 0.81 [0.66-0.98], respectively. Of the participants with an available HbA1c measurement, 26.9% had an HbA1c level ≥ 9.0%; 68.7% of these individuals were from lower- or upper-middle-income countries. Factors associated with an increased likelihood of poor glycemic control included low country income, treatment at a site with public and/or governmental funding (vs. private funding) and having public or no health insurance (vs. private). A substantial proportion of DISCOVER participants did not have an HbA1c measurement; more than one-quarter of these participants had poorly controlled type 2 diabetes. Both individual- and country-level socioeconomic factors are associated with the quality of care regarding glycemic control. Awareness of these factors could help improve the management of patients with type 2 diabetes.

Global use of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. Results from DISCOVER.

BACKGROUND: Despite strong evidence of benefit, uptake of newer glucose-lowering medications that reduce cardiovascular risk has been low. We sought to examine global trends and predictors of use of SGLT2i and GLP-1 RA in patients with type 2 diabetes. METHODS: DISCOVER is a global, prospective, observational study of patients with diabetes enrolled from 2014-16 at initiation of second-line glucose-lowering therapy and followed for 3 years. We used hierarchical logistic regression to examine factors associated with use of either an SGLT2i or GLP-1 RA at last follow-up and to assess country-level variability. RESULTS: Among 14,576 patients from 37 countries, 1579 (10.8%) were started on an SGLT2i (1275; 8.7%) or GLP-1 RA (318; 2.2%) at enrollment, increasing to 16.1% at end of follow-up, with large variability across countries (range 0-62.7%). Use was highest in patients treated by cardiologists (26.1%) versus primary care physicians (10.4%), endocrinologists (16.9%), and other specialists (22.0%; p < 0.001). Coronary artery disease (OR 1.29, 95% CI 1.08-1.54) was associated with greater use of SGLT2i or GLP-1 RA while peripheral artery disease (OR 0.73, 95% CI 0.54-1.00) and chronic kidney disease (OR 0.73, 95% CI 0.58-0.94) were associated with lower use (OR 0.73, 95% CI 0.54-1.00). The country-level median odds ratio was 3.48, indicating a very large amount of variability in the use of SGLT2i or GLP-1 RA independent of patient demographic and clinical factors. CONCLUSIONS: Global use of glucose-lowering medications with established cardiovascular benefits has increased over time but remains suboptimal, particularly in sub-groups most likely to benefit. Substantial country-level variability exists independent of patient factors, suggesting structural barriers may limit more widespread use of these medications.

Quality of life in people with type 2 diabetes in the 3 years following initiation of second-line therapy: The DISCOVER study.

AIMS: To assess changes in health-related quality of life (HRQoL) in DISCOVER, a 3-year, longitudinal, observational study of patients with type 2 diabetes initiating a second-line glucose-lowering therapy. METHODS: HRQoL was assessed using the physical and mental component summary (PCS and MCS) scores of the 36-item Short-Form Health Survey version 2 (score ranges: 0-100; higher denotes better HRQoL) and the Hypoglycaemia Fear Survey II (HFS-II; score range: 0-132 scale; higher indicates greater fear of hypoglycaemia). Latent class growth modelling (LCGM) was used to identify patients with similar score trajectories. RESULTS: Mean baseline PCS (n = 7428), MCS (n = 7453), and HFS-II (n = 5005) scores were 48.0, 45.4, and 15.4, respectively, and remained stable during follow-up. LCGM revealed subgroups with low or decreasing HRQoL. Patients in these subgroups tended to be older, had more comorbidities, and a lower socioeconomic status than in other subgroups. Use of insulin and sulfonylureas was highest in the subgroup with the highest fear of hypoglycaemia. CONCLUSIONS: Overall, HRQoL remained stable in DISCOVER patients during follow-up. However, LCGM suggests that some patient characteristics and use of sulfonylureas or insulin are associated with low or decreasing HRQoL, potentially warranting the use of alternative therapies.

Pragmatic Clinic-Based Investigation of Glycemic Variability in Patients With Type 1 Diabetes in Routine Clinical Practice and Its Association With Cardiovascular Autonomic Neuropathy: A Pilot Study.

OBJECTIVE: To evaluate the relationship between markers of glycemic variability (GV), assessed by blinded continuous glucose monitoring (CGM), and cardiovascular autonomic neuropathy (CAN) in patients with type 1 diabetes (T1D). METHODS: GV indices, such as SD and coefficient of variation were obtained by blinded CGM through an electrode inserted into the subcutaneous tissue for at least 3 consecutive days. CAN was assessed by cardiovascular reflex tests and HRV. RESULTS: Fifteen T1D patients were included: 7 (46.7%) women, aged 47.1 ± 11.6 years, with a diabetes duration of 26 years (20 to 29.5 years). Five patients (25%) were excluded from our study. The majority of our patients presented glycated hemoglobin (60%), SD (86.3%), and coefficient of variation (60%) above the established goals. Patients with defined CAN had a longer diabetes duration, higher glycated hemoglobin levels, lower glomerular filtration rate, lower prevalence of indices related to hypoglycemic stress, and short-term GV indices compared with patients without CAN. CONCLUSION: Our study showed an inverse association between GV and CAN. The most important risk factors associated with CAN were age, diabetes duration, and markers of chronic hyperglycemia. Furthermore, the difficulty in the interpretation of data extracted from the blinded CGM system, which also requires a minimum of 3 capillary blood glucose measurements for calibration, should be carefully analyzed to ensure the accuracy and usefulness of the blinded CGM system as a tool for diabetes management in developing countries. Further studies are necessary to establish the role of GV in the development of CAN in patients with T1D.

Impact of micro- and macrovascular complications of type 2 diabetes on quality of life: Insights from the DISCOVER prospective cohort study.

BACKGROUND: The key goals of management in patients with type 2 diabetes (T2D) are to prolong life and improve quality of life. Micro- and macrovascular complications of T2D not only increase the risk of morbidity and mortality, but cross-sectional studies indicate they may also worsen quality of life. We prospectively examined the association of complications that developed during the follow-up with concurrent changes in quality of life. MATERIALS AND METHODS: DISCOVER is a multinational, prospective, observational cohort study of T2D patients enrolled at initiation of second-line glucose-lowering therapy. Quality of life was assessed with the SF-36 Physical (PCS) and Mental Components Summary (MCS) scores at baseline, 6 months, and 1, 2 and 3 years. Hierarchical repeated measures regression models for PCS and MCS were constructed with complications included as time-dependent covariates; first each complication was modelled alone and then second including all interval complications (to account for different complications occurring in the same patient). RESULTS: Among 7830 patients with T2D from 30 countries (mean age 56.6 years, 47.6% women, mean duration of T2D 5.6 years), baseline mean SF-36 PCS was 48.0 ± 7.8 and SF-36 MCS was 45.5 ± 10.4. At baseline, 1422 (18.2%) patients had a known microvascular complication, and 966 (12.3%) had a macrovascular complication. Over the 3 years of the study, 641 (12.0%) developed a new microvascular complication (most commonly neuropathy) and 372 (5.8%) developed a new macrovascular complication (most commonly coronary disease). New diagnoses of coronary disease, peripheral artery disease, heart failure and neuropathy were each associated with subsequent moderate reductions in SF-36 PCS (range 0.7 to 1.6 points) and new cerebrovascular disease was associated with a reduction in SF-36 MCS (2.6 points). Results were consistent when all interval complications were considered in the same model. CONCLUSION: In a prospective, multinational study of patients with T2D, the development of macrovascular complications and neuropathy was associated with decreases in both physical and mental quality of life. Our results provide additional support for clinicians to focus on the prevention, detection and management of the complications of T2D.

Incidence rates and predictors of microvascular and macrovascular complications in patients with type 2 diabetes: Results from the longitudinal global discover study.

BACKGROUND: Micro- and macrovascular complications are a major cause of morbidity and mortality in people with type 2 diabetes (T2D). We sought to understand the global incidence rates and predictors of these complications. METHODS: We examined the incidence of vascular complications over 3 years of follow-up in the DISCOVER study-a global, observational study of people with T2D initiating second-line glucose-lowering therapy. Hierarchical Cox proportional hazards regression models examined factors associated with development of micro- and macrovascular complications during follow-up. RESULTS: Among 11,357 people with T2D from 33 countries (mean age 56.9 ± 11.7 years, T2D duration 5.7 ± 5.1 years, HbA1c 8.4 ± 1.7%), 19.0% had a microvascular complication at enrolment (most commonly neuropathy), and 13.2% had a macrovascular complication (most commonly coronary disease). Over 3 years of follow-up, 16.0% developed an incident microvascular complication, and 6.6% had an incident macrovascular complication. At the end of 3 years of follow-up, 31.5% of patients had at least one microvascular complication, and 16.6% had at least one macrovascular complication. Higher HbA1c and smoking were associated with greater risk of both incident micro- and macrovascular complications. Known macrovascular complications at baseline was the strongest predictor for development of new microvascular complications (HR 1.40, 95% CI 1.21 -1.61) and new macrovascular complications (HR 3.39, 95% CI 2.84 -4.06). CONCLUSIONS: In this global study, both the prevalence and 3-year incidence of vascular complications were high in patients with relatively short T2D duration, highlighting the need for early risk-factor modification.

Health-related quality of life in patients with type 2 diabetes initiating a second-line glucose-lowering therapy: The DISCOVER study.

AIM: To investigate factors associated with health-related quality of life (HRQoL) in patients with type 2 diabetes mellitus (T2D) at initiation of second-line glucose-lowering therapy. METHODS: DISCOVER is a 3-year, prospective observational study of patients with T2D initiating second-line glucose-lowering therapy, conducted in 38 countries. HRQoL at baseline was assessed using the physical and mental component summary (PCS; MCS) scores of the 36-Item Short Form Health Survey version 2 (SF-36v2) in 31 countries (n = 8309) and the Hypoglycaemia Fear Survey-II (HFS-II) in 23 countries (n = 6516). Factors associated with differences in HRQoL were assessed using multivariable hierarchical regression models. RESULTS: Mean PCS and MCS scores were 48.0 (standard deviation [SD]: 7.8) and 45.5 (SD: 10.4), respectively. Factors associated with significantly lower SF-36v2 scores included being female, having a history of macrovascular complications and first-line treatment with oral combinations (vs metformin monotherapy). Mean HFS-II behaviour and worry scores were 8.2 (SD: 9.9) and 7.3 (SD: 11.8), respectively. Increased fear of hypoglycaemia was significantly associated with lower SF-36v2 scores. CONCLUSIONS: Several patient-, disease- and treatment-related characteristics correlated with HRQoL, indicating that a multifactorial approach is needed to maintain HRQoL in patients with T2D.

Prevalence and progression of chronic kidney disease among patients with type 2 diabetes: Insights from the DISCOVER study.

We report the prevalence and change in severity of chronic kidney disease (CKD) in DISCOVER, a global, 3-year, prospective, observational study of patients with type 2 diabetes (T2D) initiating second-line glucose-lowering therapy. CKD stages were defined according to estimated glomerular filtration rate (eGFR). Overall, 7843 patients from 35 countries had a baseline serum creatinine measurement. Of these (56.7% male; mean age: 58.1 years; mean eGFR: 87.5 mL/min/1.73 m2 ), baseline prevalence estimates for stage 0-1, 2, 3 and 4-5 CKD were 51.4%, 37.7%, 9.4% and 1.4%, respectively. A total of 5819 patients (74.2%) also had at least one follow-up serum creatinine measurement (median time between measurements: 2.9 years, interquartile range: 1.9-3.0 years). Mean eGFR decreased slightly to 85.7 mL/min/1.73 m2 over follow-up. CKD progression (increase of ≥1 stage) occurred in 15.7% of patients, and regression (decrease of ≥1 stage) in 12.0%. In summary, a substantial proportion of patients with T2D developed CKD or had CKD progression after the initiation of second-line therapy. Renal function should be regularly monitored in these patients, to ensure early CKD diagnosis and treatment.

Associations between second-line glucose-lowering combination therapies with metformin and HbA1c, body weight, quality of life, hypoglycaemic events and glucose-lowering treatment intensification: The DISCOVER study.

AIM: To explore the effects of second-line combination therapies with metformin on body weight, HbA1c and health-related quality of life, as well as the risks of hypoglycaemia and further treatment intensification in the DISCOVER study, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy. MATERIALS AND METHODS: Adjusted changes from baseline in weight, HbA1c and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24 and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses. RESULTS: At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor (8.3%) or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8%-1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor or a GLP-1 receptor agonist was associated with greater weight loss (1.9, 2.9 and 5.0 kg, respectively) than metformin plus an SU (1.3 kg, P < .0001). Proportions of further treatment intensification were similar across combinations (19.9%-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9%-6.4%, P < .0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU. CONCLUSIONS: Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia and lower SF-36v2 scores.

Type 2 diabetes and heart failure: insights from the global DISCOVER study.

AIMS: Heart failure (HF) is increasingly recognized as a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), but the global epidemiology and treatment of HF in T2D are not well defined. This study aimed to examine the global prevalence of HF and the incidence of HF over 3 years of follow-up in patients with T2D [by presence and absence of co-existing coronary artery disease (CAD)]. METHODS AND RESULTS: DISCOVER was a 3 year, prospective, observational study of T2D patients enrolled at initiation of second-line glucose-lowering therapy. Among 14 057 patients with T2D from 36 countries, 289 (2.1%) had a diagnosis of HF at enrolment; median prevalence across countries was 2.0% (inter-quartile range 1.0-3.1%). Patients with HF at baseline were more likely to be older [HF vs. no HF: 67 ± 12 vs. 57 ± 12 years, standardized difference (StDiff) = 84%] and have longer duration of T2D (8.1 ± 7.2 vs. 5.6 ± 5.2 years, StDiff = 40%), CAD (44% vs. 6%, StDiff = 97%), atrial fibrillation (21% vs. 1%, StDiff = 66%), and kidney disease (23% vs. 4%, StDiff = 55%). Patients with HF were less likely to be on metformin (66% vs. 79%, StDiff = 28%) and thiazolidinediones (5.5% vs. 10.6%, StDiff = 19%) but had similar use of other glucose-lowering medications. Among 9313 patients with follow-up data, there were 70 incident cases of HF, which translates to an incidence of 2.6 cases per 1000 person years. Of these incident HF cases, 60% occurred in the absence of pre-existing or concomitant CAD, and 73% were diagnosed in the outpatient setting. CONCLUSIONS: In a large, global cohort of patients with T2D, the majority of incident cases of HF occurred in outpatients and in the absence of known CAD. These findings highlight the need for greater awareness of HF risk in patients with T2D.

Global patterns of comprehensive cardiovascular risk factor control in patients with type 2 diabetes mellitus: Insights from the DISCOVER study.

AIM: To investigate global patterns of cardiovascular risk factor control in patients with type 2 diabetes mellitus (T2D). METHODS: DISCOVER is an international, observational cohort study of patients with T2D beginning second-line glucose-lowering therapy. Risk factor management was examined among eligible patients (ie, those with the risk factor) at study baseline. Inter-country variability was estimated using median odds ratios (MORs). RESULTS: Among 14 343 patients with T2D from 34 countries, the mean age was 57.4 ± 12.0 years and the median (interquartile range) duration of T2D was 4.2 (2.0-8.0) years; 11.8% had documented atherosclerotic cardiovascular disease (ASCVD). Among eligible patients, blood pressure was controlled in 67.5% (9284/13756), statins were prescribed in 43.7% (5775/13208), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers were prescribed in 55.6% (5292/9512), aspirin was prescribed in 53.3% of those with established ASCVD (876/1645), and 84.4% (12 102/14343) were non-smoking. Only 21.5% of patients (3088/14343) had optimal risk factor management (defined as control of all eligible measures), with wide inter-country variability (10%-44%), even after adjusting for patient and site differences (MOR 1.47, 95% confidence interval 1.24-1.66). CONCLUSION: Globally, comprehensive control of ASCVD risk factors is not being achieved in most patients, with wide variability among countries unaccounted for by patient and site differences. Better country-specific strategies are needed to implement comprehensive cardiovascular risk factor control consistently in patients with T2D to improve long-term outcomes.

Metformin discontinuation in patients beginning second-line glucose-lowering therapy: results from the global observational DISCOVER study programme.

OBJECTIVES: To evaluate the extent to which patients with type 2 diabetes discontinue metformin therapy when initiating second-line treatment and factors associated with metformin discontinuation, using baseline data from the DISCOVER study programme. DESIGN: DISCOVER is a 3-year, prospective, observational study programme including data from 38 countries across 6 continents from 2014 to 2019. SETTING: Primary and secondary healthcare centres, hospitals and specialist diabetes centres in both urban and rural locations. PARTICIPANTS: A total of 15 992 patients with type 2 diabetes initiating second-line glucose-lowering therapy. PRIMARY AND SECONDARY OUTCOME MEASURES: The proportion of patients who discontinued metformin as a second-line therapy and the factors associated with this treatment change. RESULTS: Of the 14 668 patients (from 37 countries) with valid treatment data, 11 837 (80.7%) received metformin as first-line glucose-lowering therapy; 8488 (71.7%) received metformin monotherapy and 3349 (28.3%) received metformin as part of a combination therapy. Overall, treatment with metformin was discontinued in 15.1% (1782) of patients who received first-line metformin (14.1% (1194) and 17.6% (588) in those who received metformin as monotherapy and as part of a combination, respectively); this proportion varied across regions from 6.9% (54) in Africa to 20.6% (628) in South-East Asia. On metformin discontinuation, 73.6% (1311) of patients received a non-insulin monotherapy at second line. Factors associated with an increased odds of metformin discontinuation were older age (≥75 years) and having a history of chronic kidney disease. The probability of metformin monotherapy discontinuation was lower in patients from Africa than in those from Europe. CONCLUSIONS: A substantial number of patients discontinued taking metformin when beginning second-line therapy. Most of these patients subsequently received a non-insulin monotherapy at second line, in contradiction to international guidelines and potentially leaving them at an increased risk of hyperglycaemia and associated adverse outcomes. TRIAL REGISTRATION NUMBERS: NCT02322762 and NCT02226822.

Socioeconomic factors associated with hypoglycaemia in patients starting second-line glucose-lowering therapy: The DISCOVER study.

AIMS: Using data from DISCOVER (NCT02322762; NCT02226822), a 3-year, global, observational study programme of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we assessed socioeconomic factors associated with hypoglycaemic events and fear of hypoglycaemia. METHODS: Data were collected at baseline (second-line therapy initiation) and 6, 12 and 24 months. Factors associated with experiencing a hypoglycaemic event at baseline or during follow-up were determined using a hierarchical logistic regression model and an interval-censored survival analysis, respectively. Fear of hypoglycaemia was assessed using the hypoglycaemia fear survey-II (HFS-II). RESULTS: The overall proportion of patients reporting hypoglycaemic events during follow-up was 7.3%; this was higher in middle-income countries than in high-income countries (8.4% vs 5.8%, p < 0.001). Factors associated with an increased risk of hypoglycaemia during follow-up included living in a country with a low gross national income, use of glucose-monitoring equipment and second-line treatment with insulin, meglitinides or sulphonylureas (versus metformin). Experiencing hypoglycaemia was associated with increased HFS-II worry and overall scores. CONCLUSIONS: Our results highlight the global inequity in the treatment of type 2 diabetes. Increased risk of hypoglycaemia in middle-income countries may be explained by limited treatment options and may be underestimated because of limited access to glucose-monitoring equipment.

Novel Mutation in the Hemojuvelin Gene (HJV) in a Patient with Juvenile Hemochromatosis Presenting with Insulin-dependent Diabetes Mellitus, Secondary Hypothyroidism and Hypogonadism.

BACKGROUND Juvenile hemochromatosis is a rare genetic disease that leads to intense iron accumulation. The disease onset usually occurs before the third decade of life and causes severe dysfunction in various organs. The most classical clinical findings are hypogonadotropic hypogonadism, cardiomyopathy, liver fibrosis, glycemic changes, arthropathy and skin pigmentation. However, secondary hypothyroidism is not reported in these patients. Juvenile hemochromatosis has an autosomal recessive inheritance and might be type 2A or type 2B, due to mutation in either the hemojuvelin gene (HJV) or hepcidin antimicrobial peptide (HAMP) gene. CASE REPORT A 26-year-old female patient was admitted with a recent history of diabetic ketoacidosis. Three months after that admission, she presented with arthralgia, diffuse abdominal pain, adynamia, hair loss, darkening of the skin and amenorrhea. Severe iron overload was found and findings in the hepatic biopsy were compatible with hemochromatosis. An upper abdominal magnetic resonance imaging (MRI) showed iron deposition in the liver and pancreas and pituitary MRI exhibited accumulation on the anterior pituitary. After 16 months the patient presented with dyspnea and lower limb edema, and cardiac MRI indicated iron deposition in the myocardium. The patient was diagnosed with juvenile hemochromatosis presenting with hypogonadotropic hypogonadism, cardiomyopathy, insulin-dependent diabetes mellitus, and secondary hypothyroidism. A novel homozygous mutation, c.697delC, in the HJV gene was detected. CONCLUSIONS We describe for the first time a severe and atypical case of juvenile hemochromatosis type 2A presenting classical clinical features, as well as secondary hypothyroidism resulting from a novel mutation in the HJV gene.

Genomic ancestry and glycemic control in adolescents with type 1 diabetes: A multicenter study in Brazil.

OBJECTIVE: To determine the influence of genomic ancestry (GA) and self-reportedcolor-race (SRCR) on glycemic control in adolescents with type 1 diabetes (T1D) in an admixed population. RESEARCH DESIGN AND METHODS: This multicenter nationwide study was conducted in 14 public clinics in 10 Brazilian cities. We estimated global and individual African, European, and Native Amerindian GA proportions using a panel of 46 AIM-INDEL markers. From 1760 patients, 367 were adolescents (20.9%): 184 female (50.1%), aged 16.4 ± 1.9 years, age at diagnosis 8.9 ± 4.3 years, duration of diabetes 8.1 ± 4.3 years, years of study 10.9 ± 2.5 and HbA1c of 9.6 ± 2.4%. RESULTS: Patients SRCR as White: 176 (48.0%), Brown: 159 (43.3%), Black: 19(5.2%), Asians: 5 (1.4%) and Amerindians: 8 (2.2%). The percentage of European GA prevailed in all groups: White (71.1), Brown (58.8), Black (49.6), Amerindians (46.1), and Asians (60.5). Univariate correlation was noted between A1c and African GA, r = 0.11, P = .03; years of study, r = -0.12 P = .010, and having both private and public health care insurance (r = -0.20, P < .001). After adjustments, the multivariate logistic analysis showed that SRCR or GA did not influence glycemic control. CONCLUSIONS: A high percentage of European GA was noted in our patients, even in those who self-reported as non-White, confirming the highly admixed ethnicity of the Brazilian population. Better glycemic control was associated with having both types of health care; however, there was no association between glycemic control with GA or SRCR. Future prospective studies with other admixed populations are necessary to confirm our findings.

Health literacy and glycemic control in patients with diabetes: a tertiary care center study in Brazil.

BACKGROUND: The primary objective of our study was to determine which factors influence health literacy (HL) in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D), and the secondary one was to evaluate the influence of HL on glycemic control. METHODS: This was an observational, cross-sectional study with 347 patients (144 with T1D and 203 with T2D), conducted between December 2014/December 2017. Data were obtained from medical records and/or questionnaire. The short test of Functional Health Literacy (S-TOFHLA) was used to evaluate HL. RESULTS: Age and years of school attendance were the most important variables associated with better performance in S-TOFHLA mainly in patients with T1D. A correlation between age and years of school attendance with S-TOFHLA score was observed in both groups of patients. After an unadjusted analysis, more patients with T1D presented adequate HL [119 (82.6%) vs 87 (44.8%, p < 0.001)]. Patients with T1D had higher scores than patients with T2D (84.4 ± 21.4 vs 61.6 ± 26.8 points, p < 0.001), respectively. This difference did not persist after adjustment for age and years of school attendance (73.04 ± 2.14 ± vs 70.04 ± 1.76 points) respectively, p = 0.348). No difference was found in HbA1c levels according to S-TOFHLA. All patients with T1D and HbA1c levels < 7.0% (53 mmol/mol) had adequate HL. CONCLUSIONS: A considerable number of patients with either T1D or T2D did not have adequate HL. Overall, age and years of school attendance were the most important variables associated with better performance of S-TOFHLA. Although no difference was found in HbA1c levels according to S-TOFHLA, patients with T1D who self-reported as White, with more years of school attendance, and higher HL score reached more frequently a good glycemic control. Finally, in addition to therapeutic regimens, approaches on diabetes management should also include patients' HL evaluation along with psychological and social aspects.