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BACKGROUND: Lower-limb peripheral artery disease is one of the major complications of diabetes. Peripheral artery disease is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the peripheral artery disease population. Praliciguat is an orally available sGC (soluble guanylate cyclase) stimulator that has been reported both preclinically and in early stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in peripheral artery disease. METHODS: We evaluated the effect of praliciguat on hind limb ischemia recovery in a mouse model of type 2 diabetes. Hind limb ischemia was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. RESULTS: Twenty-eight days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (ie, weight, glycemia) or increased angiogenesis. However, treatment with praliciguat significantly increased arteriole diameter, decreased ICAM1 (intercellular adhesion molecule 1) expression, and prevented the accumulation of oxidative proangiogenic and proinflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of praliciguat therapy, we found that praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM1 mRNA expression in endothelial cells. These results suggest that praliciguat therapy may decrease ICAM1 expression in endothelial cells by downregulating Cxcl12 in myocytes. CONCLUSIONS: Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM1 expression.
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Diabetes Mellitus Tipo 2 , Enfermedad Arterial Periférica , Ratones , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptores de Leptina/genética , Células Endoteliales/metabolismo , Isquemia/metabolismo , Modelos Animales de Enfermedad , Reperfusión , Enfermedad Arterial Periférica/complicaciones , Miembro Posterior/irrigación sanguínea , Neovascularización Fisiológica , Músculo Esquelético/metabolismo , Ratones Endogámicos C57BLRESUMEN
BACKGROUND AND AIMS: Few studies have compared arm and ankle blood pressures (BPs) with regard to peripheral artery disease (PAD) and mortality. These relationships were assessed using data from three large prospective clinical trials. METHODS: Baseline BP indices included arm systolic BP (SBP), diastolic BP (DBP), pulse pressure (arm SBP minus DBP), ankle SBP, ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). These measurements were categorized into four groups using quartiles. The outcomes were PAD (the first occurrence of either peripheral revascularization or lower-limb amputation for vascular disease), the composite of PAD or death, and all-cause death. RESULTS: Among 40 747 participants without baseline PAD (age 65.6 years, men 68.3%, diabetes 50.2%) from 53 countries, 1071 (2.6%) developed PAD, and 4955 (12.2%) died during 5 years of follow-up. Incident PAD progressively rose with higher arm BP indices and fell with ankle BP indices. The strongest relationships were noted for ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, adjusted hazard ratios (95% confidence interval) for each lower fourth were 1.64 (1.31-2.04), 2.59 (2.10-3.20), and 4.23 (3.44-5.21) for ankle SBP; 1.19 (0.95-1.50), 1.66 (1.34-2.05), and 3.34 (2.75-4.06) for ABI; and 1.41 (1.11-1.78), 2.04 (1.64-2.54), and 3.63 (2.96-4.45) for APPD. Similar patterns were observed for mortality. Ankle BP indices provided the highest c-statistics and classification indices in predicting future PAD beyond established risk factors. CONCLUSIONS: Ankle BP indices including the ankle SBP and the APPD best predicted PAD and mortality.
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Índice Tobillo Braquial , Brazo , Presión Sanguínea , Enfermedad Arterial Periférica , Humanos , Masculino , Femenino , Enfermedad Arterial Periférica/fisiopatología , Enfermedad Arterial Periférica/mortalidad , Anciano , Presión Sanguínea/fisiología , Brazo/irrigación sanguínea , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: The relationship between ankle blood pressure (BP) and cardiovascular disease remains unclear. We examined the relationships between known and new ankle BP indices and major cardiovascular outcomes in people with and without type 2 diabetes. METHODS: We used data from 3 large trials with measurements of ankle systolic BP (SBP), ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). The primary outcome was a composite of cardiovascular mortality, myocardial infarction, hospitalization for heart failure, or stroke. Secondary outcomes included death from cardiovascular causes, total (fatal and non-fatal) myocardial infarction, hospitalization for heart failure, and total stroke. RESULTS: Among 42,929 participants (age 65.6 years, females 31.3%, type 2 diabetes 50.1%, 53 countries), the primary outcome occurred in 7230 (16.8%) participants during 5 years of follow-up (19.4% in people with diabetes, 14.3% in those without diabetes). The incidence of the outcome increased with lower ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, multivariable-adjusted hazard ratios (HRs, 95% CI) of the outcome for each lower fourth were 1.05 (0.98-1.12), 1.17 (1.08-1.25), and 1.54 (1.54-1.65) for ankle SBP; HR 1.06 (0.99-1.14), 1.26 (1.17-1.35), and 1.48 (1.38-1.58) for ABI; and HR 1.02 (0.95-1.10), 1.15 (1.07-1.23), and 1.48 (1.38-1.58) for APPD. The largest effect size was noted for ankle SBP (HRs 1.05 [0.90-1.21], 1.21 [1.05-1.40], and 1.93 [1.68-2.22]), and APPD (HRs 1.08 [0.93-1.26], 1.30 [1.12-1.50], and 1.97 [1.72-2.25]) with respect to hospitalization for heart failure, while only a marginal association was observed for stroke. The relationships were similar in people with and without diabetes (all p for interaction > 0.05). CONCLUSIONS: Inverse and independent associations were observed between ankle BP and cardiovascular events, similarly in people with and without type 2 diabetes. The largest associations were observed for heart failure and the smallest for stroke. Including ankle BP indices in routine clinical assessments may help to identify people at highest risk of cardiovascular outcomes.
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Índice Tobillo Braquial , Presión Sanguínea , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/mortalidad , Femenino , Masculino , Anciano , Persona de Mediana Edad , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo , Incidencia , Medición de Riesgo , Valor Predictivo de las Pruebas , Factores de Tiempo , Pronóstico , Hospitalización , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/epidemiologíaRESUMEN
Lower extremity peripheral artery disease (PAD) often results from atherosclerosis, and is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Individuals with T2DM exhibit a more severe manifestation and a more distal distribution of PAD compared to those without diabetes, adding complexity to the therapeutic management of PAD in this particular patient population. Indeed, the management of PAD in patients with T2DM requires a multidisciplinary and individualized approach that addresses both the systemic effects of diabetes and the specific vascular complications of PAD. Hence, cardiovascular prevention is of the utmost importance in patients with T2DM and PAD, and encompasses smoking cessation, a healthy diet, structured exercise, careful foot monitoring, and adherence to routine preventive treatments such as statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. It is also recommended to incorporate glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the medical management of patients with T2DM and PAD, due to their demonstrated cardiovascular benefits. However, the specific impact of these novel glucose-lowering agents for individuals with PAD remains obscured within the background of cardiovascular outcome trials (CVOTs). In this review article, we distil evidence, through a comprehensive literature search of CVOTs and clinical guidelines, to offer key directions for the optimal medical management of individuals with T2DM and lower extremity PAD in the era of GLP-1RA and SGLT2i.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Extremidad Inferior , Enfermedad Arterial Periférica , Conducta de Reducción del Riesgo , Humanos , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/terapia , Enfermedad Arterial Periférica/epidemiología , Enfermedad Arterial Periférica/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Extremidad Inferior/irrigación sanguínea , Resultado del Tratamiento , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Valor Predictivo de las Pruebas , Factores de Riesgo , Medición de Riesgo , Biomarcadores/sangre , Toma de Decisiones ClínicasRESUMEN
BACKGROUND: People with type 2 diabetes (T2D) are at elevated risk of cardiovascular disease (CVD) including stroke, yet existing real-world evidence (RWE) on the clinical and economic burden of stroke in this population is limited. The aim of this cohort study was to evaluate the clinical and economic burden of stroke among people with T2D in France. METHODS: We conducted a retrospective RWE study using data from the nationally representative subset of the French Système National des Données de Santé (SNDS) database. We assessed the incidence of stroke requiring hospitalization between 2012 and 2018 among T2D patients. Subsequent clinical outcomes including CVD, stroke recurrence, and mortality were estimated overall and according to stroke subtype (ischemic versus hemorrhagic). We also examined the treatment patterns for glucose-lowering agents and CVD agents, health care resource utilization and medical costs. RESULTS: Among 45,331 people with T2D without baseline history of stroke, 2090 (4.6%) had an incident stroke requiring hospitalization. The incidence of ischemic stroke per 1000 person-years was 4.9-times higher than hemorrhagic stroke (6.80 [95% confidence interval (CI) 6.47-7.15] versus 1.38 [1.24-1.54]). During a median follow-up of 2.4 years (interquartile range 0.6; 4.4) from date of index stroke, the rate of CVD, stroke recurrence and mortality per 1000 person-years was higher among hemorrhagic stroke patients than ischemic stroke patients (CVD 130.9 [107.7-159.0] versus 126.4 [117.2-136.4]; stroke recurrence: 86.7 [66.4-113.4] versus 66.5 [59.2-74.6]; mortality 291.5 [259.1-327.9] versus 144.1 [134.3-154.6]). These differences were not statistically significant, except for mortality (adjusted hazard ratio 1.95 [95% CI 1.66-2.92]). The proportion of patients prescribed glucagon-like peptide-1 receptor agonists increased from 4.2% at baseline to 6.6% during follow-up. The proportion of patients prescribed antihypertensives and statins only increased slightly following incident stroke (antihypertensives: 70.9% pre-stroke versus 76.7% post-stroke; statins: 24.1% pre-stroke versus 30.0% post-stroke). Overall, 68.8% of patients had a subsequent hospitalization. Median total medical costs were 12,199 (6846; 22,378). CONCLUSIONS: The high burden of stroke among people with T2D, along with the low proportion of patients receiving recommended treatments as per clinical guidelines, necessitates a strengthened and multidisciplinary approach to the CVD prevention and management in people with T2D.
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Bases de Datos Factuales , Diabetes Mellitus Tipo 2 , Accidente Cerebrovascular Hemorrágico , Hipoglucemiantes , Accidente Cerebrovascular Isquémico , Humanos , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/economía , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Masculino , Incidencia , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Francia/epidemiología , Factores de Tiempo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/economía , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/mortalidad , Accidente Cerebrovascular Isquémico/economía , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Hemorrágico/epidemiología , Accidente Cerebrovascular Hemorrágico/mortalidad , Accidente Cerebrovascular Hemorrágico/economía , Accidente Cerebrovascular Hemorrágico/terapia , Accidente Cerebrovascular Hemorrágico/diagnóstico , Medición de Riesgo , Recurrencia , Factores de Riesgo , Costos de la Atención en Salud , Resultado del Tratamiento , Hospitalización/economía , Anciano de 80 o más Años , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/economía , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/economía , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/diagnósticoRESUMEN
Chen et al. recently related the skin autofluorescence (SAF) of Advanced Glycation End-products to subclinical cardiovascular disease in the 3001 participants from the general population (Rotterdam study), with a particularly close relationship for the 413 subjects with diabetes. Because conventional vascular risk factors do not capture the risk in diabetes very well, this relationship may help to select high-risk individuals for the screening of silent myocardial ischemia, which has yet to prove its benefit in randomized controlled trials. Among 477 patients with uncontrolled and/or complicated Type 2 Diabetes, we measured the SAF ten years ago, and we registered new revascularizations during a 54-months follow-up. The patients with SAF > 2.6 Arbitrary units (AUs), the median population value, experienced more revascularizations of the coronary (17/24) and lower-limb arteries (13/17) than patients with a lower SAF, adjusted for age, sex, diabetes duration, vascular complications, and smoking habits: HR 2.17 (95% CI: 1.05-4.48), p = 0.035. The SAF has already been reported to predict cardiovascular events in three cohorts of people with diabetes. We suggest that its measurement may help to improve the performance of the screening before vascular explorations and revascularizations.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Piel , Factores de Riesgo , Productos Finales de Glicación Avanzada , FumarRESUMEN
AIM: The use of vitamin K antagonists (VKAs) may increase the risk of peripheral arterial disease (PAD) because vitamin K is a strong inhibitor of medial arterial calcification. Type 2 diabetes (T2D) exposes patients to an increased risk of PAD. We examined how the use of VKAs modulates the risk of incident PAD in people with T2D. MATERIALS AND METHODS: SURDIAGENE is a French cohort including 1468 patients with T2D with a prospective follow-up from 2002 to 2015. The primary outcome of the current analysis was the first occurrence of PAD, a composite of lower-limb amputation (LLA) or lower-limb revascularization. LLA and lower-limb revascularization were considered individually as secondary outcomes. RESULTS: During a 7-year median follow-up, PAD occurred in 147 (10%) of the 1468 participants. The use of VKAs was not significantly associated with the risk of PAD [multivariable adjusted hazard ratio (HR) 1.42, 95% confidence interval (CI), 0.88-2.31]. During the study period, LLA and lower-limb revascularization occurred in 82 (6%) and 105 (7%) participants, respectively. The use of VKAs was significantly associated with increased risk of LLA [multivariable adjusted HR 1.90 (95% CI, 1.04-3.47)], but not lower-limb revascularization [multivariable adjusted HR 1.08 (95% CI, 0.59-1.97)]. CONCLUSIONS: In this prospective study, we did not observe any excess risk of PAD requiring lower-limb revascularization in people with type 2 diabetes using VKAs. However, our data suggest a high risk of LLA in VKA users. Further studies are required to confirm this observation.
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Amputación Quirúrgica , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Enfermedad Arterial Periférica , Vitamina K , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Enfermedad Arterial Periférica/epidemiología , Femenino , Masculino , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Vitamina K/antagonistas & inhibidores , Amputación Quirúrgica/estadística & datos numéricos , Francia/epidemiología , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/prevención & control , Factores de Riesgo , Estudios de Seguimiento , Anticoagulantes/uso terapéutico , Anticoagulantes/efectos adversos , Extremidad Inferior/irrigación sanguínea , Extremidad Inferior/cirugía , IncidenciaRESUMEN
AIM: To assess clinical and biochemical measurements that can identify people with dysglycaemia (i.e. diabetes or pre-diabetes) who remain free of serious outcomes during follow-up. MATERIALS AND METHODS: We conducted exploratory analyses using data from the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study to identify independent determinants of outcome-free status in 12 537 middle-aged and older adults with prediabetes and early type 2 diabetes from 40 countries. Serious outcome-free status was defined as the absence of major cardiovascular outcomes, kidney or retinal outcomes, peripheral artery disease, dementia, cancer, any hospitalization, or death during follow-up. RESULTS: In total, 3328 (26.6%) participants remained free of serious outcomes during a median follow-up of 6.2 years (IQR 5.8, 6.7). Independent clinical determinants of outcome-free status included younger age, female sex, non-White ethnicity, shorter diabetes duration, absence of previous cardiovascular disease, current or former smokers, higher grip strength, Mini-Mental State Examination score, and ankle-brachial index, lower body mass index and kidney disease index, and non-use of renin-angiotensin system drugs and beta-blockers. In a subset of 8401 people with baseline measurements of 238 biomarkers, growth differentiation factor 15, kidney injury molecule-1, N-terminal pro-brain natriuretic peptide, uromodulin, C-reactive protein, factor VII and ferritin were independent determinants. The combination of clinical determinants and biomarkers best identified participants who remained outcome-free (C-statistics 0.71, 95% confidence interval 0.70-0.73; net reclassification improvement 0.55, 95% confidence interval 0.48-0.58). CONCLUSIONS: A set of routinely measured clinical characteristics and seven protein biomarkers identify middle-aged and older people with prediabetes or early type 2 diabetes as least likely to experience serious outcomes during follow-up.
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Diabetes Mellitus Tipo 2 , Estado Prediabético , Humanos , Femenino , Masculino , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Anciano , Estado Prediabético/sangre , Estado Prediabético/epidemiología , Estado Prediabético/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/sangre , Estudios de Seguimiento , Hipoglucemiantes/uso terapéutico , Biomarcadores/sangre , Índice Tobillo Braquial , Fragmentos de Péptidos/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Péptido Natriurético EncefálicoRESUMEN
AIMS: We investigated whether Diabetic Retinopathy (DR) is related to Diabetic Foot Ulcer (DFU) development, adjusted for the stratification of the International Work Group on Diabetic Foot (IWGDF) guidance. MATERIALS AND METHODS: DR and IWGDF stratification was registered retrospectively in patients hospitalised from 2009 to 2017 for uncontrolled and/or complicated type 2 diabetes. New DFUs were registered until 2020. Survival analyses categorised the subjects for DR, and multivariate Cox regression adjusted for confounders. RESULTS: The 522 patients (57.9% male) were 62 ± 9 years old with a diabetes duration of 14 ± 10 years, HbA1c of 8.7 ± 1.8%, 33.9% macroangiopathies and 44.8% diabetic kidney diseases. Their grades of DFU risk were 0 for 43.3%, 1 for 23.9%, 2 for 7.1%, and 3 for 25.6%. During the 52 months follow-up (Inter Quartile Range: 32-71), 58 new DFUs and 18 lower-limb amputations occurred, mostly in patients with DR present in 140 (26.8%) patients. Adjusted for age, sex and conventional risk factors (duration and control of diabetes, arterial hypertension, and dyslipidemia), and other complications (macroangiopathy and diabetic kidney disease), DR was associated with a greater incidence of DFUs. Adjusted for the IWGDF classification, DR was related to new DFUs (HR: 2.51, 95%Confidence Interval [CI]: 1.48-4.26) and amputations (HR: 3.56, 95%CI: 1.26-10.07). This relationship persisted in ascending IWGDF grades with incidences of DFUs from 2/1000 (grade 0, no DR) to 121/1000 patient-years (grade 3 and DR) and amputations from 0 (grade 0, no DR) to 38/1000 patient-years (grade 3 and DR). CONCLUSIONS: Diabetic retinopathy independently relates to the incidence of foot ulcers and amputations in patients hospitalised for type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Pie Diabético , Nefropatías Diabéticas , Retinopatía Diabética , Úlcera del Pie , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Pie Diabético/epidemiología , Pie Diabético/etiología , Pie Diabético/cirugía , Incidencia , Retinopatía Diabética/epidemiología , Retinopatía Diabética/etiología , Estudios Retrospectivos , Factores de Riesgo , Nefropatías Diabéticas/epidemiología , Amputación QuirúrgicaRESUMEN
AIMS: Real-world data are required to support glucagon-like peptide-1 receptor agonist use in type 2 diabetes (T2D). SURE France assessed once-weekly semaglutide in adults with T2D in real-world clinical practice. MATERIALS AND METHODS: This multicentre, prospective, open-label, single-arm study included adults with T2D and ≥1 documented glycated haemoglobin (HbA1c) value ≤12 weeks before semaglutide initiation. The primary endpoint was HbA1c change from baseline to end of study (EOS; ~30 weeks). Secondary endpoints included change from baseline to EOS in body weight (BW) and waist circumference (WC); and proportion achieving HbA1c targets. Baseline characteristics and safety were reported for the full analysis set (patients initiating semaglutide). Analysis of other endpoints was based on the effectiveness analysis set (study completers receiving semaglutide at EOS). RESULTS: Of 497 patients initiating semaglutide (41.6% female, mean age 58.3 years), 348 completed the study on treatment. Baseline HbA1c, diabetes duration, BW and WC, were 8.3%, 10.0 years, 98.2 kg and 114.2 cm, respectively. The most common reasons for initiating semaglutide were to improve glycaemic control (79.7%), reduce BW (69.8%) and address cardiovascular risk (24.1%). At EOS, mean changes were: HbA1c, -1.2% points [95% confidence interval (CI) -1.32; -1.10]; BW, -4.7 kg (95% CI -5.38; -4.07); and WC, -4.9 cm (95% CI -5.94; -3.88). At EOS, 81.7%, 67.7% and 51.6% of patients achieved an HbA1c target of <8.0%, <7.5% and <7.0%, respectively. No new safety concerns were identified. CONCLUSIONS: These results support the benefits of semaglutide in a real-world setting in adults with T2D in France showing a significant reduction in HbA1c and body weight.
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Diabetes Mellitus Tipo 2 , Adulto , Humanos , Femenino , Persona de Mediana Edad , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Hipoglucemiantes/efectos adversos , Hemoglobina Glucada , Estudios Prospectivos , Péptidos Similares al Glucagón/efectos adversos , Peso CorporalRESUMEN
AIM: Patient- and physician-associated barriers impact the effectiveness of basal insulin (BI) titration in the management of type 2 diabetes (T2D). We evaluated the experiences of patients with T2D and physicians with BI titration education. MATERIALS AND METHODS: In this observational, cross-sectional study, patients with T2D and physicians treating patients with T2D were identified by claims in the Optum Research Database and were invited to complete a survey. Eligible patients had 12 months of continuous health-plan enrolment with medical and pharmacy benefits during the baseline period, and recent initiation of BI therapy. Eligible physicians had initiated BI for ≥1 eligible patient with T2D during the past 6 months. RESULTS: In total, 416 patients and 386 physicians completed the survey. Ninety per cent of physicians reported treating ≥50 patients with T2D; 66% treated ≥25% of patients with BI. Whereas 74% of patients reported that BI titration was explained to them by a physician, 96% of physicians reported doing so. Furthermore, 20% of patients stated they were offered educational materials whereas 56% of physicians reported having provided materials. Physicians had higher expectations of glycaemic target achievement than were seen in the patient survey; their main concern was the patients' ability to titrate accurately (79%). CONCLUSIONS: There is a marked difference in patients' and physicians' experiences of BI titration education. Novel tools and strategies are required to enable effective BI titration, with more educational resources at the outset, and ongoing access to tools that provide clear, simple direction for self-titration with less reliance on physicians/health care providers.
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Diabetes Mellitus Tipo 2 , Médicos , Humanos , Estudios Transversales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hipoglucemiantes , Insulina , Estados Unidos/epidemiologíaRESUMEN
Several randomized controlled trials have demonstrated the benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic stroke in patients with diabetes. In this review, we summarize and discuss the potential mechanisms of stroke protection by GLP-1RAs. GLP-1RAs exert multiple anti-atherosclerotic effects contributing to stroke prevention such as enhanced plaque stability, reduced vascular smooth muscle proliferation, increased nitric oxide, and improved endothelial function. GLP-1RAs also lower the risk of stroke by reducing traditional stroke risk factors including hyperglycemia, hypertension, and dyslipidemia. Independently of these peripheral actions, GLP-1RAs show direct cerebral effects in animal stroke models, such as reduction of infarct volume, apoptosis, oxidative stress, neuroinflammation, excitotoxicity, blood-brain barrier permeability, and increased neurogenesis, neuroplasticity, angiogenesis, and brain perfusion. Despite these encouraging findings, further research is still needed to understand more thoroughly the mechanisms by which GLP-1RAs may mediate stroke protection specifically in the human diabetic brain.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Accidente Cerebrovascular , Animales , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/efectos adversos , Diabetes Mellitus Tipo 2/inducido químicamente , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/inducido químicamente , Hiperglucemia/inducido químicamenteRESUMEN
BACKGROUND: Cardiovascular risk and body-weight management are both emerging challenges of type 1 diabetes care. We evaluated the association between intraindividual variability of body-weight and risk of cardiovascular events in people with type 1 diabetes. METHODS: We analyzed 1,398 participants from the DCCT/EDIC studies. Five indices of intraindividual variability of body-weight were calculated for each participant taking into account body-weight measures obtained during the DCCT follow-up (average 6 ± 2 years). The Average Successive Variability (ASV) index, the main variable of interest, was defined as the average absolute difference between successive body-weight measures. The primary outcome was a composite of major adverse cardiovascular events (MACE: nonfatal myocardial infarction or stroke, or cardiovascular death) occurring during the subsequent EDIC follow-up (20 ± 3 years). All-cause death was a secondary outcome. Risk of outcomes were assessed by Cox proportional hazards regression analyses, adjusted for traditional cardiovascular risks factors, including BMI. RESULTS: The cumulative incidence of MACE and all-cause death during follow-up were 5.6% (n = 79) and 6.8% (n = 95), respectively. The adjusted Hazard Ratio (HR) for MACE by every increase of 1 standard deviation (SD) of ASV was 1.34 (95% CI, 1.06-1.66), p = 0.01. For all-cause death, the adjusted HR for 1 SD increase of ASV was 1.25 (1.03-1.50), p = 0.03. Similar results were observed when considering the other indices of intraindividual variability of body-weight. CONCLUSIONS: High body-weight variability (body-weight cycling) is associated with increased risk of MACE and all-cause death in people with type 1 diabetes, independently of the BMI and traditional cardiovascular risk factors.
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Sistema Cardiovascular , Diabetes Mellitus Tipo 1 , Infarto del Miocardio , Humanos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Peso Corporal , Infarto del Miocardio/complicacionesRESUMEN
BACKGROUND: Type 1 diabetes is associated with accelerated vascular aging and advanced atherosclerosis resulting in increased rates of cardiovascular disease and premature death. We evaluated associations between Leukocyte telomere length (LTL), allelic variations (SNPs) in LTL-related genes and the incidence of coronary heart disease (CHD) in adults with long-standing type 1 diabetes. METHODS: We assessed associations of LTL, measured at baseline by RT-PCR, and of SNPs in 11 LTL-related genes with the risk of coronary heart disease (CHD: myocardial infarction or coronary revascularization) and all-cause death during follow-up in two multicenter French-Belgian prospective cohorts of people with long-standing type 1 diabetes. RESULTS: In logistic and Cox analyses, the lowest tertile of LTL distribution (short telomeres) at baseline was associated with the prevalence of myocardial infarction at baseline and with increased risk of CHD (Hazard ratio 3.14 (1.39-7.70), p = 0.005, for shorter vs longer tertile of LTL) and all-cause death (Hazard ratio 1.63 (95% CI 1.04-2.55), p = 0.03, for shorter vs combined intermediate and longer tertiles of LTL) during follow-up. Allelic variations in six genes related to telomere biology (TERC, NAF1, TERT, TNKS, MEN1 and BICD1) were also associated with the incidence of CHD during follow-up. The associations were independent of sex, age, duration of diabetes, and a range of relevant confounding factors at baseline. CONCLUSIONS: Our results suggest that short LTL is an independent risk factor for CHD in people with type 1 diabetes.
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Enfermedad Coronaria , Diabetes Mellitus Tipo 1 , Infarto del Miocardio , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genética , Proteínas del Citoesqueleto/genética , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Humanos , Leucocitos , Infarto del Miocardio/complicaciones , Estudios Prospectivos , Telómero/genéticaRESUMEN
BACKGROUND: Cardiovascular disease (CVD) and nontraumatic lower-limb amputation (LLA) each results in reduced life expectancy in patients with type 1 diabetes, but the differential burden between these conditions is unknown. We compared the effects of CVD and LLA on the risk of mortality in people with type 1 diabetes. METHODS: We used pooled data from the SURGENE, GENEDIAB, and GENESIS prospective cohorts. Data were divided into: 1/absence of CVD (myocardial infarction and/or stroke) nor LLA, 2/history of CVD alone without LLA, 3/LLA alone without CVD or 4/both conditions at baseline. Participants with baseline history of peripheral artery disease were excluded from groups 1 and 2. The study endpoint was any death occurring during follow-up, regardless of the causes. RESULTS: Among 1169 participants (male 55%, age 40 ± 13 years, diabetes duration 23 ± 11 years), CVD, LLA or both were present at baseline in 49 (4.2%), 62 (5.3%) and 20 (1.7%) subjects, respectively. All-cause death occurred in 304 (26%) participants during 17-year follow-up, corresponding to 18,426 person-years and an incidence rate of 16 (95%CI, 15-18) per 1000 person-years. The risk of death increased in individuals with baseline history of CVD (adjusted HR 2.00 [95% CI 1.34-3.01], p = 0.0008) or LLA (2.26 [1.56-3.28], p < 0.0001), versus no condition, with an additive effect in people with both conditions (5.32 [3.14-9.00], p < 0.0001). No incremental risk of death was observed in people with CVD versus LLA (0.87 [0.54-1.41]). Compared with no condition, CVD and LLA were similarly associated with reduced life expectancy during follow-up: 2.79 (95% CI 1.26-4.32) and 3.38 (1.87-4.88) years, respectively. Combined conditions expose to 7.04 (4.76-9.31) less years of life expectancy (all p < 0.0001). CONCLUSIONS: CVD and LLA conferred a similar burden regarding mortality in type 1 diabetes population. Our findings encourage a careful consideration of people with type 1 diabetes and LLA as usually recommended for those with CVD, in terms of management of risk factors, treatments and prevention.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Adulto , Amputación Quirúrgica/efectos adversos , Amputación Quirúrgica/métodos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/cirugía , Diabetes Mellitus Tipo 1/diagnóstico , Humanos , Extremidad Inferior , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
PURPOSE: The aim of this study was to analyze retinal microvasculature in obese subjects as compared to a normal-weight population. METHODS: In this case-control observational study, swept-source optical coherence tomography angiography (SS-OCTA) and adaptive optics (AO) were performed in eyes of nondiabetic, nonhypertensive, obese patients and in healthy controls. AO was used to calculate the wall-to-lumen ratio (WLR). The foveal avascular zone (FAZ), the macular vessel density, and the macular perfusion density of the superficial and deep capillary plexuses were analyzed in 6 × 6 mm macular OCTA cubes. SS-OCTA was also used to measure the choroidal thickness, the retinal nerve fiber layer (RNFL), and the vascular density of the retinal peripapillary capillary plexus. RESULTS: The obese group included 45 eyes (24 patients), and the control group included 46 eyes (23 subjects). The central macular density and perfusion density were significantly lower in obese patients compared to controls, in the deep retinal layer (0.28 [0.01-0.69] vs. 1.24 [0.82-1.66], p = 0.006 and 0.006 [0.001-0.015] vs. 0.025 [0.016-0.034], p = 0.01), respectively, after adjustment for systolic blood pressure. No differences were found in macular vascular density in other areas, FAZ (circularity, area, perimeter), choroidal thickness, RNFL. WLR was increased in obese patients (0.252 [0.246-0.259] vs. 0.239 [0.231-0.245] in controls, p = 0.016). CONCLUSION: Obesity was associated with retinal microvascular changes regardless of the presence of diabetes and hypertension. Our findings suggest the presence of infraclinical microvascular changes directly associated with obesity, which can be identified noninvasively through retinal imaging.
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Vasos Retinianos , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Angiografía con Fluoresceína/métodos , Voluntarios Sanos , Obesidad/complicaciones , Obesidad/diagnósticoRESUMEN
AIMS/HYPOTHESIS: The lipid profile has not been fully investigated in individuals with peripheral artery disease (PAD). We aimed to evaluate the relationship between plasma concentrations of lipoproteins and the prevalence of lower-limb PAD at baseline and its incidence during follow-up in people with type 2 diabetes. METHODS: Plasma concentrations of total cholesterol, HDL-cholesterol, triacylglycerol and apolipoprotein (Apo) A-I, ApoA-II, ApoB-100 and Apo(a) were measured at baseline using colorimetric or MS methods in the SURDIAGENE cohort. Total cholesterol/HDL-cholesterol ratio, non-HDL-cholesterol and LDL-cholesterol were estimated using computation formulas. Logistic and Cox proportional hazard regression models were fitted to estimate OR or HR, with related 95% CI, for baseline prevalence or incidence of major PAD (lower-limb amputation or requirement of revascularisation) during follow-up by increasing lipoprotein tertiles, after adjustment for key confounders. RESULTS: Among 1468 participants (women 42%, mean ± SD age 65 ± 11 years, duration of diabetes 14 ± 10 years at baseline), 129 (8.8%) had a baseline history of major PAD. Major PAD was less prevalent at baseline in the highest (vs lowest) tertile of HDL-cholesterol (OR 0.42 [95% CI 0.26, 0.71], p = 0.001) and ApoA-I (OR 0.39 [95% CI 0.23, 0.67], p = 0.0007), and more frequent in the highest tertile of total cholesterol/HDL-cholesterol ratio (OR 1.95 [95% CI 1.18, 3.24], p = 0.01). Among 1339 participants without a history of PAD at baseline, incident PAD occurred in 97 (7.2%) during a median (25th-75th percentile) duration of follow-up of 7.1 (4.4-10.7) years, corresponding to 9685 person-years and an incidence rate of 9.8 (95% CI 8.0, 12.0) per 1000 person-years. The risk of incident PAD was lower in the top (vs bottom) tertile of HDL-cholesterol (HR 0.54 [95% CI 0.30, 0.95], p = 0.03) or ApoA-I (HR 0.50 [95% CI 0.28, 0.86], p = 0.01) and higher in the top tertile of total cholesterol/HDL-cholesterol ratio (HR 2.81 [95% CI 1.61, 5.04], p = 0.0002) and non-HDL-cholesterol (HR 1.80 [95% CI 1.06, 3.12], p = 0.03). CONCLUSIONS/INTERPRETATION: We reported independent associations between HDL-cholesterol, ApoA-I, total cholesterol/HDL-cholesterol ratio or non-HDL-cholesterol and the prevalence or the incidence of major PAD in people with type 2 diabetes. Our findings provide a picture of lipoprotein profile in people with type 2 diabetes. Graphical abstract.
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Apolipoproteína A-I/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/epidemiología , Extremidad Inferior/irrigación sanguínea , Enfermedad Arterial Periférica/epidemiología , Anciano , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Francia/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/cirugía , Prevalencia , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
In a recent meta-analysis of randomized controlled trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with diabetes, Lin and colleagues showed a positive association between SGLT2i-induced blood pressure and weight reduction and the risk of lower limb events. These results support the potential mechanism of a volume depletion effect of SGLT2i to explain the increase risk of amputation observed with this pharmacological class. Since the first result of the CANVAS trial raised a concern regarding the risk of amputation with SGLT2i, this hypothesis emerged from studies showing a higher incidence of amputations in patients with diabetes using diuretics. Furthermore, recent data found that copeptin, a surrogate marker of hydration status was also associated with lower limb outcomes. In conclusion, this assumption of diuretic-induced hypovolemia explanation highlights the fact that medications that induce a contraction of plasma volume, both traditional and novel agents with a diuretic mode of action should be introduced cautiously in patients with diabetes at high risk of diabetic foot events.
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Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Diuréticos , Humanos , Hipovolemia , Extremidad InferiorRESUMEN
BACKGROUND: Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes. METHODS: We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models. RESULTS: Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th-75th percentile, 4.7-5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3-6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21-1.94), p = 0.0004], PAD [1.32 (1.02-1.70), p = 0.03] or neuropathy (1.41 (1.11-1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers. CONCLUSIONS: PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.
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Diabetes Mellitus Tipo 2/mortalidad , Extremidad Inferior/irrigación sanguínea , Extremidad Inferior/inervación , Neoplasias/mortalidad , Enfermedad Arterial Periférica/mortalidad , Enfermedades del Sistema Nervioso Periférico/mortalidad , Anciano , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Enfermedad Arterial Periférica/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Screening for coronary artery disease (CAD) remains broadly performed in patients with type 2 diabetes (T2DM), although the lack of evidence. We conduct a real-world evidence (RWE) study to assess the risk of major clinical outcomes and economic impact of routine CAD screening in T2DM individuals at a very high cardiovascular risk. METHODS: SCADIAB is a comparative nationwide cohort study using data from the French National Health Data System. The main inclusion criteria are: age ≥ 40 years, DT2 diagnosed for ≥ 7 years, with ≥ 2 additional cardiovascular risk factors plus a history of microvascular or macrovascular disease, except CAD. We estimated ≥ 90,000 eligible participants for our study. Data will be extracted from 01/01/2008 to 31/12/2019. Eligible participants will be identified during a first 7-year selection period (2008-2015). Each participant will be assigned either in experimental (CAD screening procedure during the selection period) or control group (no CAD screening) on 01/01/2015, and followed for 5 years. The primary endpoint is the incremental cost per life year saved over 5 years in CAD screening group versus no CAD screening. The main secondary endpoints are: total 5-year direct costs of each strategy; incidence of major cardiovascular (acute coronary syndrome, hospitalization for heart failure, coronary revascularization or all-cause death), cerebrovascular (hospitalization for transient ischemic attack, stroke, or carotid revascularization) and lower-limb events (peripheral artery disease, ischemic diabetic foot, lower-limb revascularization or amputation); and the budget impact for the French Insurance system to promote the cost-effective strategy. Analyses will be adjusted for a high-dimension propensity score taking into account known and unknown confounders. SCADIAB has been funded by the French Ministry of Health and the protocol has been approved by the French ethic authorities. Data management and analyses will start in the second half of 2021. DISCUSSION: SCADIAB is a large and contemporary RWE study that will assess the economic and clinical impacts of routine CAD screening in T2DM people at a very high cardiovascular risk. It will also evaluate the clinical practice regarding CAD screening and help to make future recommendations and optimize the use of health care resources. Trial registration ClinicalTrials.gov Identifier: NCT04534530 ( https://clinicaltrials.gov/ct2/show/NCT04534530 ).