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1.
BMJ Open ; 9(7): e024954, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366635

RESUMO

OBJECTIVE: This study aimed to evaluate the association between metformin treatment and the risk of neurodegenerative disease (ND) among elderly adults with type 2 diabetes mellitus (T2DM). DESIGN/SETTING/PARTICIPANTS: This retrospective longitudinal cohort study examined the effects of the length of metformin exposure on ND among elderly US veterans with T2DM and insulin treatment using the Veterans Affairs electronic medical record database. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary clinical outcome was defined as diagnosis of ND including dementia, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and mild cognitive impairment during the follow-up period. The secondary clinical outcomes were separately measured by AD, PD, HD, dementia and mild cognitive impairment. RESULT: Adjusted by propensity score weight, a total of 5528 patients (mean age, 63.2±10.9 years; male, 98%; white, 60%) with a median follow-up of 5.2 years were selected. Those with ND or other mental disorders at baseline or who were on insulin for less than two-thirds of the study period were excluded. The incidence rate of ND was 11.48 per 1000 person-years among patients with metformin treatment, compared with 25.45 per 1000 person-years for those without metformin. Compared with no metformin use, 2-4 years and >4 years of metformin exposure were significantly associated with lower risk of ND (adjusted HR (aHR)=0.62, 95% CI 0.45 to 0.85; aHR=0.19, 95% CI 0.12 to 0.31, respectively), while metformin exposure in the first 2 years showed no significant influence. CONCLUSION: We conclude that long-term metformin therapy (>2 years) was associated with lower incidence of ND among elderly veterans with T2DM. We need to conduct a study with more representative population and more robust method for causal inferences. Further investigation into the mechanism involved is needed along with randomised trials to confirm a potential neuroprotective effect of metformin.

2.
Diabetes Care ; 42(9): 1816-1823, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31320447

RESUMO

OBJECTIVE: Although emerging evidence indicates that increased variability in cardiovascular risk factors (CVRFs) among populations at midlife or later is a reliable predictor of adverse health outcomes, it is unknown whether intraindividual CVRF variability during childhood or adolescence is an independent predictor of later-life diabetes. We aimed to examine the association of CVRF variability during childhood with diabetes in later life. RESEARCH DESIGN AND METHODS: We included 1,718 participants who participated in the Bogalusa Heart Study and had measures at least four times during childhood (aged 4-19 years). The mean follow-up period was 20.5 years. Intraindividual CVRF variabilities during childhood were calculated using SD, coefficient of variation, deviation from age-predicted values, and residual SD based upon four to eight serial measurements in childhood. RESULTS: Increased variability in BMI or HDL cholesterol (HDL-C) during childhood, irrespective of the indices used, was significantly positively associated with later-life diabetes risk independent of their respective mean levels in childhood and other possible confounding factors. In combined analysis, the magnitude of the association with diabetes risk was similar for high childhood BMI variability and high childhood HDL-C variability. After adjustments for potential confounding variables, other CVRF variabilities including systolic/diastolic blood pressure, total cholesterol, triglycerides, and LDL cholesterol were not significantly associated with diabetes. CONCLUSIONS: Increased BMI and HDL-C variabilities during childhood were significant risk factors for the development of diabetes independently of diverse risk factors, which may offer new insights into the childhood origin of adult-onset diabetes.

5.
J Clin Endocrinol Metab ; 104(10): 4492-4500, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31058974

RESUMO

CONTEXT: It is unclear how adolescent glycemic status relates to brain health in adulthood. OBJECTIVE: To assess the association between adolescent fasting plasma glucose (FPG) and MRI-based brain measures in midlife. DESIGN: Between 1973 and 1992, the Bogalusa Heart Study (BHS) collected FPG from children, 3 to 18 years old, and followed up between 1992 and 2018. Cognitive tests and brain MRI were collected in 2013 to 2016 and 2018. SETTING: Observational longitudinal cohort study. PARTICIPANTS: Of 1298 contacted BHS participants, 74 completed screening, and 50 completed MRI. MAIN OUTCOME MEASURES: Mean FPG per participant at ages <20, 20 to 40, and over 40 years old; brain white matter hyperintensity (WMH) volume, gray matter volume, and functional MRI (fMRI) activation to a Stroop task; tests of logical and working memory, executive function, and semantic fluency. RESULTS: At MRI, participants were middle aged (51.3 ± 4.4 years) and predominantly female (74%) and white (74%). Mean FPG was impaired for zero, two, and nine participants in pre-20, 20 to 40, and over-40 periods. The pre-20 mean FPG above the pre-20 median value (i.e., above 83.5 mg/dL) was associated with greater WMH volume [mean difference: 0.029% of total cranial volume, CI: (0.0059, 0.052), P = 0.015] and less fMRI activation [-1.41 units (-2.78, -0.05), P = 0.043] on midlife MRI compared with below-median mean FPG. In controlling for over-40 mean FPG status did not substantially modify the associations. Cognitive scores did not differ by pre-20 mean FPG. CONCLUSIONS: High-normal adolescent FPG may be associated with preclinical brain changes in midlife.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30938762

RESUMO

CONTEXT: Semaglutide, a once-weekly glucagon-like peptide 1 (GLP-1) analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the SUSTAIN 1-3 clinical trials. OBJECTIVE: To investigate the relationship between IR and BW across the SUSTAIN 1-3 trials. DESIGN: Post hoc analysis of the SUSTAIN 1-3 trials. SETTING: 311 sites in 30 countries. Patients or Other Participants: 2,432 subjects with T2D. INTERVENTIONS: Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg). MAIN OUTCOME MEASURE: To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW. RESULTS: Across SUSTAIN 1-3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7-4.3 kg; p<0.0001) and semaglutide 1.0 mg (4.5-6.1 kg; p<0.0001) vs comparators (1.0-1.9 kg). There were significantly greater reductions in IR with semaglutide 0.5 mg (27-36%) and semaglutide 1.0 mg (32-46%) vs comparators (17-28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70-80% and 34-94%, respectively, for semaglutide 0.5 mg and 1.0 mg vs comparator). CONCLUSIONS: Semaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1-3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.

9.
J Am Heart Assoc ; 8(9): e011246, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31020929

RESUMO

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors effectively lower LDL (low-density lipoprotein) cholesterol and have been shown to reduce cardiovascular outcomes in high-risk patients. We used real-world electronic health record data to characterize use of PCSK9 inhibitors, in addition to standard therapies, according to cardiovascular risk status. Methods and Results Data were obtained from 18 health systems with data marts within the National Patient-Centered Clinical Research Network (PCORnet) using a common data model. Participating sites identified >17.5 million adults, of whom 3.6 million met study criteria. Patients were categorized into 3 groups: (1) dyslipidemia, (2) untreated LDL ≥130 mg/dL, and (3) coronary artery disease or coronary heart disease. Demographics, comorbidities, estimated 10-year atherosclerotic cardiovascular disease risk, and lipid-lowering pharmacotherapies were summarized for each group. Participants' average age was 62 years, 50% were female, and 11% were black. LDL cholesterol ranged from 85 to 151 mg/dL. Among patients in groups 1 and 3, 54% received standard lipid-lowering therapies and a PCSK9 inhibitor was prescribed in <1%. PCSK9 inhibitor prescribing was greatest for patients with coronary artery disease or coronary heart disease and, although prescribing increased during the study period, overall PCSK9 inhibitor prescribing was low. Conclusions We successfully used electronic health record data from 18 PCORnet data marts to identify >3.6 million patients meeting criteria for 3 patient groups. Approximately half of patients had been prescribed lipid-lowering medication, but <1% were prescribed PCSK9 inhibitors. PCSK9 inhibitor prescribing increased over time for patients with coronary artery disease or coronary heart disease but not for those with dyslipidemia.

10.
J Clin Endocrinol Metab ; 104(7): 2931-2941, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30869793

RESUMO

CONTEXT: For decades, there has been epidemiologic evidence linking chronic toxic metal exposure with cardiovascular disease, suggesting a therapeutic role for metal chelation. Given the lack of compelling scientific evidence, however, the indications for metal chelation were never clearly defined. To determine the safety and efficacy of chelation therapy, the National Institutes of Health funded the Trial to Assess Chelation Therapy (TACT). TACT was the first double-blind, randomized, controlled trial to demonstrate an improvement in cardiovascular outcomes with edetate disodium therapy in patients with prior myocardial infarction. The therapeutic benefit was striking among the prespecified subgroup of patients with diabetes. DESIGN: We review the published literature focusing on the atherogenic nature of diabetes, as well as available evidence from clinical trials, complete and in progress, of metal chelation with edetate disodium therapy in patients with diabetes. RESULTS: The TACT results support the concept that ubiquitous toxic metals such as lead and cadmium may be modifiable risk factors for cardiovascular disease, particularly in patients with diabetes. CONCLUSIONS: The purpose of this review is to discuss the potential mechanisms unifying the pathogenesis of atherogenic factors in diabetes with toxic metal exposure, and the potential role of metal chelation.

12.
Am J Nephrol ; 49(4): 331-342, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921791

RESUMO

BACKGROUND: Hypertension and renal injury are common complications of type 2 diabetes mellitus (T2DM). Hyperglycemia stimulates renal proximal tubular angiotensinogen (AGT) expression via elevated oxidative stress contributing to the development of high blood pressure and diabetic nephropathy. The sodium glucose cotransporter 2 (SGLT2) in proximal tubules is responsible for the majority of glucose reabsorption by renal tubules. We tested the hypothesis that SGLT2 inhibition with canagliflozin (CANA) prevents intrarenal AGT augmentation and ameliorates kidney injury and hypertension in T2DM. METHODS: We induced T2DM in New Zealand obese mice with a high fat diet (DM, 30% fat) with control mice receiving regular fat diet (ND, 4% fat). When DM mice exhibited > 350 mg/dL blood glucose levels, both DM- and ND-fed mice were treated with 10 mg/kg/day CANA or vehicle by oral gavage for 6 weeks. We evaluated intrarenal AGT, blood pressure, and the development of kidney injury. RESULTS: Systolic blood pressure in DM mice (133.9 ± 2.0 mm Hg) was normalized by CANA (113.9 ± 4.0 mm Hg). CANA treatment ameliorated hyperglycemia-associated augmentation of renal AGT mRNA (148 ± 21 copies/ng RNA in DM, and 90 ± 16 copies/ng RNA in DM + CANA) and protein levels as well as elevation of urinary 8-isoprostane levels. Tubular fibrosis in DM mice (3.4 ± 0.9-fold, fibrotic score, ratio to ND) was suppressed by CANA (0.9 ± 0.3-fold). Furthermore, CANA attenuated DM associated increased macrophage infiltration and cell proliferation in kidneys of DM mice. CONCLUSIONS: CANA prevents intrarenal AGT upregulation and oxidative stress and which may mitigate high blood pressure, renal tubular fibrosis, and renal inflammation in T2DM.

13.
Endocr Pract ; 25(1): 69-100, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30742570

RESUMO

ABBREVIATIONS: A1C = hemoglobin A1C; AACE = American Association of Clinical Endocrinologists; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure; ACE = American College of Endocrinology; ACEI = angiotensin-converting enzyme inhibitor; AGI = alpha-glucosidase inhibitor; apo B = apolipoprotein B; ARB = angiotensin II receptor blocker; ASCVD = atherosclerotic cardiovascular disease; BAS = bile acid sequestrant; BMI = body mass index; BP = blood pressure; CCB = calcium channel blocker; CGM = continuous glucose monitoring; CHD = coronary heart disease; CKD = chronic kidney disease; DKA = diabetic ketoacidosis; DPP4 = dipeptidyl peptidase 4; eGFR = estimated glomerular filtration rate; EPA = eicosapentaenoic acid; ER = extended release; FDA = Food and Drug Administration; GLP1 = glucagon-like peptide 1; HDL-C = high-density-lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; LDL-P = low-density-lipoprotein particle; Look AHEAD = Look Action for Health in Diabetes; NPH = neutral protamine Hagedorn; OSA = obstructive sleep apnea; PCSK9 = proprotein convertase subtilisin-kexin type 9 serine protease; RCT = randomized controlled trial; SU = sulfonylurea; SGLT2 = sodium-glucose cotransporter 2; SMBG = self-monitoring of blood glucose; T2D = type 2 diabetes; TZD = thiazolidinedione.


Assuntos
Diabetes Mellitus Tipo 2 , Endocrinologistas , Algoritmos , Glicemia , Automonitorização da Glicemia , Consenso , Humanos , Pró-Proteína Convertase 9 , Estados Unidos
14.
Pharmacoeconomics ; 37(7): 921-929, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30778865

RESUMO

OBJECTIVE: Health utility decrements associated with diabetes mellitus complications are essential for calculating quality-adjusted life-years (QALYs) in patients for use in economic evaluation of diabetes interventions. Previous studies mostly focused on assessing the impact of complications on health utility at event year based on cross-sectional data. This study aimed to separately estimate health utility decrements associated with current and previous diabetes complications. RESEARCH DESIGN AND METHODS: The Health Utilities Index Mark 3 (HUI-3) was used to measure heath utility in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 8713). Five macrovascular complications (myocardial infarction [MI], congestive heart failure [CHF], stroke, angina, and revascularization surgery [RS]) and three microvascular complications (nephropathy [renal failure], retinopathy [severe vision loss], and neuropathy [severe pressure sensation loss]) were included in a set of alternative modelling approaches including the ordinary least squares (OLS) model, fixed effects model, and random effects model to estimate the complication-related health utility decrements. RESULTS: All macrovascular complications were associated with decrements of HUI-3 scores: MI (event year: - 0.042, successive years: - 0.011), CHF (event year: - 0.089, successive years: - 0.041), stroke (event year: - 0.204, successive years: - 0.101), angina (event year: - 0.010, successive years: - 0.032), and revascularization (event year: - 0.038, successive years: - 0.016) (all p < 0.05). For microvascular complications, severe vision loss (- 0.057), and severe pressure sensation loss (- 0.066) were significantly associated with decrements of HUI-3 scores (both p < 0.05). Hypoglycemia (both severe and symptomatic) was found to be associated with a 0.036 decrement of health utility at event year, and a 0.033 decrement of health utility at successive years. Results from an OLS model are preferred for supporting a microsimulation model while a fixed effects model is preferred to describe direct health impacts from complications. CONCLUSIONS: Macrovascular and microvascular complications caused QALY decrements in patients with type 2 diabetes. While only part of the total impaired QALY is experienced during the event year, further QALY decrements for successive years were quite substantial.

15.
Diabetes Care ; 42(4): 635-643, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30692238

RESUMO

OBJECTIVE: Childhood and young adulthood may represent time periods in which cardiovascular risk factors (CVRFs) and their cumulative exposure lay the foundation for future risk of chronic diseases. We examined the longitudinal burden of CVRFs since childhood in men and women in whom diabetes did and did not develop at follow-up. RESEARCH DESIGN AND METHODS: We included 1,530 participants (mean [SD] follow-up time 33.1 [8.2] years), who participated in the Bogalusa Heart Study and had been examined at least four times starting in childhood (mean age [SD] at first examination 9.4 [3.1] years). The area under the growth curve was used as a measure of cumulative exposure to CVRFs since childhood. RESULTS: In childhood, boys and girls in whom diabetes did and did not develop at follow-up had similar CVRFs. Yet, over time, women during the transition from normoglycemia to diabetes experienced greater adverse changes in total cholesterol (TC), LDL cholesterol, and fasting plasma glucose (FPG) (noted as early as 23.5 years old and persisting across adulthood up to the age of the diagnosis of diabetes); a higher burden of exposure to BMI, TC, LDL cholesterol, and FPG from childhood to midlife; and a greater change in rates of BMI, TC, LDL cholesterol, and FPG since childhood than men during the same transition (interaction P values <0.05). CONCLUSIONS: The greater exposure of women to and burden of CVRFs associated with diagnosis of diabetes may help to explain the stronger impact of diabetes as a major risk factor for cardiovascular events in women compared with men.

16.
Circ Res ; 124(6): 930-937, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30646822

RESUMO

RATIONALE: In observational studies, type 2 diabetes mellitus (T2D) has been associated with an increased risk of hypertension, and vice versa; however, the causality between these conditions remains to be determined. OBJECTIVES: This population-based prospective cohort study sought to investigate the bidirectional causal relations of T2D with hypertension, systolic and diastolic blood pressure (BP) using Mendelian randomization (MR) analysis. METHODS AND RESULTS: After exclusion of participants free of a history of heart failure, cardiovascular disease, cardiac procedures, and non-T2D diabetes mellitus, a total of 318 664 unrelated individuals with qualified genotyping data of European descent aged 37 to 73 from UK Biobank were included. The genetically instrumented T2D and hypertension were constructed using 134 and 233 single nucleotide polymorphisms, respectively. Seven complementary MR methods were applied, including inverse-variance weighted method, 2 median-based methods (simple and weighted), MR-Egger, MR-robust adjusted profile scores, MR-Pleiotropy Residual Sum and Outlier, and multivariate MR. The genetically instrumented T2D was associated with risk of hypertension (odds ratio, 1.07 [95% CI, 1.04-1.10], P=3.4×10-7), whereas the genetically determined hypertension showed no relationship with T2D (odds ratio, 0.96 [0.88-1.04], P=0.34). Our MR estimates from T2D to BP showed that the genetically instrumented T2D was associated with a 0.67 mm Hg higher systolic BP (95% CI, 0.41-0.93, P=5.75×10-7) but not with a higher diastolic BP. There was no clear evidence showing a causal effect of elevated systolic BP or diastolic BP on T2D risk. Positive pleiotropic bias was indicated in the hypertension→T2D relation (odds ratio, of MR-Egger intercept 1.010 [1.004-1.016], P=0.001) but not from T2D to hypertension (1.001 [0.998-1.004], P=0.556). CONCLUSIONS: T2D may causally affect hypertension, whereas the relationship from hypertension to T2D is unlikely to be causal. These findings suggest the importance of keeping an optimal glycemic profile in general populations, and BP screening and monitoring, especially systolic BP, in patients with T2D.

17.
Circulation ; 138(25): 2908-2918, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30566006

RESUMO

BACKGROUND: LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results) results demonstrated cardiovascular benefits for patients with type 2 diabetes mellitus at high cardiovascular risk on standard of care randomized to liraglutide versus placebo. The effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus and chronic kidney disease is unknown. Liraglutide's treatment effects in patients with and without kidney disease were analyzed post hoc. METHODS: Patients were randomized (1:1) to liraglutide or placebo, both in addition to standard of care. These analyses assessed outcomes stratified by baseline estimated glomerular filtration rate (eGFR; <60 versus ≥60 mL/min/1.73 m2) and baseline albuminuria. The primary outcome (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and secondary outcomes, including all-cause mortality and individual components of the primary composite outcome, were analyzed using Cox regression. RESULTS: Overall, 2158 and 7182 patients had baseline eGFR <60 or ≥60 mL/min/1.73 m2, respectively. In patients with eGFR <60 mL/min/1.73 m2, risk reduction for the primary composite cardiovascular outcome with liraglutide was greater (hazard ratio [HR], 0.69; 95% CI, 0.57-0.85) versus those with eGFR ≥60 mL/min/1.73 m2 (HR, 0.94; 95% CI, 0.83-1.07; interaction P=0.01). There was no consistent effect modification with liraglutide across finer eGFR subgroups (interaction P=0.13) and when analyzing eGFR as a continuous variable (interaction P=0.61). Risk reductions in those with eGFR <60 versus ≥60 mL/min/1.73 m2 were as follows: for nonfatal myocardial infarction, HR, 0.74; 95% CI, 0.55-0.99 versus HR, 0.93; 95% CI, 0.77-1.13; for nonfatal stroke, HR, 0.51; 95% CI, 0.33-0.80 versus HR, 1.07; 95% CI, 0.84-1.37; for cardiovascular death, HR, 0.67; 95% CI, 0.50-0.90 versus HR, 0.84; 95% CI, 0.67-1.05; for all-cause mortality, HR, 0.74; 95% CI, 0.60-0.92 versus HR, 0.90; 95% CI, 0.75-1.07. Risk reduction for the primary composite cardiovascular outcome was not different for those with versus without baseline albuminuria (HR, 0.83; 95% CI, 0.71-0.97; and HR, 0.92; 95% CI, 0.79-1.07, respectively; interaction P=0.36). CONCLUSIONS: Liraglutide added to standard of care reduced the risk for major cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus and chronic kidney disease. These results appear to apply across the chronic kidney disease spectrum enrolled. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT01179048.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Insuficiência Renal Crônica/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/mortalidade , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes , Liraglutida , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Placebos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/mortalidade , Acidente Vascular Cerebral/mortalidade , Análise de Sobrevida , Reino Unido/epidemiologia
18.
Diabetes ; 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389749

RESUMO

Glucagon-like peptide-1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1R expression in α cells using both antibody-dependent and -independent strategies. A novel α cell specific GLP-1R knockout (αGLP-1R-/-) mouse model was then created and used to investigate its effects on glucagon secretion and glucose metabolism. Both male and female αGLP-1R-/- mice showed higher non-fasting glucagon levels than their wild-type littermates, whereas insulin and GLP-1 levels remained similar. Female αGLP-1R-/- mice exhibited mild glucose intolerance following intraperitoneal glucose administration, and showed increased glucagon secretion in response to glucose injection compared to the wild-type animals. Furthermore, using isolated islets, we confirmed that αGLP-1R deletion did not interfere with ß cell function, but affected glucagon secretion in a glucose-dependent bidirectional manner-the αGLP-1R-/- islets failed to inhibit glucagon secretion at high glucose, and failed to stimulate glucagon secretion at very low glucose condition. More interestingly, the same phenomenon was recapitulated in vivo under hypoglycemic and postprandial (fed) conditions. Taken together, this study demonstrates that GLP-1 (via GLP-1R in α cells) plays a bidirectional role, either stimulatory or inhibitory, in glucagon secretion depending on glucose levels.

19.
Clin Pharmacol Ther ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30457671

RESUMO

Model-based meta-analysis was used to compare glycemic control, weight changes and hypoglycemia risk across 24 antihyperglycemic drugs used to treat type 2 diabetes. Electronic searches identified 229 randomized controlled studies comprising 121,914 patients. To ensure fair and unbiased treatment comparisons, the analyses adjusted for important differences between studies, including duration of treatment, baseline glycated hemoglobin, and drug dosages. At the approved doses, glycemic control was typically greatest with glucagon-like peptide 1 receptor agonists (GLP-1RAs), and least with dipeptidyl peptidase-4 (DPP-4) inhibitors. Weight loss was highly variable across GLP-1RAs, but was similar across sodium-glucose cotransporter 2 (SGLT2) inhibitors. Large weight increases were observed with sulfonylureas and thiazolidinediones. Hypoglycemia risk was highest with sulfonylureas, although gliclazide was notably lower. Hypoglycemia risk for DPP-4 inhibitors, SGLT2 inhibitors and thiazolidinediones was generally very low, but increased slightly for both GLP-1RAs and metformin. In summary, important differences between and within drug classes were identified. This article is protected by copyright. All rights reserved.

20.
Endocr Pract ; 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30084684

RESUMO

A growing body of data, guideline recommendations, algorithms, and position papers supports the use of glucagon-like peptide-1 (GLP-1) receptor agonists in type 2 diabetes (T2D), given their beneficial effects on glycemic control, weight, lipid parameters, and blood pressure, and low risk for hypoglycemia when used in patients who have not achieved glycemic goals with metformin and lifestyle interventions. Exciting new evidence continues to emerge, showing the utility of certain GLP-1 receptor agonists to decrease incident cardiovascular (CV) outcomes, and to bolster glycemic control when combined with other antihyperglycemic therapies, including basal insulin. The recent availability of fixed-ratio GLP-1 receptor agonist and basal insulin coformulations-and a new, first-ever, indication for the use of a GLP-1 receptor agonist (liraglutide) to reduce the risk of major adverse CV events (MACE) in adults with T2D and established cardiovascular disease (CVD)-increase options for improved care. In addition, semaglutide (another GLP-1 receptor agonist with positive CV outcomes data) received FDA approval in December 2017 with an indication to improve glycemic control in adults with T2D. These new developments and continuously emerging CV outcomes data should be considered in determining how GLP-1 receptor agonists may be best used in clinical practice. This Q&A presentation with 2 expert endocrinologists provides a pragmatic approach to inform the selection and use of GLP-1 receptor agonists based on the rapidly evolving evidence.

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