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- Klonoff, D. C., et al.
(författare)
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A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings
- 2022
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Ingår i: Journal of Diabetes Science and Technology. - : SAGE Publications. - 1932-2968.
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Tidskriftsartikel (refereegranskat)abstract
- Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.
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- Furtado, R. H. M., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:21, s. 1581-1591
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and >= 160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17160 patients; mean age, 64.0 +/- 6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; F<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (P-interactions = 5 0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure.
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- Bhatt, Deepak L., et al.
(författare)
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Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study
- 2019
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Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 42:5, s. 498-505
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Tidskriftsartikel (refereegranskat)abstract
- In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients >= 50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of >= 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
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| 6. |
- Wiviott, Stephen D, et al.
(författare)
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Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.
- 2019
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Ingår i: The New England journal of medicine. - 1533-4406. ; 380:4, s. 347-357
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Tidskriftsartikel (refereegranskat)abstract
- The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).
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| 7. |
- Mach, François, et al.
(författare)
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Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract
- 2018
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 39:27
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Forskningsöversikt (refereegranskat)abstract
- To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract.A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies.Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.
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| 8. |
- Spassova, I, et al.
(författare)
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Clinical and molecular characteristics associated with response to therapeutic PD-1/PD-L1 inhibition in advanced Merkel cell carcinoma
- 2022
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Based on its viral-associated or UV-associated carcinogenesis, Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Thus, clinically evident MCC occurs either in immuno-compromised patients or based on tumor-intrinsic immune escape mechanisms. This notion may explain that although advanced MCC can be effectively restrained by treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICIs), a considerable percentage of patients does not benefit from ICI therapy. Biomarkers predicting ICI treatment response are currently not available.MethodsThe present multicenter retrospective study investigated clinical and molecular characteristics in 114 patients with unresectable MCC at baseline before treatment with ICI for their association with therapy response (best overall response, BOR). In a subset of 21 patients, pretreatment tumor tissue was analyzed for activation, differentiation and spatial distribution of tumor infiltrating lymphocytes (TIL).ResultsOf the 114 patients, n=74 (65%) achieved disease control (BOR=complete response/partial response/stable disease) on ICI. A Bayesian cumulative ordinal regression model revealed absence of immunosuppression and a limited number of tumor-involved organ systems was highly associated with a favorable therapy response. Unimpaired overall performance status, high age, normal serum lactate dehydrogenase and normal serum C reactive protein were moderately associated with disease control. While neither tumor Merkel cell polyomavirus nor tumor PD-L1 status showed a correlation with therapy response, treatment with anti-PD-1 antibodies was associated with a higher probability of disease control than treatment with anti-PD-L1 antibodies. Multiplexed immunohistochemistry demonstrated the predominance of CD8+ effector and central memory T cells (TCM) in close proximity to tumor cells in patients with a favorable therapy response.ConclusionsOur findings indicate the absence of immunosuppression, a limited number of tumor-affected organs, and a predominance of CD8+ TCM among TIL, as baseline parameters associated with a favorable response to PD-1/PD-L1 ICI therapy of advanced MCC. These factors should be considered when making treatment decisions in MCC patients.
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| 9. |
- Jordan, J, et al.
(författare)
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Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients.
- 2008
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Ingår i: Clinical pharmacology and therapeutics. - : Springer Science and Business Media LLC. - 1532-6535 .- 0009-9236. ; 83:2, s. 281-7
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Tidskriftsartikel (refereegranskat)abstract
- Cholecystokinin (CCK) decreases meal size through activation of CCK-A receptors on vagal afferents. We tested the hypothesis that the selective CCK-A agonist GI181771X induces weight loss in obese patients. Patients with body mass index > or = 30 or > or = 27 kg/m2 with concomitant risk factors were randomized to 24-week, double-blind treatment with different GI181771X doses or matching placebo together with a hypocaloric diet. The primary efficacy end point was the absolute change in body weight. To monitor pancreatic and gallbladder effects, patients underwent abdominal ultrasound and magnetic resonance imaging before and after treatment. We randomized 701 patients to double-blind treatment. GI181771X did not reduce body weight and had no effect on waist circumference or other cardiometabolic risk markers. Gastrointestinal side effects were more common with GI181771X than with placebo treatment, whereas hepatobiliary or pancreatic abnormalities did not occur. CCK-A by itself does not have a central role in long-term energy balance.
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| 10. |
- Rosenstock, Julio, et al.
(författare)
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Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled With Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP-1 Receptor Agonist, Versus Thrice-Daily Prandial Insulin Lispro.
- 2014
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 37:8, s. 2317-2325
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Tidskriftsartikel (refereegranskat)abstract
- GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine.RESEARCH DESIGN AND METHODS: Patients taking basal insulin (with or without oral agents) with HbA1c 7-10.5% (53-91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of <5.6 mmol/L, and lispro was adjusted based on glucose monitoring. The primary end point was the difference in the HbA1c change from baseline at week 26.RESULTS: At week 26, HbA1c decreased from baseline by -0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and -0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, -0.16% (95% CI -0.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (-0.73 ± 0.19 kg vs. +0.81 ± 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%).CONCLUSIONS: Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA1c reduction with weight loss and lower hypoglycemia risk.
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