The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains ...undefined.
We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.
We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 95% CI 0·83–0·96, p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 0·80–0·93) and not in those without (1·00 0·87–1·16, p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 0·71–0·84, p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 0·48–0·64, p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.
SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.
None.
Aims
Identification, a priori, of those at high risk of progression from pre‐diabetes to diabetes may enable targeted delivery of interventional programmes while avoiding the burden of prevention and ...treatment in those at low risk. We studied whether the use of a machine‐learning model can improve the prediction of incident diabetes utilizing patient data from electronic medical records.
Methods
A machine‐learning model predicting the progression from pre‐diabetes to diabetes was developed using a gradient boosted trees model. The model was trained on data from The Health Improvement Network (THIN) database cohort, internally validated on THIN data not used for training, and externally validated on the Canadian AppleTree and the Israeli Maccabi Health Services (MHS) data sets. The model's predictive ability was compared with that of a logistic‐regression model within each data set.
Results
A cohort of 852 454 individuals with pre‐diabetes (glucose ≥ 100 mg/dL and/or HbA1c ≥ 5.7) was used for model training including 4.9 million time points using 900 features. The full model was eventually implemented using 69 variables, generated from 11 basic signals. The machine‐learning model demonstrated superiority over the logistic‐regression model, which was maintained at all sensitivity levels – comparing AUC 95% CI between the models; in the THIN data set (0.865 0.860,0.869 vs 0.778 0.773,0.784 P < .05), the AppleTree data set (0.907 0.896, 0.919 vs 0.880 0.867, 0.894 P < .05) and the MHS data set (0.925 0.923, 0.927 vs 0.876 0.872, 0.879 P < .05).
Conclusions
Machine‐learning models preserve their performance across populations in diabetes prediction, and can be integrated into large clinical systems, leading to judicious selection of persons for interventional programmes.
BACKGROUND:In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the ...composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown.
METHODS:In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality.
RESULTS:Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio HR, 0.62 95% CI, 0.45–0.86) than in those without HFrEF (HR, 0.88 95% CI, 0.76–1.02; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 95% CI, 0.66–1.17) and those without HF (HR, 0.88 95% CI, 0.74–1.03). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 95% CI, 0.43–0.95) and in those without HFrEF (HR, 0.76 95% CI, 0.62–0.92), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 95% CI, 0.34–0.90) but not in those without HFrEF (HR, 1.08 95% CI, 0.89–1.31; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 95% CI, 0.40–0.88;) but not in those without HFrEF (HR, 0.97 95% CI, 0.86–1.10; P for interaction=0.016).
CONCLUSIONS:In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01730534.
The complex pathological mechanisms responsible for development of type 2 diabetes are not fully addressed by conventional drugs, which are also associated with inconvenient side effects such as ...weight gain or hypoglycemia. Two types of incretin-based therapies are now in use: incretin mimetics (glucagon-like peptide-1 GLP-1 receptor agonists that bind specific receptors and mimic the action of natural GLP-1) and incretin enhancers (inhibitors of the enzyme that degrade the incretin hormones and thus prolong their activity). Both offer important advantages over previous agents. In addition to the proven glucose-lowering efficacy, they promote weight loss (or are weight neutral) by slowing gastric emptying and inducing satiety, inhibit glucagon secretion with maintenance of counterregulatory mechanisms, and exhibit cardiovascular benefits, while having a low risk profile. Importantly, short-term studies have shown that incretins/incretin-based therapies protect β-cells (by enhancing cell proliferation and differentiation and inhibiting apoptosis) and stimulate their function (by recruiting β-cells to the secretory process and increasing insulin biosynthesis/secretion). These therapies have the opportunity to interfere with the disease progression if used as an early intervention, when enough β-cell mass/function can still be preserved or restored.
Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy.
We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and ...followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.
At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio ACR <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m
(BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA
(r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well.
Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.
Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point.
A total of 16 492 patients ...with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups.
In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease.
http://www.clinicaltrials.gov. Unique identifier: NCT01107886.
To identify clinically meaningful clusters of patients with similar glycated hemoglobin (HbA1c) trajectories among patients with type 2 diabetes.
A retrospective cohort study using unsupervised ...machine learning clustering methodologies to determine clusters of patients with similar longitudinal HbA1c trajectories. Stability of these clusters was assessed and supervised random forest analysis verified the clusters' reproducibility. Clinical relevance of the clusters was assessed through multivariable analysis, comparing differences in risk for a composite outcome (macrovascular and microvascular outcomes, hypoglycemic events, and all-cause mortality) at HbA1c thresholds for each cluster.
Among 60,423 patients, three clusters of HbA1c trajectories were generated: stable (n = 45,679), descending (n = 6,084), and ascending (n = 8,660) trends, which were reproduced with 99.8% accuracy using a random forest model. In the clinical relevance assessment, HbA1c levels demonstrated a J-shape association with the risk for outcomes. HbA1c level thresholds for minimizing outcomes' risk differed by cluster: 6.0-6.4% for the stable cluster, <8.0% for the descending cluster, and <9.0 for the ascending cluster.
By applying unsupervised machine learning to longitudinal HbA1c trajectories, we have identified clusters of patients who have distinct risk for diabetes-related complications. These clusters can be the basis for developing individualized models to personalize glycemic targets.
Drug Therapies for Diabetes Weinberg Sibony, Roni; Segev, Omri; Dor, Saar ...
International journal of molecular sciences,
2023-Dec-05, Letnik:
24, Številka:
24
Journal Article
Recenzirano
Odprti dostop
The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. ...Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.
The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 ...million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors' Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.
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