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Curalin supplement for patients with type 2 diabetes mellitus.
Weinberg Sibony, R, Wainstein, J, Ish Shalom, M, Ganz, T, Rozenberg, A, Yanuv, I, Eliyahu, U, Raz, I
Diabetes/metabolism research and reviews. 2023;(4):e3624
Abstract
OBJECTIVE To examine the efficacy and safety of Curalin supplement in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Adult patients with type 2 diabetes were randomized 1:1 to receive Curalin supplement or placebo. The primary endpoint was HbA1c decrease at 1 month. The secondary endpoint was a decrease in HbA1c by more than 0.5% and 1% and a change in 7 daily blood glucose measurements. A satisfaction questionnaire was used as an exploratory endpoint. Safety variables and adverse events were assessed. RESULTS After 1 month of intervention, HbA1c was reduced by 0.94% in the Curalin arm versus 0.4% in the placebo arm (P = 0.008). 72% of Curalin patients had decreased HbA1c levels >0.5% versus 35% in the placebo arm (P < 0.05). The Treatment Satisfaction Questionnaire indicated that Curalin arm patients reported higher overall satisfaction. CONCLUSIONS Curalin treatment significantly reduced HbA1c over a 1-month period and was well-tolerated.
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Drug Therapies for Diabetes.
Weinberg Sibony, R, Segev, O, Dor, S, Raz, I
International journal of molecular sciences. 2023;(24)
Abstract
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.
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Efficacy and Safety of Dapagliflozin by Baseline Insulin Regimen and Dose: Post Hoc Analyses From DECLARE-TIMI 58.
Pollack, R, Raz, I, Wiviott, SD, Goodrich, EL, Murphy, SA, Yanuv, I, Rozenberg, A, Mosenzon, O, Langkilde, AM, Gause-Nilsson, IAM, et al
Diabetes care. 2023;(1):156-164
Abstract
OBJECTIVE The cardiorenal benefits of adding sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy for patients on insulin, particularly those on intensive regimens that include short-acting (SA) insulin, have not been explored. RESEARCH DESIGN AND METHODS In Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular (CV), renal, metabolic, and safety outcomes with dapagliflozin versus placebo by insulin dose and regimen were studied with Cox regression models. RESULTS The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied, with 2,443 (34.8%) patients receiving <0.5 IU/kg, 2,795 (39.9%) 0.5 to ≤1 IU/kg, and 1,339 (19.1%) >1 IU/kg. Dapagliflozin reduced CV death/hospitalization for heart failure among overall insulin users (hazard ratio [HR] 0.82 [95% CI 0.69-0.97]) and consistently in patients on insulin regimens with or without SA insulin (0.83 [0.67-1.03] and 0.78 [0.57-1.07], respectively, Pinteraction = 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse CV events with dapagliflozin among insulin users (0.84 [0.74-0.97]) was similar irrespective of regimen or dose (Pinteraction = 0.75 and 0.07). Dapagliflozin reduced the rate of adverse renal outcomes overall and consistently across subgroups of insulin users. Decreases in HbA1c, weight, and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens. CONCLUSIONS The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.
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Effects of dapagliflozin on hospitalisations in people with type 2 diabetes: post-hoc analyses of the DECLARE-TIMI 58 trial.
Schechter, M, Wiviott, SD, Raz, I, Goodrich, EL, Rozenberg, A, Yanuv, I, Murphy, SA, Zelniker, TA, Fredriksson, M, Johansson, PA, et al
The lancet. Diabetes & endocrinology. 2023;(4):233-241
Abstract
BACKGROUND In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease. METHODS The DECLARE-TIMI 58 trial was a double-blind, multicentre, randomised, placebo-controlled study. People with type 2 diabetes and either risk factors for or established atherosclerotic cardiovascular disease were randomly assigned (1:1) to receive oral dapagliflozin 10 mg or placebo once daily. In these post-hoc analyses, the effects of dapagliflozin on risks of first non-elective any-cause and cause-specific hospitalisation were assessed with Cox proportional hazards regression models overall and in the subset of participants without prevalent atherosclerotic cardiovascular disease. The risk of total (first plus subsequent) non-elective hospitalisations was assessed with Lin-Wei-Ying-Yang model. Investigator-reported System Organ Class terms were used to classify cause-specific hospitalisations. The trial is registered with ClinicalTrials.gov, NCT01730534. FINDINGS Between April 25, 2013, and Sept 18, 2018, 17 160 people (6422 [37·4%] women, 10 738 [62·6%] men; mean age 63·9 years [SD 6·8]) were enrolled in the original trial, of whom 10186 (59·4%) had multiple risk factors for but did not have established atherosclerotic cardiovascular disease, and 6835 (39·8%) had both no evidence of atherosclerotic cardiovascular disease and low KDIGO risk. Over a median follow-up of 4·2 years (IQR 3·9-4·4), dapagliflozin was associated with a lower risk of first non-elective hospitalisation for any cause (2779 [32·4%] of 8582 people in the dapagliflozin group vs 3036 [35·4%] of 8578 people in the placebo group; hazard ratio [HR] 0·89 [95% CI 0·85-0·94]) and total (first plus subsequent) non-elective hospitalisations for any cause (risk ratio 0·92 [95% CI 0·86-0·97]). The association between dapagliflozin use and the risk of first non-elective hospitalisation for any cause was consistent in subgroups of participants with (HR 0·92 [95% CI 0·85-0·99] and without (0·87 [0·81-0·94]) atherosclerotic cardiovascular disease at baseline (p interaction=0·31). Compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders (HR 0·91 [95% CI 0·84-1·00]), metabolism and nutrition disorders (0·73 [0·60-0·89]), renal and urinary disorders (0·61 [0·49-0·77]), and due to any other cause excluding these three causes (0·90 [0·85-0·96]). Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders (HR 0·81 [0·67-0·99]) and infections and infastations (HR 0·86 [0·78-0·96]). INTERPRETATION Dapagliflozin reduced the risk of first and total non-elective hospitalisations for any cause in people with type 2 diabetes, regardless of the presence of atherosclerotic cardiovascular disease, including hospitalisations not directly attributed to cardiac, kidney, or metabolic causes. These findings might have implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition. FUNDING AstraZeneca.
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Protective effects of SGLT-2 inhibitors across the cardiorenal continuum: two faces of the same coin.
Fontes-Carvalho, R, Santos-Ferreira, D, Raz, I, Marx, N, Ruschitzka, F, Cosentino, F
European journal of preventive cardiology. 2022;(9):1352-1360
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Abstract
The cardiovascular and renal systems are closely interconnected in health and disease. Disorders affecting one of these systems frequently involve the other. Both diseases progress through a continuous chain of events, defined as the 'cardiorenal continuum', which is initiated by risk factors that lead to subclinical disease, clinical events, and ultimately to heart failure and end-stage kidney disease. Previous studies have shown that interventions anywhere along this chain of events can interrupt the pathophysiological cascade and provide cardiovascular and/or kidney 'protection'. More recently, clinical trials with SGLT-2 inhibitors (SGLT2i) have shown a significant reduction in cardiovascular and kidney outcomes. Evidence from EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, VERTIS-CV, CREDENCE, and more recently DAPA-HF, EMPEROR-Reduced, and DAPA-CKD show that the beneficial effects of SGLT2i are observed across all stages of the cardiorenal continuum, ranging from patients with diabetes and multiple risk factors to those with established cardiovascular disease and even independently of diabetes status. This review provides a critical appraisal of the efficacy and safety of SGLT2i, demonstrating that this is a novel way to disrupt the chain of pathological events in the cardiorenal continuum and prevent cardiovascular and kidney disease in patients with and without diabetes.
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Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58.
Cahn, A, Wiviott, SD, Mosenzon, O, Goodrich, EL, Murphy, SA, Yanuv, I, Rozenberg, A, Bhatt, DL, Leiter, LA, McGuire, DK, et al
Diabetes care. 2022;(4):938-946
Abstract
OBJECTIVE Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models. RESULTS In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06-1.19], 1.08 [1.04-1.13], and 1.17 [1.11-1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05). CONCLUSIONS Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%.
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Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial.
Mosenzon, O, Raz, I, Wiviott, SD, Schechter, M, Goodrich, EL, Yanuv, I, Rozenberg, A, Murphy, SA, Zelniker, TA, Langkilde, AM, et al
Diabetes care. 2022;(10):2350-2359
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OBJECTIVE In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes. RESULTS Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001). CONCLUSIONS Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.
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Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial.
Furtado, RHM, Raz, I, Goodrich, EL, Murphy, SA, Bhatt, DL, Leiter, LA, McGuire, DK, Wilding, JPH, Aylward, P, Dalby, AJ, et al
Circulation. 2022;(21):1581-1591
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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 17 160 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; P<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 (Pinteractions=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. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT01730534.
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Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials.
Neuen, BL, Oshima, M, Agarwal, R, Arnott, C, Cherney, DZ, Edwards, R, Langkilde, AM, Mahaffey, KW, McGuire, DK, Neal, B, et al
Circulation. 2022;(19):1460-1470
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BACKGROUND Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease. However, their effect on hyperkalemia has not been systematically evaluated. METHODS A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease in whom serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory-determined serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios and corresponding 95% CIs pooled with random-effects models to obtain summary treatment effects, overall and across key subgroups. RESULTS Results from 6 trials were included comprising 49 875 participants assessing 4 SGLT2 inhibitors. Of these, 1754 participants developed serious hyperkalemia, and an additional 1119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76-0.93]), an effect consistent across studies (Pheterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 [95% CI, 0.68-0.93]; Pheterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups, including baseline kidney function, history of heart failure, and use of renin-angiotensin-aldosterone system inhibitor, diuretic, and mineralocorticoid receptor antagonist. SGLT2 inhibitors did not increase the risk of hypokalemia (hazard ratio, 1.04 [95% CI, 0.94-1.15]; Pheterogeneity=0.42). CONCLUSIONS SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease without increasing the risk of hypokalemia.
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Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.
Oyama, K, Raz, I, Cahn, A, Kuder, J, Murphy, SA, Bhatt, DL, Leiter, LA, McGuire, DK, Wilding, JPH, Park, KS, et al
European heart journal. 2022;(31):2958-2967
Abstract
AIMS: We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. CONCLUSIONS In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.