Metformin is one of the most popular oral glucose-lowering medications, widely considered to be the optimal initial therapy for patients with type 2 diabetes mellitus. Interestingly, there still ...remains controversy regarding the drug’s precise mechanism of action, which is thought to involve a reduction in hepatic glucose production. It is now recommended as first-line treatment in various guidelines, including that of the EASD and ADA. Its favoured status lies in its efficacy, low cost, weight neutrality and good safety profile. Other benefits have also been described, including improvements in certain lipids, inflammatory markers, and a reduction in cardiovascular events, apparently independent from the drug’s glucose-lowering effect. Data have emerged questioning the previous reluctance to use this agent in those with mild to moderate chronic kidney disease. Regulations guiding its use in patients with stable, modest renal dysfunction have, as a result, become more lenient in recent years. With no long-term studies comparing it against newer glucose-lowering drugs, some of which have more robust evidence for cardioprotection, metformin’s established role as ‘foundation therapy’ in type 2 diabetes may justifiably be challenged.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral glucose-lowering agents indicated for the treatment of type 2 diabetes. In the CANagliflozin cardioVascular Assessment Study (CANVAS) ...Program, the SGLT2 inhibitor canagliflozin was associated with an increased risk for lower-limb amputation (LLA) (including minor and major amputation) versus placebo (hazard ratio HR 1.97 95% CI 1.41, 2.75) in patients with type 2 diabetes and high cardiovascular risk. In the EMPA-REG OUTCOME trial in patients with type 2 diabetes and established cardiovascular disease, the proportion of patients with LLA was similar between those treated with empagliflozin and placebo. Here, Inzucchi et al report further analyses of LLA in the EMPA-REG OUTCOME trial.
Sodium–glucose cotransporter 2 (SGLT2) inhibitors belong to a novel class of glucose-lowering medications that reduce plasma glucose concentrations by inhibiting glucose reabsorption by the kidney, ...inducing glucosuria. Their actions encompass reductions in HbA
1c
, fasting and postprandial blood glucose levels, body weight and BP. To date, empagliflozin and canagliflozin have additionally been shown to improve cardiovascular outcomes in high-risk individuals and to slow the progression of diabetic kidney disease. Adverse effects associated with this class include urinary frequency, dehydration, genitourinary tract infections and, rarely, euglycaemic diabetic ketoacidosis. Of the SGLT2 inhibitors, only canagliflozin has been linked to a higher risk of lower-extremity amputations and bone fractures compared with placebo. Optimal prescribing of agents within this relatively new drug category requires a full understanding of their risks in addition to their benefits.
Diagnosis of Diabetes Inzucchi, Silvio E
The New England journal of medicine,
08/2012, Letnik:
367, Številka:
6
Journal Article
Recenzirano
This article reviews recommendations for diabetes screening, which vary with respect to whether and how to screen. The American Diabetes Association recommends screening persons 45 of age or older or ...with other risk factors by means of fasting glucose or glycated hemoglobin testing.
Foreword
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
Stage
A 42-year-old asymptomatic man with hypertension presents for his annual physical examination. His medications include atenolol combined with chlorthalidone (at doses of 50 mg and 25 mg, respectively, per day). Both parents had type 2 diabetes mellitus later in life. He does not smoke cigarettes. His body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is 32.3, and his blood pressure is 130/80 mm Hg. Would you screen the patient for diabetes, and if so, how?
The Clinical Problem
Type 2 diabetes is a complex disease that is typically diagnosed in midlife . . .
Over the past two years, our understanding of anti-hyperglycemic medications used to treat patients with type 2 diabetes (T2D) has fundamentally changed. Before the EMPA-REG OUTCOME trial, agents ...used to lower blood glucose were felt to prevent or delay the development of microvascular complications, but were not known to definitively reduce cardiovascular risk or mortality. Previous studies with then novel sodium-glucose cotransport-2 (SGLT2) inhibitors demonstrated improvements in several cardiovascular and renal risk factors, including HbA1c, blood pressure, weight, renal hyperfiltration, and albuminuria. However, as with other antihyperglycemic drugs, it could not be known if these salutary effects would translate into improved cardiorenal outcomes. In the EMPA-REG OUTCOME trial, SGLT2 inhibition with empagliflozin reduced the primary outcome of major adverse cardiovascular events (MACE), while also reducing mortality, hospitalization for heart failure, and progression of diabetic kidney disease. In the CANVAS Program trials using canagliflozin, the rates of the 3-point MACE endpoint, the risk of heart failure and the renal composite endpoint were also reduced, albeit with an increased risk of lower extremity amputation and fracture. As a result, clinical practice guidelines recommend the consideration of SGLT2 inhibition in high-risk patient subgroups for cardiovascular risk reduction. Ongoing primary renal endpoint trials will inform the cardio-metabolic-renal community about how to optimally treat patients with chronic kidney disease – including those with and without diabetes. Our aim is to review the rationale for renal protection with SGLT2 inhibitors, and their current place in the clinical management of patients with kidney disease.
In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established ...cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio HR 0.62 95% CI 0.49, 0.77). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin.
Effects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed.
Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA
. In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death.
In this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.
In this cardiovascular safety trial, lorcaserin facilitated sustained weight loss without a higher risk of major adverse cardiovascular events than that with placebo in a high-risk population of ...overweight or obese patients.
Stopping metformin often results in poorly controlled glycemia and/or the need for other agents with their own adverse-effect profiles. ... is the now widespread use of estimated glomerular ...filtration rate (eGFR) in lieu of serum creatinine levels creating even more confusion, especially in those with abnormalities in one but not the other indirect measure of renal function?
Abstract
Objective
The risks of cardio-renal complications of diabetes increase with age. In the EMPA-REG OUTCOME® trial, empagliflozin reduced cardiovascular (CV) mortality by 38% in patients with ...type 2 diabetes (T2D) and CV disease. Here we compare outcomes with empagliflozin in older patients in EMPA-REG OUTCOME.
Methods
Patients with T2D and CV disease were randomised to empagliflozin 10 or 25 mg, or placebo plus standard of care. In post hoc analyses, risks of 3-point major adverse CV events (3P-MACE: composite of CV death, non-fatal myocardial infarction (MI) or non-fatal stroke), CV death, hospitalisation for heart failure, all-cause mortality, all-cause hospitalisation and incident/worsening nephropathy were evaluated for empagliflozin versus placebo by baseline age (<65, 65 to <75, ≥75 years). Adverse events (AEs) were analysed descriptively.
Results
Effect of empagliflozin on all outcomes was consistent across age categories (P ≥ 0.05 for interactions) except 3P-MACE. The 3P-MACE hazard ratios (HRs) were 1.04 (95% confidence interval CI 0.84, 1.29), 0.74 (0.58, 0.93) and 0.68 (0.46, 1.00) in patients aged <65, 65 to <75, and ≥75 years, respectively (P = 0.047 for treatment-by-age group interaction). Corresponding CV death HRs were 0.72 (95% CI 0.52, 1.01), 0.54 (0.37, 0.79) and 0.55 (0.32, 0.94), respectively (P = 0.484 for treatment-by-age group interaction). Across age categories, empagliflozin AEs reflected its known safety profile. Rates of bone fractures, renal AEs and diabetic ketoacidosis were similar between empagliflozin and placebo across age categories.
Conclusions
In the EMPA-REG OUTCOME trial, empagliflozin reduced risks of CV mortality, heart failure and renal outcomes, supporting its cardio-renal benefits in older patients.
BACKGROUND:In the EMPA-REG OUTCOME trial (BI 10773 Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic ...cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure. We investigated whether these effects varied across the spectrum of baseline cardiovascular risk.
METHODS:Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention.
RESULTS:Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline (P>0.05 for randomized group-by-subgroup interactions).
CONCLUSIONS:Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events. Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01131676.
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