Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been ...investigated in human diabetes.
We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry.
Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 interquartile range {IQR}, 4.4 g/3 hours and 9.2 IQR, 5.2 g/3 hours) and after meal ingestion (median, 29.0 IQR, 12.5 g/5 hours and 28.2 IQR, 15.4 g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 IQR, 14 g and 37 IQR, 11 g vs. 34 IQR, 11 g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 IQR, 16 g and 70 IQR, 21 g vs. 93 IQR, 18 g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 IQR, 35 pmol • min(-1) • m(-2) • mM(-1) and 55 IQR, 39 pmol • min(-1) • m(-2) • mM(-1) vs. 44 IQR, 32 pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged.
In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.
To investigate the efficacy, safety, and tolerability of empagliflozin in patients with type 2 diabetes and hypertension.
Patients (N = 825) with type 2 diabetes and hypertension (mean seated ...systolic blood pressure SBP 130-159 mmHg and diastolic blood pressure DBP 80-99 mmHg) were randomized (double blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks.
At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP (ambulatory blood pressure monitoring ABPM) was -3.44 mmHg (95% CI -4.78, -2.09) with 10 mg empagliflozin and -4.16 mmHg (-5.50, -2.83) with 25 mg empagliflozin (both P < 0.001). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP (ABPM) was -1.36 mmHg (95% CI -2.15, -0.56) with 10 mg empagliflozin and -1.72 mmHg (95% CI -2.51, -0.93) with 25 mg empagliflozin (both P < 0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference versus placebo in change from baseline in HbA1c at week 12 was -0.62% (95% CI -0.72, -0.52) (-6.8 mmol/mol 95% CI -7.9, -5.7) with 10 mg empagliflozin and -0.65% (95% CI -0.75, -0.55) (-7.1 mmol/mol 95% CI -8.2, -6.0) with 25 mg empagliflozin (both P < 0.001). Empagliflozin was well tolerated. One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion.
Empagliflozin was associated with significant and clinically meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension.
We investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 ...diabetes mellitus (T2DM).
Patients inadequately controlled on MDI insulin ± metformin (mean HbA1c 8.3% 67 mmol/mol; BMI 34.8 kg/m(2); insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25 mg (n = 189), or placebo (n = 188) for 52 weeks. Insulin dose was to remain stable in weeks 1-18, adjusted to meet glucose targets in weeks 19-40, then stable in weeks 41-52. The primary end point was change from baseline in HbA1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA1c at week 52.
Adjusted mean ± SE changes from baseline in HbA1c were -0.50 ± 0.05% (-5.5 ± 0.5 mmol/mol) for placebo versus -0.94 ± 0.05% (-10.3 ± 0.5 mmol/mol) and -1.02 ± 0.05% (-11.1 ± 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P < 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA1c of -0.81 ± 0.08% (-8.9 ± 0.9 mmol/mol), -1.18 ± 0.08% (-12.9 ± 0.9 mmol/mol), and -1.27 ± 0.08% (-13.9 ± 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA1c <7% (<53 mmol/mol) with empagliflozin (31-42%) versus placebo (21%; both P < 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (-9 to -11 international units/day) and weight (-2.4 to -2.5 kg) versus placebo (all P < 0.01) at week 52.
In obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.
To investigate the efficacy and tolerability of empagliflozin as an add-on to metformin therapy in patients with type 2 diabetes.
Patients with HbA1c levels of ≥7% to ≤ 10% (≥53 to ≤86 mmol/mol) ...while receiving metformin (≥1,500 mg/day) were randomized and treated with once-daily treatment with empagliflozin 10 mg (n = 217), empagliflozin 25 mg (n = 213), or placebo (n = 207) for 24 weeks. The primary end point was the change in HbA1c level from baseline at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24.
At week 24, adjusted mean (SE) changes from baseline in HbA1c were -0.13% (0.05)% (-1.4 0.5 mmol/mol) with placebo, -0.70% (0.05)% (-7.7 0.5 mmol/mol) with empagliflozin 10 mg, and -0.77% (0.05)% (-8.4 0.5 mmol/mol) with empagliflozin 25 mg (both P < 0.001). Empagliflozin significantly reduced MDG level and systolic and diastolic blood pressure (BP) versus placebo. Adjusted mean (SE) changes from baseline in weight were -0.45 kg (0.17 kg) with placebo, -2.08 kg (0.17 kg) with empagliflozin 10 mg, and -2.46 kg (0.17 kg) with empagliflozin 25 mg (both P < 0.001). Adverse events (AEs) were similar across groups (placebo 58.7%; empagliflozin 49.5-57.1%). Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients receiving placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Events consistent with urinary tract infections were reported in 4.9%, 5.1%, and 5.6% of patients, and events consistent with genital infections were reported in 0%, 3.7%, and 4.7% of patients, respectively.
Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin therapy significantly improved glycemic control, weight, and BP, and were well-tolerated.
To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin.
Subjects were randomized ...to a combination of empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 141), empagliflozin 10 mg (n = 140), or linagliptin 5 mg (n = 132) as add-on to metformin for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.
At week 24, reductions in HbA1c (mean baseline 7.90-8.02% 62.8-64.1 mmol/mol) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin; adjusted mean (SE) changes from baseline were -1.19% (0.06) (-13.1 mmol/mol 0.7) with empagliflozin 25 mg/linagliptin 5 mg, -1.08% (0.06) (-11.8 mmol/mol 0.7) with empagliflozin 10 mg/linagliptin 5 mg, -0.62% (0.06) (-6.8 mmol/mol 0.7) with empagliflozin 25 mg, -0.66% (0.06) (-7.2 mmol/mol 0.7) with empagliflozin 10 mg, and -0.70% (0.06) (-7.6 mmol/mol 0.7) with linagliptin 5 mg (P < 0.001 for all comparisons). In these groups, respectively, 61.8, 57.8, 32.6, 28.0, and 36.1% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) had HbA1c <7% (<53 mmol/mol) at week 24. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across treatment arms (68.6-73.0%), with no hypoglycemic AEs requiring assistance.
Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated.
Diabetes is a leading cause of chronic kidney disease (CKD) worldwide. Optimum glycaemic control in patients with type 2 diabetes is important to minimise the risk of microvascular and macrovascular ...complications and to slow the progression of CKD. We assessed the efficacy and safety of empagliflozin as an add-on treatment in patients with type 2 diabetes and CKD.
We did a phase 3, randomised, double-blind, parallel-group, placebo-controlled trial at 127 centres in 15 countries. Patients with HbA1c of 7% or greater to 10% or less were eligible for inclusion. Patients with stage 2 CKD (estimated glomerular filtration rate eGFR ≥60 to <90 mL/min per 1·73 m(2); n=290) were randomly assigned (1:1:1) to receive empagliflozin 10 mg or 25 mg or placebo once daily for 52 weeks. Patients with stage 3 CKD (eGFR ≥30 to <60 mL/min per 1·73 m(2); n=374) were randomly assigned (1:1) to receive empagliflozin 25 mg or placebo for 52 weeks. Randomisation was done with a computer-generated random sequence and stratified by renal impairment, HbA1c, and background antidiabetes medication. Treatment assignment was masked from patients and investigators. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01164501.
In patients with stage 2 CKD, adjusted mean treatment differences versus placebo in changes from baseline in HbA1c at week 24 were -0·52% (95% CI -0·72 to -0·32) for empagliflozin 10 mg and -0·68% (-0·88 to -0·49) for empagliflozin 25 mg (both p<0·0001). In patients with stage 3 CKD, adjusted mean treatment difference versus placebo in change from baseline in HbA1c at week 24 was -0·42% (-0·56 to -0·28) for empagliflozin 25 mg (p<0·0001). In patients with stage 2 CKD, adverse events were reported over 52 weeks by 83 patients (87%) on placebo (15 severe 16% and 11 serious 12%), 86 (88%) on empagliflozin 10 mg (six severe 6% and six serious 6%) and 78 (80%) on empagliflozin 25 mg (eight severe 8% and seven serious 7%). In patients with stage 3 CKD, adverse events were reported over 52 weeks by 156 patients (83%) on placebo (15 severe 8% and 23 serious 12%) and 156 (83%) on empagliflozin 25 mg (18 severe 10% and 22 serious 12%).
In patients with type 2 diabetes and stage 2 or 3 CKD, empagliflozin reduced HbA1c and was well tolerated. However, our findings might not be applicable to the general population of patients with type 2 diabetes and renal impairment.
Boehringer Ingelheim, Eli Lilly.
Given the multi-faceted pathogenesis of atherosclerosis in type 2 diabetes mellitus (T2DM), it is likely that interventions to mitigate this risk must address cardiovascular (CV) risk factors beyond ...glucose itself. Sodium glucose cotransporter-2 (SGLT-2) inhibitors are newer antihyperglycaemic agents with apparent multiple effects. Inherent in their mode of action to decrease glucose reabsorption by the kidneys by increasing urinary glucose excretion, these agents improve glycaemic control independent of insulin secretion with a low risk of hypoglycaemia. In this review, we outline those CV risk factors that this class appears to influence and provide the design features and trial characteristics of six ongoing outcome trials involving more than 41,000 individuals with T2DM. Those risk factors beyond glucose that can potentially be modulated positively with SGLT-2 inhibitors include blood pressure, weight, visceral adiposity, hyperinsulinaemia, arterial stiffness, albuminuria, circulating uric acid levels and oxidative stress. On the other hand, small increases in low-density lipoprotein (LDL)-cholesterol levels have also been observed for the class, which theoretically might offset some of these benefits. The potential translational impact of these effects is being tested with outcome trials, also reviewed in this article, powered to assess both macrovascular as well as certain microvascular outcomes in T2DM. These are expected to begin to report in late 2015.
Adipokines and insulin resistance Rabe, Katja; Lehrke, Michael; Parhofer, Klaus G ...
Molecular medicine (Cambridge, Mass.),
11/2008, Letnik:
14, Številka:
11-12
Journal Article
Recenzirano
Odprti dostop
Obesity is associated with an array of health problems in adult and pediatric populations. Understanding the pathogenesis of obesity and its metabolic sequelae has advanced rapidly over the past ...decades. Adipose tissue represents an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive mediators (adipokines) that signal to organs of metabolic importance including brain, liver, skeletal muscle, and the immune system--thereby modulating hemostasis, blood pressure, lipid and glucose metabolism, inflammation, and atherosclerosis. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones adiponectin, chemerin, leptin, omentin, resistin, retinol binding protein 4, tumor necrosis factor-alpha and interleukin-6, vaspin, and visfatin on insulin resistance.
We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not ...received drug treatment in the preceding 12 weeks.
In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813.
Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0·74% (95% CI -0·88 to -0·59; p<0·0001) for empagliflozin 10 mg, -0·85% (-0·99 to -0·71; p<0·0001) for empagliflozin 25 mg, and -0·73% (-0·88 to -0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four 2% severe and six 3% serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight 4% severe and eight 4% serious), 135 (60%) patients in the empagliflozin 25 mg group (seven 3% severe and five 2% serious), and 119 (53%) patients in the sitagliptin group (five 2% severe and six 3% serious).
Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment.
Boehringer Ingelheim and Eli Lilly.
Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the ...sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes.
In this double-blind phase 3 trial, patients (aged ≥18 years) with type 2 diabetes and HbA1c concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1:1 ratio with a computer-generated random sequence, stratified by HbA1c, estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1-4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0·3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set-ie, patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is registered with ClinicalTrials.gov, number NCT01167881. A 104-week extension is ongoing.
Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA1c with empagliflozin versus glimepiride was -0·11% (95% CI -0·19 to -0·02; p=0·0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose ≤3·9 mmol/L or requiring assistance) at week 104 were reported in 19 (2%) patients treated with empagliflozin and 189 (24%) patients treated with glimepiride.
Empagliflozin might be an effective and a well tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycaemic control on metformin.
Boehringer Ingelheim and Eli Lilly.
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