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1.  Long-Term Safety and Efficacy of Empagliflozin, Sitagliptin, and Metformin 
Diabetes Care  2013;36(12):4015-4021.
To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes.
In this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin.
Changes from baseline in HbA1c at week 90 were −0.34 to −0.63% (−3.7 to −6.9 mmol/mol) with empagliflozin, −0.56% (−6.1 mmol/mol) with metformin, and −0.40% (−4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were −2.2 to −4.0 kg with empagliflozin, −1.3 kg with metformin, and −0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2–74.1% of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0–5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8–12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin.
Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes.
PMCID: PMC3836134  PMID: 24186878
2.  Empagliflozin as Add-on to Metformin Plus Sulfonylurea in Patients With Type 2 Diabetes 
Diabetes Care  2013;36(11):3396-3404.
To investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes.
Patients inadequately controlled on metformin and sulfonylurea (HbA1c ≥7 to ≤10%) were randomized and treated with once-daily empagliflozin 10 mg (n = 225), empagliflozin 25 mg (n = 216), or placebo (n = 225) for 24 weeks. The primary end point was change from baseline in HbA1c 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 −0.17% (0.05) for placebo vs. −0.82% (0.05) and −0.77% (0.05) for empagliflozin 10 and 25 mg, respectively (both P < 0.001). Empagliflozin significantly reduced MDG, weight, and systolic (but not diastolic) blood pressure versus placebo. Adverse events were reported in 62.7, 67.9, and 64.1% of patients on placebo and empagliflozin 10 and 25 mg, respectively. Events consistent with urinary tract infection were reported in 8.0, 10.3, and 8.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 13.3, 18.0, and 17.5%, respectively; males: 2.7, 2.7, and 0%, respectively). Events consistent with genital infection were reported in 0.9, 2.7, and 2.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 0.9, 4.5, and 3.9%, respectively; males: 0.9% in each group).
Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin plus sulfonylurea improved glycemic control, weight, and systolic blood pressure and were well tolerated.
PMCID: PMC3816918  PMID: 23963895
3.  Expression of Human Chemerin Induces Insulin Resistance in the Skeletal Muscle but Does Not Affect Weight, Lipid Levels, and Atherosclerosis in LDL Receptor Knockout Mice on High-Fat Diet 
Diabetes  2010;59(11):2898-2903.
Chemerin is a recently discovered hepatoadipokine that regulates adipocyte differentiation as well as chemotaxis and activation of dendritic cells and macrophages. Chemerin was reported to modulate insulin sensitivity in adipocytes and skeletal muscle cells in vitro and to exacerbate glucose intolerance in several mouse models in vivo. In humans, chemerin was shown to be associated with multiple components of the metabolic syndrome including BMI, triglycerides, HDL cholesterol, and hypertension. This study aimed to examine the effect of chemerin on weight, glucose and lipid metabolism, as well as atherosclerosis in vivo.
We used recombinant adeno-associated virus to express human chemerin in LDL receptor knockout mice on high-fat diet.
Expression of chemerin did not significantly alter weight, lipid levels, and extent of atherosclerosis. Chemerin, however, significantly increased glucose levels during the intraperitoneal glucose tolerance test without affecting endogenous insulin levels and the insulin tolerance test. Chemerin reduced insulin-stimulated Akt1 phosphorylation and activation of 5′AMP-activated protein kinase (AMPK) in the skeletal muscle, but had no effect on Akt phosphorylation and insulin-stimulated AMPK activation in the liver and gonadal adipose tissue.
Chemerin induces insulin resistance in the skeletal muscle in vivo. Chemerin is involved in the cross talk between liver, adipose tissue, and skeletal muscle.
PMCID: PMC2963549  PMID: 20724582
4.  Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™) 
Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.
Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.
Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m2, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m2. The study is expected to report in 2015.
EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.
Trial registration NCT01131676
PMCID: PMC4072621  PMID: 24943000
Blood pressure; Body weight; Empagliflozin; Glycemic control; Macrovascular; Microvascular; SGLT2 inhibitor; Type 2 diabetes
5.  Adipokines and Insulin Resistance 
Molecular Medicine  2008;14(11-12):741-751.
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-α and interleukin-6, vaspin, and visfatin on insulin resistance.
PMCID: PMC2582855  PMID: 19009016
7.  The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus 
Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity.
Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4–6 mmol/L) and hyperglycaemia (blood glucose 9–11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily).
In response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p < 0.0001) and aortic positions (+0.1 ± 13.4 to -6.2 ± 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 ± 1.1 to 5.2 ± 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions.
Empagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects.
Trial registration
Clinical trial registration: NCT01392560
PMCID: PMC3915232  PMID: 24475922
Diabetes mellitus; Systemic blood pressure; SGLT2 inhibition; Empagliflozin; Hyperglycaemia; Arterial stiffness; Heart rate variability
8.  Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients 
Background. 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.
Methods. We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m2, 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.
Results. 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.
Conclusions. 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.
PMCID: PMC3904627  PMID: 24463454
9.  Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control 
Sulfonylureas (SUs) are commonly used in the treatment of type 2 diabetes (T2DM), usually as second-line treatment after the failure of metformin. However, SUs are associated with poor durability, hypoglycemia and weight gain. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor in development for the treatment of T2DM. In Phase II/III trials, empagliflozin reduced hyperglycemia, body weight and blood pressure, with a low incidence of hypoglycemia. The aim of this Phase III study is to compare the effects of empagliflozin and the SU glimepiride as second-line therapy in patients with T2DM inadequately controlled with metformin immediate release (IR) and diet/exercise.
After a 2-week placebo run-in, patients were randomized to receive empagliflozin 25 mg once daily (qd) or glimepiride 1–4 mg qd double-blind for 2 years, in addition to metformin IR. Patients who participate in the initial 2-year randomization period will be eligible for a 2-year double-blind extension. The primary endpoint is change from baseline in HbA1c. Secondary endpoints are change from baseline in body weight, the incidence of confirmed hypoglycemia and changes in systolic and diastolic blood pressure. Exploratory endpoints include markers of insulin secretion, body composition and responder analyses. Safety endpoints include the incidence of adverse events (AEs) (including macro- and microvascular adverse events) and changes from baseline in clinical laboratory parameters.
Between August 2010 and June 2011, 1549 patients were randomized and 1545 patients were treated. At baseline, mean (SD) age was 55.9 (10.4) years, HbA1c was 7.92 (0.84)%, body mass index was 30.11 (5.59) kg/m2, systolic blood pressure was 133.5 (15.9) mmHg and diastolic blood pressure was 79.5 (9.4) mmHg.
This is the largest study to compare the efficacy and safety of an SGLT2 inhibitor with an SU in patients with T2DM inadequately controlled on metformin to date. In addition to determining the effects of these treatments on glycemic control over the long term, this study will investigate effects on beta-cell function, cardiovascular risk factors and markers of renal function/damage. The results will help to inform the choice of second-line treatment in patients with T2DM who have failed on metformin.
Trial registration NCT01167881.
PMCID: PMC3844307  PMID: 24007456
Blood pressure; Body weight; Empagliflozin; Glimepiride; Glycemic control; Macrovascular; Microvascular; SGLT2 inhibitor; Sulfonylurea; Type 2 diabetes
10.  MMP-1 serum levels predict coronary atherosclerosis in humans 
Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease.
260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time) to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified.
In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85); p < 0.05) in a model adjusted for age, sex, BMI, classical cardiovascular risk factors, hsCRP, adiponectin, pericardial fat volume and medication. Specification of plaque morphology revealed significant association of MMP-1 serum levels with non-calcified plaques (OR: 1.16 (CI: 1.0-1.34); p = 0.05) and calcified plaques (OR: 1.22 (CI: 1,03-1.45); p < 0.05) while association with mixed plaques was lost in the fully adjusted model. No associations were found between MMP9 serum levels and total plaque burden or plaque morphology.
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
PMCID: PMC2754422  PMID: 19751510
11.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques 
PLoS ONE  2009;4(3):e4733.
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
Methodology/Principal Findings
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
PMCID: PMC2649379  PMID: 19266101
12.  Serum concentrations of cortisol, interleukin 6, leptin and adiponectin predict stress induced insulin resistance in acute inflammatory reactions 
Critical Care  2008;12(6):R157.
Inflammatory stimuli are causative for insulin resistance in obesity as well as in acute inflammatory reactions. Ongoing research has identified a variety of secreted proteins that are released from immune cells and adipocytes as mediators of insulin resistance; however, knowledge about their relevance for acute inflammatory insulin resistance remains limited. In this study we aimed for a clarification of the relevance of different insulin resistance mediating factors in an acute inflammatory situation.
Insulin resistance was measured in a cohort of 37 non-diabetic patients undergoing cardiac surgery by assessment of insulin requirement to maintain euglycaemia and repeated measurements of an insulin glycaemic index. The kinetics of cortisol, interleukin 6 (IL6), tumour necrosis factor α (TNFα), resistin, leptin and adiponectin were assessed by repeated measurements in a period of 48 h.
Insulin resistance increased during the observation period and peaked 22 h after the beginning of the operation. IL6 and TNFα displayed an early increase with peak concentrations at the 4-h time point. Serum levels of cortisol, resistin and leptin increased more slowly and peaked at the 22-h time point, while adiponectin declined, reaching a base at the 22-h time point. Model assessment identified cortisol as the best predictor of insulin resistance, followed by IL6, leptin and adiponectin. No additional information was gained by modelling for TNFα, resistin, catecholamine infusion rate, sex, age, body mass index (BMI), operation time or medication.
Serum cortisol levels are the best predictor for inflammatory insulin resistance followed by IL6, leptin and adiponectin. TNFα, and resistin have minor relevance as predictors of stress dependent insulin resistance.
PMCID: PMC2646322  PMID: 19087258
13.  Genetic variants of adiponectin receptor 2 are associated with increased adiponectin levels and decreased triglyceride/VLDL levels in patients with metabolic syndrome 
Adiponectin acts as an antidiabetic, antiinflammatory and antiatherogenic adipokine. These effects are assumed to be mediated by the recently discovered adiponectin receptors AdipoR1 and AdipoR2.
The purpose of this study was to determine whether variations in the AdipoR1 and AdipoR2 genes may contribute to insulin resistance, dyslipidemia and inflammation.
We sequenced all seven coding exons of both genes in 20 unrelated German subjects with metabolic syndrome and tested genetic variants for association with glucose, lipid and inflammatory parameters.
We identified three AdipoR2 variants (+795G/A, +870C/A and +963C/T) in perfect linkage disequilibrium (r2 = 1) with a minor allele frequency of 0.125. This haplotype was associated with higher plasma adiponectin levels and decreased fasting triglyceride, VLDL-triglyceride and VLDL-cholesterol levels. No association, however, was observed between the AdipoR2 SNP cluster and glucose metabolism.
To our knowledge, this is the first study to identify an association between genetic variants of the adiponectin receptor genes and plasma adiponectin levels. Furthermore, our data suggest that AdipoR2 may play an important role in triglyceride/VLDL metabolism.
PMCID: PMC1482678  PMID: 16700915
14.  Comparison of Current Guidelines for Primary Prevention of Coronary Heart Disease 
In primary prevention of atherosclerotic disease, it is difficult to decide when medical treatment should be initiated. The main goal of the study was to compare different guidelines for coronary heart disease (CHD) risk assessment and initiation of lipid-lowering therapy.
Cross-sectional evaluation.
An outpatient lipid and diabetes clinic in a university hospital.
Risk factor data obtained on 100 consecutive patients (58 men and 42 women) without clinical evidence of cardiovascular disease were used to compare the Framingham risk equation, the U.S. National Cholesterol Education Program (Adult Treatment Panel III) (NCEP ATP III) guidelines, the joint European Societies guidelines, the joint British guidelines, the revised Sheffield table, and the Munster Heart Study calculator (PROCAM) CHD risk assessment and lipid-lowering therapy.
Guidelines could be applied to different subsets of the cohort, ranging from 22% (PROCAM) to 95% of the cohort (revised Sheffield table). All guidelines (except PROCAM) could be applied to a total of 62 patients. Guidelines predicted ≥20% risk for developing CHD over 10 years in 53% (NCEP ATP III), 26% (European) and 32% (British), while Framingham predicted this risk level in 34%. CHD risk was estimated to be ≥3%/year in 5% according to Sheffield, while Framingham predicted this risk in 13%. Lipid-lowering drug therapy is recommended in 52% by NCEP ATP III, while European, British, and Sheffield guidelines recommend this in 26%, 35%, and 5%, respectively.
Guidelines for assessing CHD risk and lipid-lowering therapy differ greatly. Therefore, these algorithms must be used with caution.
PMCID: PMC1494828  PMID: 12648250
atherosclerosis; guideline; coronary heart disease; risk assessment; primary prevention; lipid-lowering therapy

Results 1-14 (14)