The efficiency of dapagliflozin as add-on therapy in obese patients with resistant hypertension and chronic kidney disease

Abstract Background Obesity, insulin resistance, renal dysfunction, hyperuricemia are some of the most common causes of resistant hypertension (RH). A close relationship exists between RH and fluid retention. Currently, there is no consensus regarding pathogenetic therapy of RH and there are no studies on the effects of sodium–glucose cotransporter-2 (SGLT2) inhibitors in obese patients with RH and chronic kidney disease (CKD). The aim was to evaluate the effects of dapagliflozin (D) in obese P with RH and CKD stages 3a. Methods 45 obese P (mean body mass index (BMI) 34.2 kg/m2, waist circumference (WC) 104 cm) with true RH and CKD 3a (eGFR 45–59 mL/min/1.73m2) were included in the study under conventional therapy full doses of appropriate combinations (mean 3.7 antihypertensive drugs). The D at daily doses of 10 mg was added to previous treatment. The blood pressure (BP) was measured in the office and by ambulatory BP monitoring. Anthropometry, metabolic profile, including oral glucose tolerance test with insulin, homeostatic model assessment HOMA-R, hematocrit (Hct), uric acid, potassium (K), serum creatinine, calculated GFR were performed at baseline and after 12 weeks treatment. Results At baseline were excellent correlations between BMI and SBP (r=0.45, P<0.01), eGFR and DBP (r=−0.33, P<0.05), eGFR and Hct (r=0.31, P<0.05), BMI and HOMA-R (r=0.34, P<0.05). At baseline mean HOMA-R was 2,8±0.7, eGFR 53.50±3.26 ml/min/1.73 m2, uric acid 469±23 nmol/L, K 4,9±0.9 mmol/L. The asymptomatic hyperuricemia was observed in 57%, impaired glucose tolerance in the 37%. After 12 weeks administration of D, the mean 24 h ambulatory BP effectively decreased (−7.6/−4.3 mmHg; P<0.05 for both; respectively. Also, there were significant decreases in BMI (−2,1 kg/m2, P<0.01), WC (−4,8 cm, P<0.01), fasting glucose (−0,8 mmol/L, P<0.01) and uric acid (−42 nmol/L, P<0.01) without changes in insulin secretion and not significant improvement in HOMA-R (2,8±0.7 versus 2.4±0.4). Mean eGFR and K on D remained unchanged, however, the albumin/creatinine ratio decreased significantly (P<0.05). Also, the Hct significantly increased after start of D (P<0.01). By linear regression analysis, the independent associated factor for the change SBP was baseline BMI (P<0.05) and for the change DBP baseline eGFR (P<0.05). Conclusion Dapagliflozin shows an additional antihypertensive effect when added to the prior combination therapy in obese patients with RH and CKD 3a without risk of hyperkalemia. Dapagliflozin increase hematocrit, possibly due to its diuretic effects and hemoconcentration. So, positive antihypertensive effect D is due to natriuretic effect and decrease fluid retention. Furthermore, there is also a strong indication that the BP effect is also influenced by weight loss and dapagliflozin administration decreased body mass index, waist circumference, fasting glucose and uric acid, with a tendency to decrease the insulin resistance without changes in insulin secretion. FUNDunding Acknowledgement Type of funding sources: None.

Download Full-text

Effect of Dapagliflozin on Insulin Secretion and Insulin Sensitivity in Patients with Prediabetes

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0664-7583 ◽

2018 ◽

Vol 128 (08) ◽

pp. 506-511 ◽

Cited By ~ 5

Author(s):

Alejandra M. Ramírez-Rodríguez ◽

Manuel González-Ortiz ◽

Esperanza Martínez-Abundis

Keyword(s):

Body Mass Index ◽

Body Weight ◽

Uric Acid ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Waist Circumference ◽

Body Mass ◽

Fasting Glucose ◽

Controlled Clinical Trial ◽

Double Blind

Abstract Aim To evaluate the effect of dapagliflozin on insulin secretion and insulin sensitivity in patients with prediabetes. Methods A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 adults diagnosed with prediabetes and without pharmacological treatment. Patients were randomly assigned into two groups of 12 patients each to receive 10 mg of oral dapagliflozin or placebo once a day during 12 weeks. At baseline and at the end of the study, anthropometric and metabolic measurements were evaluated, including the first phase of insulin secretion, total insulin secretion, and insulin sensitivity. Results After dapagliflozin administration, there were significant decreases in body weight (80.8±16.3 vs. 77.8±14.9 kg, p=0.019), body mass index (30.3±3.5 vs. 29.2±3.1 kg/m2, p=0.023), waist circumference (100.6±13.5 vs. 96.2±11.8 cm, p=0.003), fasting glucose (5.9±0.4 vs. 5.1±0.3 mmol/L, p<0.001) and uric acid (334.3±70.8 vs. 262.9±60.7 mmol/L, p=0.032), with a tendency to increase the insulin sensitivity (1.94±0.72 vs. 2.63±1.04, p=0.064). Conclusion Dapagliflozin administration in patients with prediabetes decreased body weight, body mass index, waist circumference, fasting glucose, and uric acid, with a tendency to increase the insulin sensitivity without changes in insulin secretion.

Download Full-text

The effect of combination therapy of insulin glargine, metformin, and sitagliptin on insulin secretion, insulin resistance, and metabolic parameters in obese subjects with type 2 diabetes

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1610497z ◽

2016 ◽

Vol 144 (9-10) ◽

pp. 497-502

Author(s):

Teodora Beljic-Zivkovic ◽

Milica Marjanovic-Petkovic ◽

Miljanka Vuksanovic ◽

Ivan Soldatovic ◽

Dobrila Kanlic ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Body Mass Index ◽

Waist Circumference ◽

Insulin Glargine ◽

Body Mass ◽

Fasting Glucose ◽

C Peptide ◽

Obese Subjects

Introduction. A combination of drugs is required for treatment of obese subjects with diabetes, due to multiple pathogenic mechanisms implicated in the development of both diabetes and obesity. Objective. Assessment of the effect of sitagliptin added to insulin glargine and metformin, in obese subjects with type 2 diabetes. Methods. A total of 23 obese subjects on metformin and insulin glargine participated in the study. Titration of insulin glargine during a one-month period preceded the addition of 100 mg of sitagliptin daily. Body mass index, waist circumference, fasting, and prandial glucose were measured monthly, lipids and hemoglobin A1c (HbA1c) every three months, insulin, c-peptide and glucagon at the start and after six months of treatment. Homeostatic models for insulin secretion (HOMA B) and insulin resistance (HOMA IR) were calculated. Results. Participants were 58.65 ?} 7.62 years of age with a body mass index of 35.06 ?} 5.15 kg/m2, waist circumference of 115.04 ?} 15.5 cm, and the duration of diabetes of 4.11 ?} 2.57 years. With the titration of insulin glargine, target fasting glucose levels were not achieved. Waist circumference and body mass index decreased during three months of sitagliptin treatment, thereafter remaining stable. HbA1c decreased significantly after three and six months of therapy. C-peptide increased significantly, while glucagon level fell. HOMA indexes were unchanged. Conclusion. Sitagliptin can improve diabetes control and induce modest weight loss in obese subjects poorly controlled on insulin glargine and metformin. Titration of insulin glargine to optimal fasting glucose values is a prerequisite of success of this combination therapy.

Download Full-text

Fasting insulin reflects heterogeneous physiological processes: role of insulin clearance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00013.2011 ◽

2011 ◽

Vol 301 (2) ◽

pp. E402-E408 ◽

Cited By ~ 36

Author(s):

Mark O. Goodarzi ◽

Jinrui Cui ◽

Yii-Der I. Chen ◽

Willa A. Hsueh ◽

Xiuqing Guo ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Waist Circumference ◽

Mexican Americans ◽

Fasting Glucose ◽

Insulin Clearance ◽

Oral Glucose ◽

Metabolic Clearance ◽

Insulinogenic Index ◽

Fasting Insulin

Several processes contribute to variation in fasting insulin concentration, including fasting glucose, insulin resistance, insulin secretion, and insulin clearance. Our goal was to determine the relative contribution of each of these insulin-related traits, plus anthropometric parameters, to fasting insulin among 470 Mexican Americans. The euglycemic hyperinsulinemic clamp yielded insulin sensitivity (M value) and metabolic clearance rate of insulin (MCRI). Acute insulin secretion was estimated by the insulinogenic index (IGI30) from the oral glucose tolerance test. Regression (univariate) and generalized estimating equations (multivariate) were used to describe the relationship of insulin-related traits to fasting insulin. Univarate analyses were used to select which traits to include in the multivariate model. In multivariate analysis, MCRI, M, BMI, waist circumference, and fasting glucose were independently associated with fasting insulin. Decreasing M and MCRI were associated with increasing fasting insulin, whereas increasing BMI, waist circumference, and fasting glucose were associated with increasing fasting insulin. Standardized coefficients allowed determination of the relative strength of each trait's association with fasting insulin in the entire cohort (strongest to weakest): MCRI (−0.35, P < 0.0001), M (−0.24, P < 0.0001), BMI (0.20, P = 0.0011), waist circumference (0.16, P = 0.021), and fasting glucose (0.11, P = 0.014). Fasting insulin is a complex phenotype influenced by several independent processes, each of which might have its own environmental and genetic determinants. One of the most associated traits was insulin clearance, which has implications for studies that have used fasting insulin as a surrogate for insulin resistance.

Download Full-text

Abstract 10397: Higher Waist Circumference is the Start of Cardiovascular Structural and Functional Changes in Childhood Obesity

Circulation ◽

10.1161/circ.132.suppl_3.10397 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Kenji Harada ◽

Yukiko Harada ◽

Manatomo Toyono

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Uric Acid ◽

Waist Circumference ◽

Fasting Glucose ◽

Volume Ratio ◽

Left Ventricular ◽

Model Assessment ◽

Functional Changes ◽

Late Diastole

Background: Higher waist circumference (WC) is associated with cardiovascular disease, however, little is known about the association between WC and cardiovascular functional change in children. The purpose of this study is to examine the relationships between numbers of cardiovascular risk factors and left ventricular (LV) geometry and function in children. Methods: Echocardiography was performed in 311 children aged 7 to 13 years. Left atrial (LA) diameter, LV end-diastolic volume, ejection fraction, mass, mass-to-volume ratio, and carotid artery intima media-thickness (IMT) were measured. Transmitral peak flow velocities during early and late diastole and mitral annular myocardial velocities during early (Em) and late diastole (Am) were measured. LA systolic force and aortic stiffness were calculated. Lipids, uric acid, fasting glucose, insulin, high sensitive CRP, and homeostasis model assessment for insulin resistance (HOMA-IR) were also assessed. Subjects were divided into 4 groups: A group, WC within normal range; B group, increased WC; C group, increased WC plus any one of the following individual factors of hypertension, dyslipidemia (low high-density lipoprotein-cholesterol and/or high triglyceride), and raised fasting glucose; D group, metabolic syndrome. Results: Compared with the A group, LA diameter, mass/volume ratio, HOMA-IR, and uric acid were greater in the B group (p<0.05 for all). With increasing number of metabolic syndrome disorders (C and D groups), dyslipidemia, increased Hs-CRP, decreased Em/Am, enhanced LA systolic force, increased IMT, and aortic stiffening were observed (Table). Conclusions: Higher WC is associated with insulin resistance, hyperuricemia, and concentric LV hypertrophy. Cardiovascular structural and functional changes become apparent with increasing number of metabolic syndrome disorders. Our findings suggest that primary prevention programs should be initiated in children with increased WC.

Download Full-text

Associations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab551 ◽

2021 ◽

Author(s):

Nandini Nair ◽

Eric Vittinghoff ◽

Mark J Pletcher ◽

Elizabeth C Oelsner ◽

Norrina B Allen ◽

...

Keyword(s):

Insulin Resistance ◽

Body Mass Index ◽

Young Adult ◽

Waist Circumference ◽

Body Mass ◽

Young Adulthood ◽

Fasting Glucose ◽

Later Life ◽

Overweight And Obesity ◽

Incident Diabetes

Abstract Context The independent contribution of young adult exposure to overweight and obesity to later life incident diabetes is not well studied. Objective To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18 to 39 years) with incident diabetes later in life (≥40 years). Design Pooled data from six US prospective cohorts (ARIC, CARDIA, CHS, Framingham Offspring, Health ABC, MESA). Setting Population-based cohort studies. Participants 30,780 participants (56.1% female, 69.8% non-Hispanic White) without a diagnosis of diabetes by age 40. Interventions We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life. Main Outcome Measure(s) Incident diabetes defined as fasting glucose ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, or use of diabetes medications. Results During a 9-year median follow-up, 4,323 participants developed incident diabetes. Young adult BMI and WC were associated with later life incident diabetes after controlling for later life exposures (hazard ratios [HR] 1.99 for BMI ≥30 kg/m 2 and 2.13 for WC >88cm [women]/>102cm [men] compared to normal ranges). Young adult homeostatic model of insulin resistance (HOMA-IR) mediated 49% and 44% of the association between BMI and WC with later life incident diabetes. HDL and triglycerides mediated a smaller proportion of these associations. Conclusions Elevated BMI and WC during young adulthood were independently associated with later life incident diabetes. Insulin resistance appears to be a key mediator.

Download Full-text

The effects of metformin plus sulfonylurea therapy on clinical features of the metabolic syndrome

Medicinski pregled ◽

10.2298/mpns1010611k ◽

2010 ◽

Vol 63 (9-10) ◽

pp. 611-615 ◽

Cited By ~ 1

Author(s):

Branka Koprivica ◽

Teodora Beljic-Zivkovic ◽

Tatjana Ille

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Metabolic Syndrome ◽

Body Mass Index ◽

Waist Circumference ◽

Glycemic Control ◽

Body Mass ◽

Combined Therapy

Introduction. Insulin resistance is a well-known leading factor in the development of metabolic syndrome. The aim of this study was to evaluate metabolic effects of metformin added to sulfonylurea in unsuccessfully treated type 2 diabetic patients with metabolic syndrome. Material and methods. A group of thirty subjects, with type 2 diabetes, secondary sulfonylurea failure and metabolic syndrome were administered the combined therapy of sulfonylurea plus metformin for six months. Metformin 2000 mg/d was added to previously used sulfonylurea agent in maximum daily dose. Antihypertensive and hypolipemic therapy was not changed. The following parameters were assessed at the beginning and after six months of therapy: glycemic control, body mass index, waist circumference, blood pressure, triglycerides, total cholesterol and its fractions, homeostatic models for evaluation of insulin resistance and secretion (HOMA R, HOMA B) and C- peptide. Results. Glycemic control was significantly improved after six months of the combined therapy: (fasting 7.89 vs. 10.61 mmol/l. p<0.01; postprandial 11.12 vs. 12.61 mmol/l. p<0.01, p<0.01; glycosylated hemoglobin 6.81 vs. 8.83%. p<0.01). the body mass index and waist circumference were significantly lower (26.7 vs. 27.8 kg/m2, p<0.01 and 99.7 vs. 101.4 cm for men, p<0.01; 87.2 vs. 88.5 for women, p<0.01). Fasting plasma triglycerides decreased from 3.37 to 2.45 mmol/l (p<0.001) and HOMA R from 7.04 to 5.23 (p<0.001). No treatment effects were observed on blood pressure, cholesterol, and residual insulin secretion. Conclusion. Administration of metformin in type 2 diabetes with metabolic syndrome decreased cardiovascular risk factors by reducing glycemia, triglycerides, BMI, central obesity and insulin resistance.

Download Full-text

Body mass index and waist circumference are better predictors of insulin resistance than total body fat percentage in middle-aged and elderly Taiwanese

Medicine ◽

10.1097/md.0000000000008126 ◽

2017 ◽

Vol 96 (39) ◽

pp. e8126 ◽

Cited By ~ 19

Author(s):

Yiu-Hua Cheng ◽

Yu-Chung Tsao ◽

I-Shiang Tzeng ◽

Hai-Hua Chuang ◽

Wen-Cheng Li ◽

...

Keyword(s):

Insulin Resistance ◽

Body Mass Index ◽

Waist Circumference ◽

Body Mass ◽

Body Fat ◽

Body Fat Percentage ◽

Middle Aged ◽

Fat Percentage ◽

Total Body Fat ◽

Total Body

Download Full-text

Physical Activity, Measures of Obesity, and Cardiometabolic Risk: The Multi-Ethnic Study of Atherosclerosis (MESA)

Journal of Physical Activity and Health ◽

10.1123/jpah.2012-0068a ◽

2014 ◽

Vol 11 (4) ◽

pp. 831-837 ◽

Cited By ~ 9

Author(s):

Paul A. McAuley ◽

Haiying Chen ◽

Duck-chul Lee ◽

Enrique Garcia Artero ◽

David A. Bluemke ◽

...

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Waist Circumference ◽

Impaired Fasting Glucose ◽

Central Obesity ◽

Cardiometabolic Risk ◽

Fasting Glucose ◽

Reference Group ◽

Model Assessment ◽

Ethnic Study

Background:The influence of higher physical activity on the relationship between adiposity and cardiometabolic risk is not completely understood.Methods:Between 2000–2002, data were collected on 6795 Multi-Ethnic Study of Atherosclerosis (MESA) participants. Self-reported intentional physical activity in the lowest quartile (0–105 MET-minutes/week) was categorized as inactive and the upper three quartiles (123–37,260 MET-minutes/week) as active. Associations of body mass index (BMI) and waist circumference categories, stratified by physical activity status (inactive or active) with cardiometabolic risk factors (dyslipidemia, hypertension, upper quartile of homeostasis model assessment of insulin resistance [HOMA-IR] for population, and impaired fasting glucose or diabetes) were assessed using logistic regression analysis adjusting for age, gender, race/ethnicity, and current smoking.Results:Among obese participants, those who were physically active had reduced odds of insulin resistance (47% lower; P < .001) and impaired fasting glucose/diabetes (23% lower; P = .04). These associations were weaker for central obesity. However, among participants with a normal waist circumference, those who were inactive were 63% more likely to have insulin resistance (OR [95% CI] 1.63 [1.24–2.15]) compared with the active reference group.Conclusions:Physical activity was inversely related to the cardiometabolic risk associated with obesity and central obesity.

Download Full-text

Insulin resistance in relation to clinical, endocrine and metabolic profile of infertile women with polycystic ovary syndrome

Bangabandhu Sheikh Mujib Medical University Journal ◽

10.3329/bsmmuj.v14i1.50989 ◽

2021 ◽

Vol 14 (1) ◽

pp. 1-6

Author(s):

Shakeela Ishrat ◽

Marufa Hossain ◽

Subrata Kumar Biswas

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Body Mass Index ◽

Waist Circumference ◽

Polycystic Ovary Syndrome ◽

Body Mass ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

Infertile Women ◽

Significant Difference

The objective of this study is to explore how hyperinsulinemia and insulin resistance relate to the clinical, endocrine and metabolic factors in the infertile women with polycystic ovary syndrome. This study was conducted on 121 consecutive infertile women with polycystic ovary syndrome attending the Infertility unit from January 2017 to December 2017. They were divided into two groups: insulin resistant and insulin sensitive. There was significant difference in body mass index and waist circumference between the two groups. Serum lipids were not associated with insulin resistance. Hyperinsulinemia was significantly associated with metabolic syndrome. Reducing body mass index and waist circumference may improve insulin resistance in infertile women with polycystic ovary syndrome. Screening the infertile women with polycystic ovary syndrome for hyperinsulinemia and insulin resistance and subsequent counseling is recommended to address the long-term risks of metabolic syndrome.

Download Full-text