ABSTRACT
AIMS: To assess whether people with type 2 diabetes transferring from higher basal insulin doses (> 20 units) to a starting dose of 16 units of insulin degludec/liraglutide (IDegLira) benefit from IDegLira with/without transient loss of glycaemic control. METHODS: Post hoc analysis of DUAL V and VII assessed fasting self-measured blood glucose (SMBG) over weeks 1-8, changes in HbA1c, body weight and mean insulin dose over 26 weeks, and percentage of participants achieving HbA1c < 53 mmol/mol (7.0%) by end of trial in participants with type 2 diabetes uncontrolled with basal insulin. IDegLira was compared with continued up-titration of insulin glargine (IGlar U100) in DUAL V, or switching to basal-bolus therapy in DUAL VII (IGlar U100 and insulin aspart), across pre-trial insulin dose groups (20-29, 30-39 and 40-50 units/day). RESULTS: In all subgroups, participants treated with IDegLira experienced significant improvements in HbA1c by end of trial, which were greater than with IGlar U100 up-titration (estimated treatment difference -5.86, -6.59 and -6.91 mmol/mol for pre-trial insulin doses of 20-29, 30-39 and 40-50 units/day, respectively) and similar to basal-bolus therapy (estimated treatment difference -0.16, -1.0 and -0.01 mmol/mol for pre-trial insulin doses of 20-29, 30-39 and 40-50 units/day, respectively). Compared with IGlar U100 and basal-bolus therapy, IDegLira participants experienced weight loss vs. weight gain, lower rates of hypoglycaemia and a lower mean end of trial total daily insulin dose. In both trials, mean fasting SMBG decreased from weeks 1 to 8 across all subgroups, despite a temporary increase in mean fasting SMBG in the 40-50 units pre-trial insulin dose group during week 1 [mean increase (sd) +1.1 (2.0) mmol/l for DUAL V and +1.1 (2.1) mmol/l for DUAL VII], which reverted to baseline by week 4. CONCLUSIONS: Regardless of pre-trial insulin dose, IDegLira resulted in improved clinical outcomes, even in participants transferring from 40-50 units of basal insulin, despite a transient (< 4 weeks), clinically non-relevant, elevation in pre-breakfast SMBG. (Clinical Trial Registry Number NCT01952145 and NCT02420262).
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin/metabolism , Hypoglycemic Agents/therapeutic use , Insulin, Long-Acting/therapeutic use , Liraglutide/therapeutic use , Aged , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Drug Combinations , Drug Substitution , Female , Glycemic Control , Humans , Insulin Glargine/therapeutic use , Male , Middle Aged , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
AIM: To evaluate whether management of people with Type 2 diabetes shared between a specialized outpatient clinic and primary health care has noninferior HbA1c outcomes compared with mono-sectorial management in a specialized outpatient clinic. METHODS: A randomized controlled, noninferiority study. People with moderate hyperglycaemia, hypertension and/or incipient complications were eligible for the study. All participants had annual comprehensive check-ups at the outpatient clinic. Quarterly check-ups were conducted by general practitioners (GPs) for the shared care group and by endocrinologists at the outpatient clinic for the control group. The primary outcome was the mean difference in HbA1c from baseline to 12 months of follow-up. The noninferiority margin for HbA1c was 4.4 mmol/mol. RESULTS: A total of 140 people were randomized [age 65.0 ± 0.9 years, HbA1c 52 ± 0.8 mmol/mol (6.9 ± 0.1%), systolic BP 135.6 ± 1.1 mmHg; all mean ± sem]. Peripheral neuropathy was present in 68% of participants and microalbuminuria in 19%; 15% had history of a previous major cardiovascular event. Among study completers (n = 133), HbA1c increased by 2.3 mmol/mol (0.2%) in the shared care group and by 1.0 mmol/mol (0.1%) in the control group, with a between-group difference of 1.3 mmol/mol [90% confidence interval (CI) -1.3, 3.9] (0.1%, 90% CI -0.1, 0.4). Noninferiority was confirmed in both per protocol and intention to treat analyses. CONCLUSION: We found that our shared care programme was noninferior to specialized outpatient management in maintaining glycaemic control in this group of people with Type 2 diabetes. Shared care should be considered for the future diabetes management of Type 2 diabetes.
Subject(s)
Ambulatory Care Facilities , Diabetes Mellitus, Type 2/therapy , Glycated Hemoglobin/drug effects , Hyperglycemia/therapy , Hypertension/therapy , Primary Health Care , Aged , Analysis of Variance , Critical Pathways , Delivery of Health Care, Integrated/organization & administration , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Female , Follow-Up Studies , Glycated Hemoglobin/metabolism , Humans , Hyperglycemia/blood , Hyperglycemia/physiopathology , Hypertension/blood , Hypertension/physiopathology , MaleABSTRACT
The data in this article describe the use of dietary supplements in Danish patients with type 1 diabetes (T1D) and type 2 diabetes (T2D). The data were collected from a web-based dietary survey on dietary habits in 774 patients with T1D (nâ¯=â¯426) and T2D (nâ¯=â¯348). The data demonstrate that 99% of the patients with diabetes use dietary supplements with no gender differences. In comparison, only 64% in the general population use dietary supplements [2]. A higher proportion of people in the general population use multivitamin/mineral supplementation as compared to patients with diabetes (48% vs. 34-37%) and a higher proportion of women than men with diabetes use multivitamin/mineral supplementation (T1D: 43% women vs. 26% men and T2D: 45% women vs. 34% men). More patients with diabetes than the general population use supplements such as calcium together with vitamin D, vitamin D, vitamin B, vitamin C, vitamin E, magnesium, calcium, Q10, ginger, garlic, and other herbal supplements.
ABSTRACT
BACKGROUND: Epidemiological studies strongly suggest that psoriasis predisposes to type 2 diabetes. Several theories have been proposed to explain how these disease entities might be pathophysiologically connected. OBJECTIVES: Our primary objective was to elucidate whether clinical data support the notion of common pathophysiological denominators in patients with psoriasis and type 2 diabetes, and thus to delineate the association between the two conditions that has arisen on the basis of epidemiological studies. METHODS: We reviewed clinical studies investigating parameters of glucose metabolism in patients with psoriasis. The PubMed and Embase databases were searched for studies investigating glucose metabolism in adult patients with psoriasis as a primary or secondary end point. Studies had to include a relevant control group. RESULTS: Twenty-six clinical studies reporting on insulin resistance, glucose tolerance or insulin secretion were eligible for review. The results were widely conflicting, with less than half of the studies showing results suggestive of defective glucose metabolism in patients with psoriasis. In general, the studies suffered from a lack of information regarding possible confounders and patient characteristics. Furthermore, the research methods varied, and in all but one study they might not have been appropriate to detect early and subtle defects in glucose metabolism. CONCLUSIONS: The available literature does not unequivocally support common pathophysiological denominators in psoriasis and type 2 diabetes. Well-designed clinical studies are needed to expose potential diabetogenic defects in the glucose metabolism in patients with psoriasis.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Psoriasis/metabolism , Diabetes Mellitus, Type 2/etiology , Humans , Psoriasis/complicationsABSTRACT
OBJECTIVE: Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period. METHOD: One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels. RESULTS: From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide. CONCLUSION: The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.
Subject(s)
Hypoglycemic Agents/pharmacology , Liraglutide/pharmacology , Obesity/drug therapy , Overweight/drug therapy , Prediabetic State/drug therapy , Adolescent , Adult , Aged , Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Blood Glucose/drug effects , Body Weight/drug effects , C-Peptide/drug effects , Clozapine/adverse effects , Clozapine/therapeutic use , Denmark/epidemiology , Fasting , Female , Follow-Up Studies , Glucagon-Like Peptide-1 Receptor/agonists , Glycated Hemoglobin/drug effects , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Lipid Metabolism/drug effects , Liraglutide/administration & dosage , Liraglutide/therapeutic use , Male , Middle Aged , Obesity/chemically induced , Obesity/epidemiology , Olanzapine/adverse effects , Olanzapine/therapeutic use , Overweight/chemically induced , Overweight/epidemiology , Placebos/administration & dosage , Prediabetic State/chemically induced , Prediabetic State/epidemiology , Schizophrenia/blood , Schizophrenia/diagnosis , Schizophrenia/drug therapy , Young AdultABSTRACT
BACKGROUND: Ghrelin, an orexigenic peptide, is secreted from endocrine cells in the gastric mucosa. Circulating levels rise in the preprandial phase, suggesting an anticipatory or cephalic phase of release, and decline in the postprandial phase, suggesting either the loss of a stimulatory factor or inhibition by factors released when nutrients enter the intestine. We hypothesized that vagal signals are not required for the (i) preprandial increase or (ii) postprandial suppression of ghrelin levels. Further, we wanted to investigate the hypothesis that (iii) glucagon-like peptide-1 might be implicated in the postprandial decline in ghrelin levels. METHODS: We measured ghrelin levels in plasma from sham-feeding and meal studies carried out in vagotomized individuals and controls, and from a GLP-1 infusion study carried out in fasting healthy young individuals. KEY RESULTS: We find that (i) ghrelin secretion is unchanged during indirect vagal stimulation as elicited by modified sham-feeding in vagotomized individuals and matched controls, (ii) ghrelin secretion is similarly suppressed after meal ingestion in vagotomized individuals and controls, and (iii) infusion of GLP-1 does not lower ghrelin levels. CONCLUSIONS & INFERENCES: We conclude that for postprandial suppression of circulating ghrelin levels, a circulating factor (but not GLP-1) or short (duodeno-gastric) reflexes seem to be implicated.
Subject(s)
Eating/physiology , Ghrelin/blood , Glucagon-Like Peptide 1/blood , Postprandial Period/physiology , Vagus Nerve/physiology , Aged , Female , Glucagon-Like Peptide 1/administration & dosage , Humans , Male , Middle Aged , Postprandial Period/drug effects , Vagotomy/trends , Vagus Nerve/drug effects , Vagus Nerve/surgeryABSTRACT
BACKGROUND AND AIMS: The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. METHODS AND RESULTS: Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). CONCLUSION: Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.
Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/blood , Gastric Inhibitory Polypeptide/blood , Glucagon-Like Peptide 1/blood , Incretins/blood , Insulin-Secreting Cells/metabolism , Insulin/blood , Aged , Biomarkers/blood , Blood Glucose/metabolism , Case-Control Studies , Denmark , Diabetes Mellitus, Type 2/diagnosis , Female , Glucose Tolerance Test , Humans , Insulin/metabolism , Insulin Secretion , Male , Middle Aged , Models, Biological , Time FactorsABSTRACT
AIMS: To investigate the effects of exercise in combination with a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, or placebo for the treatment of type 2 diabetes. METHODS: Thirty-three overweight, dysregulated and sedentary patients with type 2 diabetes were randomly allocated to 16 weeks of either exercise and liraglutide or exercise and placebo. Both groups had three supervised 60-minute training sessions per week including spinning and resistance training. RESULTS: Glycated haemoglobin (HbA1c) levels dropped by a mean ± standard deviation of 2.0% ± 1.2% (from 8.2% ± 1.4%) in the exercise plus liraglutide group vs 0.3% ± 0.9% (from 8.0% ± 1.2%) in the exercise plus placebo group ( P < .001), and body weight was reduced more with liraglutide (-3.4 ± 2.9 kg vs -1.6 ± 2.3 kg; P < .001). Compared with baseline, similar reductions were seen in body fat (exercise plus liraglutide: -2.5% ± 1.4% [ P < .001]; exercise plus placebo: -2.2% ± 1.9% [ P < .001]) and similar increases were observed in maximum oxygen uptake (exercise plus liraglutide: 0.5 ± 0.5 L O2 /min [ P < .001]; exercise plus placebo: 0.4 ± 0.4 L O2 /min [ P = .002]). Greater reductions in fasting plasma glucose (-3.4 ± 2.3 mM vs -0.3 ± 2.6 mM, P < .001) and systolic blood pressure (-5.4 ± 7.4 mm Hg vs -0.6 ± 11.1 mm Hg, P < .01) were seen with exercise plus liraglutide vs exercise plus placebo. The two groups experienced similar increases in quality of life during the intervention. CONCLUSIONS: In obese patients with type 2 diabetes, exercise combined with GLP-1RA treatment near-normalized HbA1c levels and caused a robust weight loss when compared with placebo. These results suggest that a combination of exercise and GLP-1RA treatment is effective in type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/therapy , Exercise Therapy/methods , Glucagon-Like Peptide-1 Receptor/agonists , Hypoglycemic Agents/therapeutic use , Liraglutide/therapeutic use , Obesity/therapy , Adult , Aged , Blood Glucose/metabolism , Blood Pressure , Body Mass Index , Body Weight , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Drug Therapy, Combination , Female , Glycated Hemoglobin/metabolism , Humans , Male , Metformin/therapeutic use , Middle Aged , Obesity/complications , Obesity/metabolism , Oxygen Consumption , Physical Fitness , Quality of Life , Resistance Training , Weight LossABSTRACT
AIMS: To investigate whether the use of antibiotics from infancy to adolescence influences the risk of Type 1 diabetes. METHODS: We conducted a population-based case-control study, including all Type 1 diabetes cases in Denmark among children born between 1997 and 2012 (n = 1578). Odds ratios associating Type 1 diabetes with use of antibiotics were calculated using conditional logistic regression. RESULTS: Overall, we found no association between the use of antibiotics and risk of Type 1 diabetes. Furthermore, no associations were seen specifically for broad-spectrum, narrow-spectrum, bactericidal or bacteriostatic types of antibiotics or for the most frequently used individual classes of antibiotics. No differences were observed in subgroups defined by sex or by age at time of diagnosis. However, filling five or more antibiotic prescriptions in the first 2 years of life specifically was associated with a higher odds ratio of 1.35 (95% CI 1.10-1.64). This association appeared to be driven by exposure to broad-spectrum antibiotics within the second year of life. CONCLUSION: Antibiotic exposure in childhood is generally not associated with the risk of developing Type 1 diabetes. Future studies should investigate the effects of multiple exposures to broad-spectrum antibiotics during the second year of life.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Diabetes Mellitus, Type 1/epidemiology , Adolescent , Case-Control Studies , Child , Child, Preschool , Denmark/epidemiology , Female , Humans , Infant , Infant, Newborn , Logistic Models , Male , Odds Ratio , Risk FactorsABSTRACT
Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.
Subject(s)
Cholecystokinin/blood , Diabetes Mellitus, Type 2/blood , Adult , Aged , Cross-Over Studies , Energy Intake , Female , Gallbladder Emptying , Gastric Emptying , Humans , Male , Middle Aged , Postprandial PeriodABSTRACT
AIM: To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake. METHODS: On four separate days, nine patients with type 2 diabetes, and 10 matched healthy control subjects received bolus instillations of (i) CDCA, (ii) colesevelam, (iii) CDCA + colesevelam or (iv) placebo. At baseline and for 180 min after instillation, blood was sampled. RESULTS: In both the type 2 diabetes group and the healthy control group, CDCA elicited an increase in GLP-1 levels compared with colesevelam, CDCA + colesevelam and placebo, respectively (p < 0.05). The interventions did not affect plasma glucose, insulin or C-peptide concentrations in any of the groups. CDCA elicited a small increase in plasma insulin : glucose ratio compared with colesevelam, CDCA + colesevelam and placebo in both groups. Compared with colesevelam, CDCA + colesevelam and placebo, respectively, CDCA increased glucagon and delayed gastric emptying in both groups. CONCLUSIONS: CDCA increased GLP-1 and glucagon secretion, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which, in turn, may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans.
Subject(s)
Chenodeoxycholic Acid/pharmacology , Colesevelam Hydrochloride/pharmacology , Diabetes Mellitus, Type 2/metabolism , Glucagon-Like Peptide 1/metabolism , Aged , Bile Acids and Salts/antagonists & inhibitors , Bile Acids and Salts/metabolism , Blood Glucose/drug effects , Blood Glucose/metabolism , C-Peptide/blood , Diabetes Mellitus, Type 2/blood , Double-Blind Method , Female , Gastric Emptying/drug effects , Glucagon-Like Peptide 1/blood , Humans , Incretins/blood , Insulin/blood , Insulin/metabolism , Insulin Secretion , Male , Middle Aged , PlacebosABSTRACT
OBJECTIVE: We evaluated whether patients with histologically verified nonalcoholic fatty liver disease (NAFLD) have an impaired incretin effect and hyperglucagonaemia. METHODS: Four groups matched for age, sex and body mass index were studied: (i) 10 patients with normal glucose tolerance and NAFLD; (ii) 10 patients with type 2 diabetes and NAFLD; (iii) eight patients with type 2 diabetes and no liver disease; and (iv) 10 controls. All participants underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycaemic intravenous glucose infusion (IIGI). We determined the incretin effect by relating the beta cell secretory responses during the OGTT and IIGI. Data are presented as medians (interquartile range), and the groups were compared by using the Kruskal-Wallis test. RESULTS: Controls exhibited a higher incretin effect [55% (43-73%)] compared with the remaining three groups (P < 0.001): 39% (44-71%) in the nondiabetic NAFLD patients, 20% (-5-50%) in NAFLD patients with type 2 diabetes, and 2% (-8-6%) in patients with type 2 diabetes and no liver disease. We found fasting hyperglucagonaemia in NAFLD patients with [7.5 pmol L(-1) (6.8-15 pmol L(-1))] and without diabetes [7.5 pmol L(-1) (5.0-8.0 pmol L(-1))]. Fasting glucagon levels were lower but similar in patients with type 2 diabetes and no liver disease [4.5 pmol L(-1) (3.0-6.0 pmol L(-1))] and controls [3.4 pmol L(-1) (1.8-6.0 pmol L(-1) )]. All groups had similar glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide responses. CONCLUSIONS: Patients with NAFLD have a reduced incretin effect and fasting hyperglucagonaemia, with the latter occurring independently of glucose (in)tolerance.
Subject(s)
Diabetes Mellitus, Type 2/complications , Glucagon/blood , Incretins/metabolism , Non-alcoholic Fatty Liver Disease/complications , Adult , Blood Glucose/metabolism , C-Reactive Protein/metabolism , Fasting/blood , Female , Gastric Inhibitory Polypeptide/metabolism , Glucagon-Like Peptide 1/metabolism , Glucose Intolerance/complications , Glucose Intolerance/diet therapy , Humans , Insulin/metabolism , Male , Middle AgedSubject(s)
Blood Glucose/metabolism , Gastrointestinal Hormones/metabolism , Psoriasis/metabolism , Adult , Aged , Area Under Curve , Body Mass Index , C-Reactive Protein/metabolism , Case-Control Studies , Female , Glycated Hemoglobin/metabolism , Humans , Insulin/metabolism , Male , Middle Aged , Postprandial Period/physiology , Young AdultABSTRACT
AIM: To evaluate, using post hoc analyses, whether the novel combination of a basal insulin, insulin degludec, and a glucagon-like peptide-1 receptor agonist, liraglutide (IDegLira), was consistently effective in patients with type 2 diabetes (T2D), regardless of the stage of T2D progression. METHODS: Using data from the DUAL I extension [insulin-naïve patients uncontrolled on oral antidiabetic drugs (OADs), n = 1660, 52 weeks] and DUAL II (patients uncontrolled on basal insulin plus OADs, n = 398, 26 weeks) randomized trials, the efficacy of IDegLira was investigated with regard to measures of disease progression stage including baseline glycated haemoglobin (HbA1c), disease duration and previous insulin dose. RESULTS: Across four categories of baseline HbA1c (≤7.5-9.0%), HbA1c reductions were significantly greater with IDegLira (1.1-2.5%) compared with IDeg or liraglutide alone in DUAL I. In DUAL II, HbA1c reductions were significantly greater with IDegLira (0.9-2.5%) than with IDeg in all but the lowest HbA1c category. In DUAL I, insulin dose and hypoglycaemia rate were lower across all baseline HbA1c categories for IDegLira versus IDeg, while hypoglycaemia was higher with IDegLira than liraglutide, irrespective of baseline HbA1c. In DUAL II, insulin dose and hypoglycaemia rate were similar with IDegLira and IDeg (maximum dose limited to 50 U) independent of baseline HbA1c. The reduction in HbA1c with IDegLira was independent of disease duration and previous insulin dose but varied depending on pre-trial OAD treatment. CONCLUSIONS: IDegLira effectively lowered HbA1c across a range of measures, implying suitability for patients with either early or advanced T2D.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin/analysis , Hypoglycemic Agents/administration & dosage , Insulin, Long-Acting/administration & dosage , Liraglutide/administration & dosage , Aged , Diabetes Mellitus, Type 2/blood , Drug Therapy, Combination , Female , Glycated Hemoglobin/drug effects , Humans , Hypoglycemia/chemically induced , Male , Metformin/administration & dosage , Middle Aged , Randomized Controlled Trials as Topic , Time Factors , Treatment OutcomeABSTRACT
Compared with bariatric surgery, less invasive and reversible techniques to counteract obesity and type 2 diabetes (T2D) have been developed, including the EndoBarrier Gastrointestinal Liner [duodenal-jejunal bypass sleeve (DJBS)]. We conducted a systematic review and meta-analyses of eligible trials to evaluate the efficacy and safety of the DJBS. Five randomized controlled trials (RCTs; 235 subjects) and 10 observational studies (211 subjects) were included. The risk of bias was evaluated as high in all studies. The mean body mass index ranged from 30 to 49.2 kg/m(2) and 10-100% of the subjects had T2D. Meta-analysis showed that the DJBS was associated with significant mean differences in body weight and excess weight loss of -5.1 kg [95% confidence interval (CI) -7.3, -3.0; four trials; n = 151; I(2) = 37%] and 12.6% (95% CI 9.0, 16.2; four trials; n = 166; I(2) = 24%), respectively, compared with diet modification. The mean differences in glycated haemoglobin (-0.9%; 95% CI -1.8, 0.0) and fasting plasma glucose (-3.7 mM; 95% CI -8.2, 0.8) among subjects with T2D did not reach statistical significance. Adverse events consisted mainly of abdominal pain, nausea and vomiting. No deaths occurred. Future high-quality long-term RCTs are needed to further assess efficacy and safety.
Subject(s)
Diabetes Mellitus, Type 2/surgery , Jejunoileal Bypass/instrumentation , Obesity/surgery , Abdominal Pain/etiology , Adult , Blood Glucose/analysis , Body Mass Index , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/etiology , Duodenum/surgery , Fasting/blood , Female , Glycated Hemoglobin/analysis , Humans , Jejunoileal Bypass/adverse effects , Jejunoileal Bypass/methods , Jejunum/surgery , Male , Middle Aged , Nausea/etiology , Obesity/complications , Observational Studies as Topic , Randomized Controlled Trials as Topic , Treatment Outcome , Vomiting/etiology , Weight LossABSTRACT
For decades, extensive research has aimed to clarify the role of pancreas and gut-derived peptide hormones in the regulation of glucose homeostasis and feeding behavior. Among these are the beta-cell hormone amylin and the intestinal L cell hormone glucagon-like peptide-1 (GLP-1). They exhibit distinct and yet several similar physiological actions including suppression of food intake, postprandial glucagon secretion, and gastric emptying-altogether lowering plasma glucose and body weight. These actions have been clinically exploited by the development of amylin and GLP-1 hormone analogs now used for treatment of diabetes and obesity. This review will outline the physiology and pharmacological potential of amylin and GLP-1, respectively, and focus on innovative peptide drug development leading to drugs acting on two or more distinct receptors, such as an amylin and GLP-1 peptide hybrid, potentially producing a more effective treatment strategy to combat the rapidly increasing global obesity.
Subject(s)
Glucagon-Like Peptide 1/therapeutic use , Islet Amyloid Polypeptide/therapeutic use , Obesity/drug therapy , Animals , Diabetes Mellitus/drug therapy , Eating , Glucagon-Like Peptide 1/analogs & derivatives , Humans , Insulin-Secreting Cells/drug effects , Islet Amyloid Polypeptide/chemistryABSTRACT
Treatment with liraglutide leads to weight loss. We investigated whether blood-to-cerebrospinal fluid (CSF) transfer of liraglutide occurs, and if so, whether it associates with clinical weight loss following liraglutide treatment in humans. We performed lumbar puncture and blood sampling in eight patients with type 2 diabetes (mean (range)): age 63 (54-79) years; actual body weight: 90 (75-118) kg treated with 1.8 mg liraglutide for 14 (5-22) months and with a treatment-induced weight loss of 8.4 (7-11) kg. We measured liraglutide in plasma and CSF with a radioimmunoassay specific for the N-terminus of the GLP-1 moiety of liraglutide. Mean plasma liraglutide was 31 (range: 21-63) nmol l(-1). The mean CSF-liraglutide concentration was 6.5 (range: 0.9-13.9) pmol l(-1). Ratio of CSF: plasma-liraglutide concentrations was 0.02 (range: 0.07-0.002)% and plasma liraglutide did not correlate with CSF-liraglutide levels (P=0.67). Body weight loss tended to correlate with plasma-liraglutide levels (P=0.06), but not with CSF-liraglutide levels (P=0.69). In conclusion, we measured very low concentrations of liraglutide in CSF, and the levels of CSF liraglutide did not correlate with the actual clinical weight loss in these patients. The amount of liraglutide in plasma tended to correlate with the clinical weight loss.
Subject(s)
Anti-Obesity Agents/pharmacology , Blood-Brain Barrier/drug effects , Body Weight/drug effects , Diabetes Mellitus, Type 2/drug therapy , Liraglutide/pharmacology , Aged , Biomarkers/blood , Diabetes Mellitus, Type 2/blood , Female , Glucagon-Like Peptide 1/analogs & derivatives , Glucagon-Like Peptide 1/therapeutic use , Humans , Male , Middle Aged , Treatment OutcomeABSTRACT
BACKGROUND: Patients with psoriasis have an increased risk of type 2 diabetes. The gastrointestinal system plays a major role in normal glucose metabolism, and in healthy individuals, postprandial insulin secretion is largely mediated by the gut incretin hormones. This potentiation is termed the incretin effect and is reduced in type 2 diabetes. The impact of psoriasis on gastrointestinal factors involved in glucose metabolism has not previously been examined. OBJECTIVE: To investigate whether the incretin effect, gastrointestinal-mediated glucose disposal (GIGD) and/or secretion of glucagon and gut incretin hormones are impaired in normal glucose-tolerant patients with psoriasis. METHODS: Oral glucose tolerance tests and intravenous isoglycaemic glucose infusions were performed in 12 patients with moderate-to-severe psoriasis and 12 healthy matched control subjects. RESULTS: In patients with psoriasis, the incretin effect (39% vs. 57%, P = 0.02) and GIGD (53% vs. 61%, P = 0.04) were significantly reduced compared to control subjects. In addition, patients were glucose intolerant and showed exaggerated glucose-dependent insulinotropic polypeptide responses. CONCLUSION: These novel findings support the notion that psoriasis is a prediabetic condition and suggest that gastrointestinal-related mechanisms are involved in the increased susceptibility to type 2 diabetes in patients with psoriasis.
Subject(s)
Diabetes Mellitus, Type 2 , Glucagon/metabolism , Glucose/metabolism , Incretins/metabolism , Insulin/metabolism , Prediabetic State , Psoriasis , Adult , Aged , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Female , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/physiopathology , Glucose Tolerance Test/methods , Humans , Insulin-Secreting Cells/metabolism , Male , Middle Aged , Prediabetic State/diagnosis , Prediabetic State/metabolism , Prediabetic State/physiopathology , Psoriasis/diagnosis , Psoriasis/metabolism , Psoriasis/physiopathology , Reproducibility of Results , Severity of Illness IndexABSTRACT
BACKGROUND: It has been proposed that glucagon-like peptide-1 receptor (GLP-1R) agonists used for the treatment of patients with type 2 diabetes might also improve their psoriasis. OBJECTIVE: To assess the efficacy and safety of the GLP-1R agonist liraglutide in glucose-tolerant patients with plaque psoriasis. METHODS: A total of 20 obese (body mass index > 25 kg/m(2)), glucose-tolerant patients with plaque psoriasis (psoriasis area and severity index (PASI) of at least 8) were randomized 1:1 to once-daily subcutaneous injections with liraglutide or placebo for an 8-week period. The primary end points were improvement in PASI and dermatology life quality index (DLQI). Secondary end points included changes in weight and high sensitive C-reactive protein (hsCRP) levels, as well as adverse events. RESULTS: After 8 weeks of treatment, no significant change in PASI was found in the liraglutide group (mean±standard deviation: -2.6 ± 2.1) compared with the placebo group (-1.3 ± 2.4) (P = 0.228). No difference in DLQI was observed between the groups [-2.5 ± 4.4 (liraglutide) vs. -3.7 ± 4.8 (placebo); P = 0.564]. HsCRP did not change in any of the groups (0.26 ± 1 (placebo) vs. 0.25 ± 2.2 (liraglutide); P = 0.992). Liraglutide treatment resulted in a bodyweight loss of 4.7 ± 2.5 kg compared with 1.6 ± 2.7 kg in the placebo group (P = 0.014) accompanied by decreased cholesterol levels. No serious adverse events occurred during the 8-week observation period. The most common complaint was transient nausea, which occurred in 45% of the liraglutide-treated patients but in none from the placebo group. CONCLUSION: Liraglutide treatment for 8 weeks did not significantly change PASI, DLQI, or hsCRP in a small group of glucose-tolerant obese patients with plaque psoriasis compared with placebo. A significant weight loss and decrease in cholesterol levels was observed in liraglutide-treated patients.
Subject(s)
Adalimumab/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Glucose Tolerance Test , Liraglutide/therapeutic use , Psoriasis/drug therapy , Registries , Adult , Female , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
Sevelamer is a calcium-free and metal-free phosphate-binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid-lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These 'novel' effects are most probably derived from the bile acid-binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose-lowering effect of the drug.