Effects of finerenone in people with chronic kidney disease and type 2 diabetes are independent of HbA1c at baseline,HbA1c variability,diabetes duration and insulin use at baseline

Aim

To evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, diabetes duration and baseline insulin use on cardiorenal outcomes and diabetes progression.

Materials and Methods

Composite efficacy outcomes included cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure), kidney (kidney failure, sustained ≥ 57% estimated glomerular filtration rate decline or renal death) and diabetes progression (new insulin initiation, increase in antidiabetic medication, 1.0% increase in HbA1c from baseline, new diabetic ketoacidosis diagnosis or uncontrolled diabetes).

Results

In 13 026 participants, risk reductions in the cardiovascular and kidney composite outcomes with finerenone versus placebo were consistent across HbA1c quartiles (P interaction .52 and .09, respectively), HbA1c variability (P interaction .48 and .10), diabetes duration (P interaction .12 and .75) and insulin use (P interaction .16 and .52). HbA1c variability in the first year of treatment was associated with a higher risk of cardiovascular and kidney events (hazard ratio [HR] 1.20; 95% confidence interval [CI] 1.07-1.35; P = .0016 and HR 1.36; 95% CI 1.21-1.52; P < .0001, respectively). There was no effect on diabetes progression with finerenone or placebo (HR 1.00; 95% CI 0.95-1.04). Finerenone was well-tolerated across subgroups; discontinuation and hospitalization because of hyperkalaemia were low.

Conclusions

Finerenone efficacy was not modified by baseline HbA1c, HbA1c variability, diabetes duration or baseline insulin use. Greater HbA1c variability appeared to be associated with an increased risk of cardiorenal outcomes.     

Proportion of patients at HbA1c target <7% with eight classes of antidiabetic drugs in type 2 diabetes: systematic review of 218 randomized controlled trials with 78 945 patients

Aim: We assessed the efficacy of eight classes of diabetes medications used in current clinical practice [metformin, sulphonylureas, α‐glucosidase inhibitors, thiazolidinediones, glinides, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 (GLP‐1) analogues and insulin analogues] to reach the HbA1c target <7% in type 2 diabetes. Methods: MEDLINE, EMBASE and the Cochrane CENTRAL were searched from inception through April 2011 for randomized controlled trials (RCTs) involving antidiabetic drugs. RCTs had to report the effect of any diabetes medication on the HbA1c levels, to include at least 30 subjects in every arm of the study, and to report the effect of therapy after a minimum of 12 weeks. Data were summarized across studies using random‐effects meta‐regression. Results: A total of 218 RCTs (339 arms and 77 950 patients) met the inclusion criteria. The proportion of patients who achieved the HbA1c goal ranged from 25.9% (95% CI 18.5–34.9) with α‐glucosidase inhibitors to 63.2% (54.1–71.5) with the long‐acting GLP‐1 analogue. There was a progressive decrease of the proportion of patients at target for each 0.5% increase in baseline HbA1c, ranging from 57.8% for HbA1c ≤7.5% to 20.8% for HbA1c ≥10% (p for trend <0.0001), with some difference between insulin and non‐insulin drugs: for insulin, the proportion of patients at goal reached a plateau for basal HbA1c value >9.0% with no further decrease, whereas for non‐insulin drugs the relationship was continuous without any evidence of plateau. Conclusions: There is a considerable variability with regard to attainment of HbA1c goal of <7% among the different classes of diabetes medications; baseline HbA1c is an important determinant of observed efficacy.     

Murine monoclonal glutamic acid decarboxylase (GAD)65 antibodies recognize autoimmune-associated GAD epitope regions targeted in patients with type 1 diabetes mellitus and Stiff-man syndrome

To study the immune response to glutamic acid decarboxylase (GAD) in insulin-dependent diabetes mellitus, monoclonal GAD antibodies after fusion of splenocytes from a nondiabetes-susceptible BALB/c mouse immunized with human recombinant GAD65 were generated. Of the 44 monoclonals, 35 are specific for the GAD65 isoform, whereas 9 also react with GAD67. Some 37 monoclonals, including all GAD65/67 reactive antibodies, react with GAD by Western blot analysis. The remaining 7 GAD65 monoclonals bind GAD only in an immunoprecipitation assay, which implies that they target epitopes dependent on the conformation of the GAD molecule. The¹²⁵I-GAD binding of the GAD65 monoclonals reactive on Western blotting was significantly diminished by all 3 sera from Stiff-man syndrome patients but only by 3/30 (10%) sera from type 1 diabetic patients. In contrast, the 7 monoclonal antibodies reactive with a conformation-dependent GAD epitope were competitive with 83% of GAD-autoantibody-positive sera from these diabetic patients. Using chimeric GAD65/67 proteins, the epitope region targeted by these monoclonals was mapped to the middle of GAD65 (amino acids 221–442). This central conformation-dependent GAD region was also targeted by sera from patients with type 1 diabetes. In conclusion, our data show that evne after common immunization of a nondiabetes-susceptible mouse strain, monoclonals were obtained which preferentially react with the GAD65 linear amino-terminus (amino acids 4–17) and a conformation-dependent region located in the middle of GAD targeted by autoantibodies, indicating that this GAD region is not restricted to the autoimmune response associated with the Stiff-man syndrome and the bete-cell destruction in type 1 diabetes mellitus.     

Impact of obesity on the increasing incidence of type 1 diabetes

Published estimates of the incidence of type 1 diabetes (T1D) in children in the last decade varies between 2% and 4% per annum. If this trend continued, the disease incidence would double in the next 20 years. The risk of developing T1D is determined by a complex interaction between multiple genes (mainly human leukocyte antigens) and environmental factors. Notwithstanding that genetic susceptibility represents a relevant element in T1D risk, genetics alone cannot explain the increase in incidence. Various environmental factors have been suggested as potential triggers for T1D, including several viruses and the hygiene hypothesis; however, none of these seems to explain the large increase in T1D incidence observed over the last decades. Several studies have demonstrated that the prevalence of childhood/adolescence overweight and obesity has risen during the past 30 years in T1D. Currently, at diagnosis, the majority of patients with T1D have normal or elevated body weight and ~50% of patients with longstanding T1D are either overweight or obese. The growing prevalence of obesity in childhood and adolescence offers a plausible explanation for the increase in T1D incidence observed in recent decades. Possible mechanisms of the enhancement of β-cell autoimmunity by obesity include: a) insulin resistance-induced β-cell secretory demand triggering autoimmunity through cytokine release, neo-epitope antigen formation and increase in β-cell apoptosis, and b) obesity-induced low-grade inflammation with pro-inflammatory cytokines secreted by locally infiltrating macrophages, which contribute to the presentation by islet cells of autoantigens generally not accessible to T cells. Further studies are needed to clarify whether the control of body weight can prevent or delay the current and continuing rise in T1D incidence.     

A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes

Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 (LY), a novel, long‐acting glucagen‐like peptide‐1 analogue, administered once weekly to subjects with type 2 diabetes. Methods: This was a placebo‐controlled, parallel‐group, subject‐ and investigator‐blind study of LY in subjects (N = 43) with type 2 diabetes mellitus controlled with diet and exercise alone or with a single oral antidiabetic medication. Subjects taking metformin or thiazolidinediones continued on their therapy. Subjects receiving sulfonylurea, acarbose, repaglinide or nateglinide were switched to metformin prior to enrollment. Subjects received five once‐weekly doses of 0.05, 0.3, 1, 3, 5 or 8 mg. Effects on glucose, insulin and C‐peptide concentrations were determined during fasting and following standard test meals. The pharmacokinetics of LY and its effects on HBA1c, glucagon, body weight, gastric emptying and safety parameters were assessed. Results: Once‐weekly administration of LY significantly reduced (p < 0.01) fasting plasma glucose, 2‐h post‐test meal postprandial glucose and area under the curve (AUC) of glucose after test meals at doses ≥1 mg. These effects were seen after the first dose and were sustained through the weekly dosing cycle. Most doses produced statistically significant increases in insulin and C‐peptide AUC when normalized for glucose AUC. Statistically significant reductions in HBA1c were observed for all dose groups except 0.3 mg. The most commonly reported adverse effects (AEs) were nausea (35 events), headache (20 events), vomiting (18 events) and diarrhoea (8 events). Conclusions: LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.     

Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes

We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2 diabetes inadequately controlled on oral agents (including metformin) were randomized to insulin glargine or detemir. Secretagogues were stopped or maintained at the site-investigators' discretion. During the study, 57.6% of patients continued their secretagogue treatment. Compared with patients stopping secretagogues, those who continued experienced significantly more hypoglycaemia and weight gain. Insulin doses, however, were significantly lower: 0.6 ± 0.4 versus 0.8 ± 0.4 U/kg/day (p < 0.001). The difference between groups in mean HbA1c reduction was not statistically significant. In conclusion, in type 2 diabetic patients starting basal insulin analogue therapy, continuing both metformin and secretagogues results in more hypoglycaemia and weight gain and lower insulin doses than only maintaining metformin.     

Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes

Aim: To evaluate the dose–response relationship of the recombinant glucagon‐like peptide‐1 (7‐36) amide (rGLP‐1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11‐h serum glucose profiles. Methods: In a double‐blind, parallel, placebo‐controlled trial, 47 patients were randomized to placebo or rGLP‐1 (1.25, 2.5, 5.0 or 8.5 pmol/kg/min) by CSCI for 7 days. On day 1 (pretreatment) and on day 8, patients underwent monitoring of fasting, postprandial, and 11‐h profiles of glucose and hormones. Results: Fasting serum glucose decreased by 76.2, 53.9, 37.0 and 22.7 mg/dl for the 8.5, 5.0, 2.5 and 1.25 pmol/kg/min rGLP‐1 groups, respectively, compared to a decrease of 1.1 mg/dl for placebo (p = 0.0002, 0.005, 0.064 and 0.27, respectively). Mean 11‐h serum glucose area under the curve decreased by 36.3, 23.3, 16.9 and 10.0% for 8.5, 5.0, 2.5 and 1.25 pmol/kg/min rGLP‐1, respectively, compared to no change for placebo (p = 0.0001, 0.0019, 0.012 and 0.14, respectively). Mean fasting C‐peptide increased dose dependently with rGLP‐1 (p = 0.0023 for the highest dose) and decreased with placebo. There were no serious safety concerns and no instances of hypoglycaemia. Conclusions: rGLP‐1 produced continuous improvements in glycaemic control across a broad dose range of up to 8.5 pmol/kg/min.