Lipoprotein(a) levels in a global population with established atherosclerotic cardiovascular disease.

OBJECTIVE: Lipoprotein(a) (Lp(a)) is an important genetically determined risk factor for atherosclerotic vascular disease (ASCVD). With the development of Lp(a)-lowering therapies, this study sought to characterise patterns of Lp(a) levels in a global ASCVD population and identify racial, ethnic, regional and gender differences. METHODS: A multicentre cross-sectional epidemiological study to estimate the prevalence of elevated Lp(a) in patients with a history of myocardial infarction, ischaemic stroke or peripheral artery disease conducted at 949 sites in 48 countries in North America, Europe, Asia, South America, South Africa and Australia between April 2019 and July 2021. Low-density lipoprotein cholesterol (LDL-C) and Lp(a) levels were measured either as mass (mg/dL) or molar concentration (nmol/L). RESULTS: Of 48 135 enrolled patients, 13.9% had prior measurements of Lp(a). Mean age was 62.6 (SD 10.1) years and 25.9% were female. Median Lp(a) was 18.0 mg/dL (IQR 7.9-57.1) or 42.0 nmol/L (IQR 15.0-155.4). Median LDL-C was 77 mg/dL (IQR 58.4-101.0). Lp(a) in women was higher, 22.8 (IQR 9.0-73.0) mg/dL, than in men, 17.0 (IQR 7.1-52.2) mg/dL, p<0.001. Black patients had Lp(a) levels approximately threefold higher than white, Hispanic or Asian patients. Younger patients also had higher levels. 27.9% of patients had Lp(a) levels >50 mg/dL, 20.7% had levels >70 mg/dL, 12.9% were >90 mg/dL and 26.0% of patients exceeded 150 nmol/L. CONCLUSIONS: Globally, Lp(a) is measured in a small minority of patients with ASCVD and is highest in black, younger and female patients. More than 25% of patients had levels exceeding the established threshold for increased cardiovascular risk, approximately 50 mg/dL or 125 nmol/L.

Licogliflozin, a Novel SGLT1 and 2 Inhibitor: Body Weight Effects in a Randomized Trial in Adults with Overweight or Obesity.

OBJECTIVE: The aim of this study was to explore the dose response of licogliflozin, a dual inhibitor of sodium/glucose cotransporter 1 (SGLT1) and 2 (SGLT2), by evaluating change in body weight in adults with overweight or obesity. METHODS: This dose-response analysis evaluated change in body weight following 24 weeks with four once-daily and twice-daily licogliflozin doses (2.5-150 mg) versus placebo (primary end point). A further 24-week analysis evaluated the efficacy and safety of two once-daily licogliflozin doses in maintaining initial weight reduction. RESULTS: Licogliflozin once daily or twice daily produced a significant dose-response signal for weight loss versus placebo (P < 0.0001). However, mean adjusted percent changes in body weight after 24 weeks were modest, ranging from -0.45% to -3.83% (in the 50 mg twice daily group [95% CI: -5.26% to -2.48%]; n = 75). Responder analysis of ≥ 5% weight loss at week 24 revealed significant differences versus placebo, which were most pronounced with highest doses of 50 mg twice daily (45.3%) and 150 mg once daily (42.9%) (both P < 0.01). While weight loss was greater at higher doses, gastrointestinal adverse events were also more frequent. The 50-mg once-daily dose had perhaps the best balance between efficacy and tolerability. CONCLUSIONS: Licogliflozin produced significant reductions in body weight versus placebo. However, the magnitude of weight reduction was modest.

Effects of the dual sodium-glucose linked transporter inhibitor, licogliflozin vs placebo or empagliflozin in patients with type 2 diabetes and heart failure.

AIMS: Explore the efficacy, safety and tolerability of the dual sodium-glucose cotransporter (SGLT) 1 and 2 inhibitor, licogliflozin in patients with type-2 diabetes mellitus (T2DM) and heart failure. METHODS: This multicentre, parallel-group phase IIA study randomized 125 patients with T2DM and heart failure (New York Heart Association II-IV; plasma N-terminal pro b-type natriuretic peptide [NT-proBNP] >300 pg/mL) to licogliflozin (2.5 mg, 10 mg, 50 mg) taken at bedtime, empagliflozin (25 mg) or placebo (44 patients completed the study). The primary endpoint was change from baseline in NT-proBNP after 12 weeks. Secondary endpoints included change from baseline in glycated haemoglobin, fasting plasma glucose, weight, blood pressure, fasting lipid profile, high-sensitivity c-reactive protein, and safety and tolerability. RESULTS: Licogliflozin 10 mg for 12 weeks significantly reduced NT-proBNP vs placebo (Geometric mean ratio 0.56 [95% confidence interval: 0.33, 0.95], P = .033). A trend was observed with 50 mg licogliflozin (0.64 [95% confidence interval: 0.40, 1.03], P = .064), with no difference between licogliflozin and empagliflozin. The largest numerical decreases in glycated haemoglobin were with licogliflozin 50 mg (-0.58 ± 0.34%) and empagliflozin (-0.44 ± 1.18%) vs placebo (-0.04 ± 0.91%). The reduction in body weight was similar with licogliflozin 50 mg (-2.15 ± 2.40 kg) and empagliflozin (-2.25 ± 1.89 kg). A numerical reduction in systolic blood pressure was seen with licogliflozin 50 mg (-9.54 ± 16.88 mmHg) and empagliflozin (-6.98 ± 15.03 mmHg) vs placebo (-2.85 ± 11.97 mmHg). Adverse events (AEs) were mild, including hypotension (6.5%), hypoglycaemia (8.1%) and inadequate diabetes control (1.6%). The incidence of diarrhoea (4.9%) was lower than previously reported. CONCLUSION: The reduction in NT-proBNP with licogliflozin suggests a potential benefit of SGLT1 and 2 inhibition in patients with T2DM and heart failure.

Factors that may Account for Cardiovascular Risk Reduction with a Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, in Young Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: In a meta-analysis, we observed a significant 37% relative risk reduction in prospectively adjudicated major adverse cardiac events [MACEs, comprising of non-fatal myocardial infarction, non-fatal stroke, cardiovascular (CV) death] with vildagliptin vs. comparators in younger (< 65 years) patients with type 2 diabetes mellitus (T2DM), while the risk was similar in older patients (≥ 65 years). We carried out an exploratory analysis to identify the patient characteristics and on-treatment effects that may have contributed to the different outcomes in the two age groups. METHODS: On-treatment differences (vildagliptin vs. comparators) for the change from baseline in CV risk factors were analyzed using an analysis of covariance model with the baseline value for each variable of interest, treatment and study as covariates. Additional adjustments for background antihypertensive and statin use were performed when analyzing changes in blood pressure and lipids, respectively. Baseline characteristics and patient demographics were analyzed using descriptive statistics. RESULTS: Patients aged < 65 years had shorter diabetes duration (4.4 vs. 8.2 years) and slightly higher glycated hemoglobin (HbA1c) at baseline (8.3% vs. 8.0%) than patients aged ≥ 65 years. More patients in the  ≥ 65 year age group had hypertension (73.1% vs. 51.3%), dyslipidemia (53.3% vs. 43.9%) and a history of CV events (32.2% vs. 12.9%). There were small, but statistically significant differences in the change in HbA1c and total cholesterol in favor of vildagliptin relative to comparators, which were similar in both age groups. Significant differences were observed in the reduction in systolic blood pressure (SBP) (- 0.52 mmHg; 95% CI - 0.97, - 0.07; p = 0.023), low-density lipoprotein (LDL cholesterol) (- 0.12 mmol/l; 95% CI - 0.19, - 0.04; p = 0.002) and weight (- 0.48 kg; 95% CI - 0.95, - 0.01; p < 0.047) in patients < 65 years, but not in patients ≥ 65 years. The incidence of hypoglycemic events was lower in patients treated with vildagliptin [2.1 and 3.5 per 100 subject years exposure (SYEs) in < 65 and ≥ 65 years, respectively] than with comparators (5.8 and 7.5 per 100 SYEs, respectively). CONCLUSION: Based on our findings, it can be hypothesized that the positive effects of vildagliptin on SBP, LDL cholesterol, hypoglycemia and weight observed in younger, but not in older patients could be associated with the lower risk of MACE in younger patients with T2DM. FUNDING: Novartis.

Effects of Vildagliptin on Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart Failure: A Randomized Placebo-Controlled Trial.

OBJECTIVES: This study sought to examine the safety of the dipeptidyl peptidase-4 inhibitor, vildagliptin, in patients with heart failure and reduced ejection fraction. BACKGROUND: Many patients with type 2 diabetes mellitus have heart failure and it is important to know about the safety of new treatments for diabetes in these individuals. METHODS: Patients 18 to 85 years of age with type 2 diabetes and heart failure (New York Heart Association functional class I to III and left ventricular ejection fraction [LVEF] <0.40) were randomized to 52 weeks treatment with vildagliptin 50 mg twice daily (50 mg once daily if treated with a sulfonylurea) or matching placebo. The primary endpoint was between-treatment change from baseline in echocardiographic LVEF using a noninferiority margin of -3.5%. RESULTS: A total of 254 patients were randomly assigned to vildagliptin (n = 128) or placebo (n = 126). Baseline LVEF was 30.6 ± 6.8% in the vildagliptin group and 29.6 ± 7.7% in the placebo group. The adjusted mean change in LVEF was 4.95 ± 1.25% in vildagliptin treated patients and 4.33 ± 1.23% in placebo treated patients, a difference of 0.62 (95% confidence interval [CI]: -2.21 to 3.44; p = 0.667). This difference met the predefined noninferiority margin of -3.5%. Left ventricular end-diastolic and end-systolic volumes increased more in the vildagliptin group by 17.1 ml (95% CI: 4.6 to 29.5 ml; p = 0.007) and 9.4 ml (95% CI: -0.49 to 19.4 ml; p = 0.062), respectively. Decrease in hemoglobin A1c from baseline to 16 weeks, the main secondary endpoint, was greater in the vildagliptin group: -0.62% (95% CI: -0.93 to -0.30%; p < 0.001; -6.8 mmol/mol; 95% CI: -10.2 to -3.3 mmol/mol). CONCLUSIONS: Compared with placebo, vildagliptin had no major effect on LVEF but did lead to an increase in left ventricular volumes, the cause and clinical significance of which is unknown. More evidence is needed regarding the safety of dipeptidyl peptidase-4 inhibitors in patients with heart failure and left ventricular systolic dysfunction. (Effect of Vildagliptin on Left Ventricular Function in Patients With Type 2 Diabetes and Congestive Heart Failure; NCT00894868).

DPP-4 inhibitor treatment: ß-cell response but not HbA1c reduction is dependent on the duration of diabetes.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by enhancing insulin and suppressing glucagon secretion. Since T2DM is associated with progressive loss of ß-cell function, we hypothesized that the DPP-4 inhibitor action to improve ß-cell function would be attenuated with longer duration of T2DM. METHODS: Data from six randomized, placebo-controlled trials of 24 weeks duration, where ß-cell response to vildagliptin 50 mg twice daily was assessed, were pooled. In each study, the insulin secretory rate relative to glucose (ISR/G 0-2h) during glucose load (standard meal or oral glucose tolerance test) was assessed at baseline and end of study. The mean placebo-subtracted difference (PSD) in the change in ISR/G 0-2h from baseline for each study was evaluated as a function of age, duration of T2DM, baseline ISR/G 0-2h, glycated hemoglobin (HbA1c), fasting plasma glucose, body mass index, and mean PSD in the change in HbA1c from baseline, using univariate model. RESULTS: There was a strong negative association between the PSD in the change from baseline in ISR/G 0-2h and duration of T2DM (r= -0.89, p<0.02). However, there was no association between the PSD in the change from baseline in ISR/G 0-2h and the PSD in the change from baseline in HbA1c (r=0.33, p=0.52). None of the other characteristics were significantly associated with mean PSD change in ISR/G 0-2h. CONCLUSION: These findings indicate that the response of the ß-cell, but not the HbA1c reduction, with vildagliptin is dependent on duration of T2DM. Further, it can be speculated that glucagon suppression may become the predominant mechanism via which glycemic control is improved when treatment with a DPP-4 inhibitor, such as vildagliptin, is initiated late in the natural course of T2DM.

Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance.

Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.

Effect of race and ethnicity on vildagliptin efficacy: A pooled analysis of phase II and III studies.

AIMS: To determine the impact of race and ethnicity on the efficacy, body weight and hypoglycaemia incidence with vildagliptin treatment in patients with type 2 diabetes mellitus using patient-level data from the vildagliptin clinical trial programme. METHODS: Data from 22 randomized, placebo-controlled global and local (Japan, China) registration studies of vildagliptin (50 mg once-daily or twice-daily) of ≥12-week duration were analysed by race (Caucasian [n = 2764] and Asian [n = 2232]) and by ethnicity (Japanese, Chinese, and Indian). The placebo-subtracted differences in the change in glycated haemoglobin (HbA1c) and body weight from baseline to week 12 or week 24 were evaluated by race or ethnicity using repeated measure analysis of unstructured covariance. Hypoglycaemia incidences were summarized using descriptive statistics. RESULTS: The HbA1c reduction from baseline with vildagliptin was similar across the racial/ethnic subgroups (-0.83% ± 0.02% to -1.01% ± 0.05%). Placebo-corrected HbA1c reduction was similar between Caucasian (-0.68% ± 0.03%) and Asian (-0.80% ± 0.03%) patients ( P value for interaction = .56); analysis by race and ethnicity showed better efficacy ( P < .02) in Japanese patients. Japanese patients were drug-naïve and treated with a single oral anti-diabetes drug only; they showed no response to placebo. Weight neutrality of vildagliptin was demonstrated in all groups (0.47 ± 0.11 kg to -0.29 ± 0.08 kg). Hypoglycaemic events (≥1) were infrequent in all ethnic subgroups. CONCLUSIONS: The glycaemic efficacy of vildagliptin was similar in Caucasian and Asian patients. The slightly better efficacy observed in Japanese patients was driven by the absence of placebo effect and might be explained by their earlier stage of diabetes compared to other subgroups.

Vildagliptin added to sulfonylurea improves glycemic control without hypoglycemia and weight gain in Chinese patients with type 2 diabetes mellitus.

OBJECTIVE: The aim of the present study was to assess the efficacy and safety of vildagliptin as add-on to sulfonylurea therapy in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy. METHODS: The 24-week randomized double-blind placebo-controlled study compared vildagliptin 50 mg, q.d., with placebo as add-on to glimepiride in T2DM patients who were inadequately controlled (HbA1c 7.5%-11.0% [58-97 mmol/mol]) on a stable dose of sulfonylurea for ≥12 weeks before study entry. RESULTS: In all, 279 patients were randomized to receive either vildagliptin (n = 143) or placebo (n = 136). At baseline, overall mean age was 58.5 years, body weight 68.1 kg, duration of diabetes 6.9 years and daily glimepiride dose 3.3 mg. After 24 weeks, the adjusted mean change (AMΔ) in HbA1c was -0.7% (-8 mmol/mol; baseline 8.6%, 70 mmol/mol) in the vildagliptin group and -0.2% (-2 mmol/mol; baseline 8.7%, 72 mmol/mol) in the placebo group, with a treatment difference of -0.5% (-5 mmol/mol; P < 0.001). The between-group difference in AMΔ in fasting plasma glucose was -0.4 mmol/L (P = 0.160). There was a slight, but not significant, decrease in body weight in both groups. No hypoglycemic events were reported in either group, including those patients reaching HbA1c <7.0%. Patients in the vildagliptin and placebo groups reported low and comparable incidences of adverse events (14.0% vs. 17.8%) and serious adverse events (0.7% in each group). CONCLUSION: Vildagliptin 50 mg, q.d., added to sulfonylurea monotherapy is effective in Chinese patients with T2DM, without increasing the risk of hypoglycemia and weight gain.

Vildagliptin-insulin combination improves glycemic control in Asians with type 2 diabetes.

AIM: To assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in Asian patients with type 2 diabetes mellitus (T2DM). METHODS: This was a post hoc analysis of a subgroup of Asian patients from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. A total of 173 patients were randomized 1:1 to receive treatment with vildagliptin 50 mg bid (n = 87) or placebo (n = 86) for 24 wk. Changes in HbA1c and fasting plasma glucose (FPG), from baseline to study endpoint, were analyzed using an analysis of covariance model. Change from baseline to endpoint in body weight was summarized by treatment. Safety and tolerability of vildagliptin was also evaluated. RESULTS: After 24 wk, the difference in adjusted mean change in HbA1c between vildagliptin and placebo was 0.82% (8.96 mmol/mol; P < 0.001) in Asian subgroup, 0.85% (9.29 mmol/mol; P < 0.001) in patients also receiving metformin, and 0.73% (7.98 mmol/mol; P < 0.001) in patients without metformin, all in favor of vildagliptin. There was no significant difference in the change in FPG between treatments. Weight was stable in both treatment groups (+0.3 kg and -0.2 kg, for vildagliptin and placebo, respectively). Overall, vildagliptin was safe and well tolerated with similarly low incidences of hypoglycemia (8.0% vs 8.1%) and no severe hypoglycemic events were experienced in either group. CONCLUSION: In Asian patients inadequately controlled with insulin (with or without concomitant metformin), insulin-vildagliptin combination treatment significantly reduced HbA1c compared with placebo, without an increase in risk of hypoglycemia or weight gain.

Meta-analysis of insulin aspart versus regular human insulin used in a basal-bolus regimen for the treatment of diabetes mellitus.

BACKGROUND: The objective of the current study was to compare the efficacy of two different insulin formulations, insulin aspart (IAsp) and regular human insulin (RHI), for prandial insulin coverage with neutral protamine Hagedorn (NPH) insulin as basal insulin using a meta-analysis approach. The primary endpoint was change in A1c over time. Secondary endpoints included incidence of hypoglycemia and postprandial glycemic control. METHODS: Clinical trials (Type 1 and Type 2 diabetes) complying with Good Clinical Practice, and with individual patient data, were included in the meta-analysis. Trials were randomized, consisting of (at least) two treatment arms and had a minimum duration of 12 weeks. Estimates were calculated using fixed-effects and random-effects models. Heterogeneity was assessed for each analysis. The effect of baseline parameters on A1c was analyzed in extended simultaneous models. RESULTS: The mean difference in A1c was 0.1% (95% confidence interval [CI] [-0.15; -0.04], P < 0.001) in favor of IAsp. Higher accumulated dose of IAsp, higher age and increased rates of hypoglycemia were associated with improved A1c outcome. Fasting plasma glucose was not significantly different between regimens. Postprandial glucose was significantly lower after treatment with IAsp compared with RHI, but the analysis did present a significant level of heterogeneity (P < 0.001). The overall rate of hypoglycemia was the same with both regimens, but nocturnal hypoglycemia was significantly lower with IAsp. CONCLUSIONS: A basal-bolus regimen with IAsp as bolus insulin provided minimal, but statistically significant, improvement in overall glycemic control with a lower rate of nocturnal hypoglycemic episodes, compared with a corresponding regimen with bolus RHI.

Initiation with once-daily BIAsp 30 results in superior outcome compared to insulin glargine in Asians with type 2 diabetes inadequately controlled by oral anti-diabetic drugs.

We compare the efficacy and safety of once-daily biphasic insulin aspart 70/30 (BIAsp 30) and insulin glargine in Asian subjects with type 2 diabetes inadequately controlled with oral anti-diabetic drugs (OADs). In a 26-week, open-labelled, randomised, parallel-group, multinational, multicentre, treat-to-target trial, 155 insulin-naïve Asian subjects were treated with either BIAsp 30 or insulin glargine, both in combination with metformin and glimepiride. Change in HbA(1c) at end of treatment with BIAsp 30 was superior to insulin glargine (BIAsp 30-glargine=-0.36%, 95% CI [-0.64; -0.07], p=0.015). Mean self-measured plasma glucose (SMPG) at bedtime was significantly lower with BIAsp 30 than insulin glargine (7.98+/-0.34 mmol/L vs. 9.16+/-0.33 mmol/L, p=0.0078). Incidences of minor and daytime hypoglycaemia were higher with BIAsp 30 than those with glargine, but the difference did not reach the statistical significance. No difference was seen in nocturnal hypoglycaemia. The incidence of adverse events was comparable between treatments, with low incidence of serious adverse events and major hypoglycaemia. Mean body weight increased slightly in both groups. In insulin-naïve Asian subjects with type 2 diabetes who are inadequately controlled with OADs, once-daily BIAsp 30 is superior to insulin glargine.

Insulin's 85th anniversary--An enduring medical miracle.

In 1922, the discovery of insulin led to a revolution in diabetes management. Since then, many improvements have been made to insulin preparations: early preparations of bovine and porcine insulins were purified and their duration of action prolonged, giving rise to the introduction of Neutral Protamine Hagedorn (NPH) insulin and monocomponent insulins. Then, with the advances in genetic engineering in the 1980s, it became possible to produce recombinant human insulin. Nowadays, modern molecular biology techniques enable the production of insulin analogues, which have several advantages over human insulin preparations including a reduced risk of hypoglycaemia. Insulin delivery is still predominantly via subcutaneous injections, but alternative routes of insulin administration are being investigated. Pulmonary delivery has emerged as the most feasible option thus far but oral delivery is an ultimate goal, although basic problems of insulin stability in the gut and absorption from the gastrointestinal tract still need to be resolved. The availability of a true artificial pancreas by means of a closed-loop system, linking continuous glucose monitoring with insulin-pump technology, would also constitute a significant advance, but major technological problems still need to be overcome.