Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers,including circulating progenitor cells,in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m², HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.     

Efficacy and safety of trelagliptin in combination with insulin therapy in Japanese patients with type 2 diabetes: Results from a randomized,Phase IV study

We aimed to explore the efficacy and safety of once‐weekly trelagliptin 100 mg as an add‐on therapy to insulin in Japanese patients with type 2 diabetes mellitus with inadequate glycaemic control. Patients with haemoglobin A1c (HbA1c) 7.5% to 10.0% who were receiving 8 to 40 units of insulin per day were randomized to receive, with insulin, trelagliptin 100 mg (A/A, n = 116) or placebo (P/A, n = 124) for a 12‐week double‐blind (DB) phase, after which all received trelagliptin for a 40‐week open‐label phase. Primary endpoints were HbA1c change from baseline to the end of the DB phase and adverse events (AEs). HbA1c significantly decreased in the A/A group vs the P/A group at the end of the DB phase (least square mean difference, ?0.63% [95% CI, ?0.83 to ?0.44]: P < .0001). The frequency of treatment‐emergent AEs during the DB phase was 44.0% in the A/A group and 47.6% in the P/A group. No patient experienced severe hypoglycaemia during trelagliptin treatment. Once‐weekly trelagliptin 100 mg therapy with insulin demonstrated a significant reduction in HbA1c. Long‐term treatment was well‐tolerated, with no clinically significant hypoglycaemia, suggesting that trelagliptin with insulin is a meaningful treatment option in this patient population.     

Intensive glucose-lowering and the risk of vascular events and premature death in patients with decreased kidney function: The ADVANCE trial

To assess the effects of intensive glucose control on the risk of major clinical outcomes according to estimated glomerular filtration rate (eGFR) levels in people with type 2 diabetes. Of 11 140 ADVANCE trial participants, 11 096 with baseline eGFR measurements were included, and classified into three eGFR groups: ≥90 mL/min/1.73 m²; 60 to 89 mL/min/1.73 m²; and < 60 mL/min/1.73 m². Relative risk reduction of randomized intensive glucose control with regard to the composite outcome of major macro- and microvascular events, all-cause death and cardiovascular death did not significantly vary by eGFR level (P for heterogeneity ≥0.49). The risk of severe hypoglycaemia increased with intensive glucose control; however, this risk did not vary across eGFR groups (P for heterogeneity = 0.83). The risk–benefit profile of intensive glucose control in patients with type 2 diabetes and impaired kidney function appears similar to that observed in those with preserved kidney function.     

Efficacy and safety of linagliptin as add-on therapy to insulin in Chinese patients with type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled trial

This 24-week, double-blind, placebo-controlled, phase III trial evaluated the efficacy and safety of linagliptin in 206 Chinese patients with inadequately controlled (glycated haemoglobin [HbA1c] 7.5%–10.0%) type 2 diabetes mellitus (T2DM) receiving insulin (basal or premixed) ± metformin. Patients were randomized (1:1) to receive linagliptin 5 mg/d or placebo. The decrease from baseline in HbA1c (primary endpoint) was greater with linagliptin than with placebo (−0.61% vs. −0.20%, adjusted mean difference −0.40%; P = 0.0016). Linagliptin demonstrated significantly greater improvement in 2-hour postprandial glucose (−1.77 mmol/L [−31.95 mg/dL]; P < 0.001), and a numerical reduction in fasting plasma glucose (−0.34 mmol/L [−6.2 mg/dL]; P = 0.2241) versus placebo. Proportionally more patients on linagliptin achieved a HbA1c reduction of ≥0.5% versus those on placebo (odds ratio 2.293, P < 0.01). Adverse events in both groups were similar, with no new safety findings or clinically relevant changes in body weight. Among investigator-defined hypoglycaemic events (linagliptin: 17.3%; placebo: 12.7%; odds ratio 1.48, P = 0.337), none were severe. In Chinese patients with T2DM, linagliptin add-on to insulin improved glycaemic control and was well tolerated, without increased risk of hypoglycaemia or weight gain.     

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4‐week,double‐blind,randomized, placebo‐controlled phase 2 trial

Aims

This phase 2, double‐blind, randomized, placebo‐controlled trial ( ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.

Materials and methods

Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%‐10.0%, entered a 2‐week, open‐label, placebo run‐in period, followed by a 4‐week, double‐blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment.

Results

PD: Empagliflozin resulted in a dose‐dependent significant increase in 24‐hour UGE compared with placebo (UGE placebo‐corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose‐dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose‐dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported.

Conclusions

Based on this short‐duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non‐Japanese participants.     

Empagliflozin as add‐on to linagliptin in a fixed‐dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52‐week,randomized, placebo‐controlled trial

Aims

This double‐blind, randomized, placebo‐controlled trial ( ClinicalTrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add‐on to linagliptin (Lina) 5 mg (fixed‐dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients.

Methods

The trial (40 sites; May 2015‐March 2017) involved screening 433 adults (≥20 years) who were treatment‐naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%‐10.0% after ≥16 weeks of using Lina (pre‐enrolment or during a 16‐week, open‐label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once‐daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up‐titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks.

Results

Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, ?0.93% vs 0.21%; adjusted mean difference, ?1.14%) and Week 52 (?1.16% vs 0.06%; adjusted mean difference, ?1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin‐associated events (eg, increased urination, increased blood ketones). There were no adjudication‐confirmed diabetic ketoacidosis events or lower limb amputations.

Conclusions

These results support the notion that empagliflozin‐linagliptin in fixed‐dose combination is a therapeutic option for Japanese patients with type 2 diabetes.     

Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL,a randomized trial

Aim

To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants.

Materials and methods

In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m²). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed.

Results

Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m², glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants.

Conclusion

SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.