This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin.

This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24.

Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia.

For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

We aimed to compare efficacy and safety between gemigliptin add-on and escalation of the metformin dose in patients with inadequately controlled type 2 diabetes mellitus (T2DM) despite treatment with metformin and SGLT2 inhibitors.

This study was a multicenter, randomized, open-label, active-controlled, parallel-group comparative study. Patients with T2DM uncontrolled on metformin and SGLT2 inhibitors were randomized to receive gemigliptin 50 mg as an add-on (GEM group, n = 37) or escalation of the metformin dose (500 mg, MET group, n = 38) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) from baseline to week 24.

At weeks 12 and 24, the reduction in HbA1c levels was significantly greater in the GEM group than in the MET group (GEM vs. MET = -0.64% ± 0.34% vs. -0.36% ± 0.50%, p = 0.009 at week 12; -0.61% ± 0.35% vs. -0.33% ± 0.70%, p = 0.045 at week 24). The proportions of patients who achieved target HbA1c levels of <7.0% at weeks 12 and 24 and <6.5% at week 12 were greater in the GEM group than in the MET group. An index of β-cell function was also significantly improved in the GEM group. The safety profiles were similar between the two groups.

Gemigliptin add-on therapy may be more effective than metformin dose escalation in patients with T2DM insufficiently controlled using metformin and SGLT2 inhibitors, without safety concerns. This trial is registered with CRIS_number: KCT0003520.

Environmental sustainable analytical methods were developed by mathematical modification of UV absorption spectra for quality control study of multicomponent formulations consisting of remogliflozin (REM) and teneligliptin (TEN), with good sensitivity and selectivity. Then analytes were quantified by measuring the peak amplitude of the first derivative spectra at zero crossing points at 230.2 nm and 213.8 nm for REG and TEN in the first derivative method. The second method involves the formation of ratio spectra and taking the absorption difference at two selected wavelengths of peak and trough of a spectrum. In the ratio first derivative method peak amplitudes were measured at 235.2 nm and 259.1 nm for simultaneous quantification of REM and TEN respectively. The fourth method was based on the measurement of the peak amplitude of zero-order spectra of analytes generated from the mixture spectrum by subtraction of a constant from the ratio spectrum followed by multiplication with divisor spectrum, Further, the proposed methods were validated systematically to confirm the linearity, precession, accuracy, sensitivity, and selectivity. Finally, validated UV spectroscopic methods were applied for simultaneous quantification of REM and TEN from formulation, and laboratory mixed solutions and statistically compared with the reported HPLC method. Further, recently developed AGREE, Hexagonal greenness and white analytical chemistry, a whiteness evaluation tools were applied to the proposed UV spectroscopic methods and found to be safer analytical methods, compared to the reported expensive, time-consuming and toxic HPLC method. Hence, proposed UV spectroscopic methods could be used for routine quality control of formulations containing REM and TEN.

A rapid and reproducible hydrophilic liquid chromatography (HILIC) process was established for concomitant determination of remogliflozin etabonate (RE), vildagliptin (VD), and metformin (MF) in a formulation. A face-centered central composite experimental design was employed to optimize and predict the chromatographic condition by statistically studying the surface response model and design space with desirability close to one. A HILIC column with a simple mobile phase of acetonitrile (65% v/v) and 20 mM phosphate buffer (35% v/v, pH 6, controlled with orthophosphoric acid) was used to separate RE, VD, and MF. RE, VD, and MF were separated in 3.6 min using an isocratic mode mobile phase flow at a flow rate of 1.4 mL at room temperature, and the analytes were examined by recording the absorption at 210 nm. The developed HILIC method was thoroughly validated for all parameters recommended by ICH, and linearity was observed in the ranges 20−150 µg/mL, 10−75 µg/mL, and 50−750 µg/mL for RE, VD, and MF, respectively, along with excellent regression coefficients (r2 > 0.999). The calculated percentage relative deviation and relative error ascertained the precision and accuracy of the method. The selectivity and accuracy were further confirmed by the high percentage recovery of added standard drugs to the formulation using the standard addition technique. The robustness of the HILIC processes was confirmed by developing a half-normal probability plot and Pareto chart, as the slight variation of a single factor had no significant influence on the assay outcomes. Utilization of the optimized HILIC procedure for concurrent quantification of RE, VD, and MF in solid dosage forms showed accurate and reproducible results. Hence, the fast HILIC method can be regularly employed for the quality assurance of pharmaceutical preparations comprising RE, VD, and MF.

Dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter type 2 inhibitors (SGLT2is) offer new options for the oral management of type 2 diabetes mellitus (T2DM), with the advantage in the elderly population to be devoid of a high risk of hypoglycaemia. SGLT2is have also shown benefits regarding cardiovascular (heart failure) and renal protection, including in patients with T2DM aged ≥ 65 years while DPP-4is have only proved cardiovascular and renal safety without superiority compared with placebo. The glucose-lowering efficacy of the two pharmacological classes is almost similar including in older patients with T2DM. However, the tolerance and safety profile may be highly different and overall more favourable with DPP-4is than with SGLT2is. Some adverse events have been reported with SGLT2is which may be more prevalent or severe in older patients than in younger patients. The present comprehensive review focuses on the benefit/risk balance in the elderly population with T2DM by comparing the profile of DPP-4is and SGLT2is regarding the following potential issues: metabolic disorders (hypoglycaemia and diabetic ketoacidosis); cardiac and vascular issues (atheromatous cardiovascular disease, heart failure, volume reduction hypotension, and lower limb amputations); renal endpoints including acute renal injury; risk of infections; digestive disorders; bone and skin adverse events; and cancer risk. Both DPP-4is and SGLT2is have their own advantages and disadvantages. Personalised treatment is recommended based upon the efficacy/safety profile of each drug class and individual patient characteristics that may be markedly different among the heterogeneous population of older individuals with T2DM.

The FDA's approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or ligands alter normal physiological functions, as in metabolic diseases such as Type 2 diabetes. In this study, the synthetic cal14.2b (s-cal14.2b) from the unusual Californiconus californicus demonstrated bioactivity on NIT-1 insulinoma cell lines stimulating insulin secretion detecting by high performance liquid chromatography (HPLC). Accordingly, s-cal14.2b increased the CaV1.2/1.3 channel-current by 35 ± 4% with a recovery τ of 10.3 ± 4 s in primary cell culture of rat pancreatic β-cells. The in vivo results indicated a similar effect of insulin secretion on mice in the glucose tolerance curve model by reducing the glucose from 500 mg/dL to 106 mg/dL in 60 min, compared to the negative control of 325 mg/dL at the same time. The PET-SCAN with radiolabeling 99mTc-s-cal14.2b demonstrated biodistribution and accumulation in rat pancreas with complete depuration in 24 h. These findings show the potential therapeutic use of s-cal14.2b in endocrinal pathologies such as early stages of Type 2 Diabetes where the pancreas's capability to produce insulin is still effective.

Efficacy and safety of dapagliflozin plus saxagliptin (DAPA + SAXA) were compared with insulin glargine (INS) in patients with type 2 diabetes (T2D) in a 52-week extension study.

This international Phase 3 study randomized adults with T2D on metformin with/without sulphonylurea. They received DAPA + SAXA or INS for 24 weeks (short-term) with a 28-week (long-term) extension. Week 52 exploratory endpoints included adjusted mean change from baseline in glycated haemoglobin A_1c (HbA1c) and body weight, and a proportion of patients achieving optimal glycaemic response without hypoglycaemia and without requiring rescue medication.

Of the 1163 patients enrolled, 643 received treatment; 600 (DAPA + SAXA, 306; INS, 294) entered the long-term phase. At 52 weeks, HbA1c [adjusted least squares (LS) mean; 95% confidence interval (CI)] decreased more with DAPA + SAXA (-1.5% [-1.6%, -1.4%]) than with INS (-1.3% [-1.4%, -1.1%]); the LS mean difference (95% CI) was -0.25% (-0.4%, -0.1%; P = 0.009). Total body weight reduced with DAPA + SAXA [LS mean (95% CI): -1.8 kg (-2.4, -1.3)] and increased with INS [LS mean (95% CI): +2.8 kg (2.2, 3.3)]. More patients on DAPA + SAXA (17.6%) achieved HbA1c <7.0% without hypoglycaemia versus those on INS (9.1%). Rescue medication was required by 77 patients (23.8%) and 97 patients (30.4%) in the DAPA + SAXA and INS groups, respectively.

DAPA + SAXA treatment was non-inferior to INS in reducing HbA1c and body weight, and in achieving optimal glycaemic control without hypoglycaemia in patients with T2D 52 weeks after initiation.

Type 2 diabetes mellitus is a multifactorial condition characterized by high level of sugar in the blood. To control hyperglycemia, combination therapy is recommended if monotherapy fails to achieve glycemic control. The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose cotransporter type 2 (SGLT2) inhibitor is a promising option of the combination therapies in terms of safety as well as efficacy. Despite of the value of combination therapy of these two agents, the pharmacokinetic drug interactions between these two classes of agents have been evaluated in a few drugs. Thus, we reviewed the potential pharmacokinetic drug interaction based on the in vitro metabolism- and transporter-mediated drug interaction information as well as drug interaction studies in human, between a DPP-4 inhibitor and a SGLT2 inhibitor which are marketed in South Korea.

This review evaluated the efficacy and safety of a combination therapy comprising a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) in type 2 diabetes.

A literature search through to May 2017 was carried out of PubMed, Embase and the Cochrane Central Register of Controlled Trials. Studies were eligible if they were randomized controlled trials (RCTs) comparing SGLT2i plus DPP4i (SGLT2i/DPP4i) against DPP4i±placebo or SGLT2i±placebo and published in English. The primary outcome was change in HbA_1c from baseline.

Eight RCTs comparing SGLT2i/DPP4i and DPP4i, and five RCTs comparing SGLT2i/DPP4i and SGLT2i, with three RCTs involving both comparisons, were included in the present review. SGLT2i/DPP4i resulted in a greater mean HbA_1c reduction [weighted mean difference (WMD]): -0.62%] than did DPP4i alone, which was a much less marked reduction (WMD: -0.35%) than with SGLT2i alone. Also, significant differences in body weight loss from baseline were observed only with SGLT2i/DPP4i vs. DPP4i, but not vs. SGLT2i. The risk of hypoglycaemic events was low and similar between treatment groups. When subjects were stratified based on baseline HbA_1c, any reduction by SGLT2i/DPP4i in relation to DPP4i was proportional to baseline HbA_1c levels. However, compared with SGLT2i, HbA_1c reductions with SGLT2i/DPP4i were modest regardless of baseline HbA_1c.

Combination therapy with SGLT2i and DPP4i is both efficacious and safe. In particular, a marked additional glucose-lowering effect is evident when SGLT2i is combined with or added to DPP4i, and not vice versa. However, baseline HbA_1c determined the additional glucose-lowering effects of SGLT2i in combined treatment with DPP4i.

Saxagliptin (a dipeptidyl peptidase-4 inhibitor, DPP-4i) and dapagliflozin (a sodium-glucose cotransporter type 2 inhibitor, SGLT2i) improve glucose control in type 2 diabetes (T2D) through different potentially complementary mechanisms, thus offering the opportunity for a combined therapy. Area covered: The characteristics of the saxagliptin/dapagliflozin combination are analysed, focusing on: 1) pharmacokinetic and pharmacodynamic properties; 2) efficacy and safety in phase III trials with concurrent and sequential add-on therapy; and 3) potential use in clinical practice, including in special populations (cardiovascular disease, heart failure, chronic kidney disease, elderly). Expert commentary: Conclusions drawn from clinical trials investigating combination with the separate drugs are considered to apply to the fixed-dose combination (FDC) that demonstrates bioequivalence. Dual saxagliptin/dapagliflozin therapy is more potent than either monotherapy and can be used as an initial combination or a stepwise sequential approach. Dual therapy is generally well tolerated and may be used in special populations, with some limitations because of the presence of dapagliflozin. However, the latter may offer some advantages because of multiple effects attributed to SGLT2i. The best place of this dual combination for the management of T2D and the profile of patients who will make the most of this combined therapy remains to be defined.