Cardiovascular and renal outcomes of initial combination therapy with glucose-lowering agents versus a stepwise approach in newly diagnosed or treatment-naïve type 2 diabetes: A systematic review and meta-analysis.

AIM: To evaluate the efficacy and safety of the initial combination therapy versus a stepwise approach in newly diagnosed type 2 diabetes (T2D) by conducting a systematic review and meta-analysis of observational cohort studies and randomized controlled trials (RCTs). METHODS: Studies were identified from MEDLINE, Embase, the Cochrane Library, and through search of bibliographies to January 2022. Study-specific risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Eight articles including four unique RCTs (n = 5527 participants) and one observational cohort study (n = 200) that compared initial combination therapy versus stepwise therapy were included. The RR for myocardial infarction comparing initial combination therapy versus stepwise therapy was 1.21 (95% CI 0.74-2.00). Initial combination therapy reduced levels of fasting plasma glucose and glycated haemoglobin: mean differences -0.97 mmol/L (95% CI -1.41, -0.53) and -24.92 mmol/mol (95% CI -25.67, -24.27), respectively. Initial combination therapy versus stepwise therapy reduced lipid levels, blood pressure and intima media thickness, with no differences in body composition variables, neuropathy, retinopathy or adverse events. Single-study results showed that initial combination therapy reduced creatinine levels and urine albumin excretion rate. The quality of the evidence ranged from moderate to very low. CONCLUSIONS: Except for improving cardiometabolic and glycaemic variables, a limited number of studies characterized by small sample sizes show that initial combination therapy for newly diagnosed T2D may be similar in efficacy and safety to stepwise therapy with respect to cardio-renal outcomes. There is a lack of sufficient evidence to recommend initial combination therapy with glucose-lowering agents in newly diagnosed T2D with the aim of preventing cardio-renal outcomes. Definitive RCTs are warranted.

Application of a new strategy of initial combination therapy with intravitreal dexamethasone intravitreal implant and ranibizumab in macular edema secondary to retinal vein occlusion / 中华眼底病杂志

Objective:To observe the short-term efficacy and safety of a new strategy of dexamethasone intravitreal implant (DEX) combined with ranibizumab in the treatment of retinal vein occlusion (RVO) secondary to macular edema (ME) (RVO-ME).Methods:A prospective clinical interventional study. From May 2020 to September 2021, 78 RVO-ME patients with 78 eyes diagnosed in the eye examination of Department of Ophthalmology of The First Affiliated Hospital of Anhui University of Science&Technology were included in the study. Among them, there were 35 males and 43 females, all with monocular disease. Branch retinal vein occlusion (BRVO) was found in 40 patients with 40 eyes; central retinal vein occlusion (CRVO) was found in 38 patients with 38 eyes. According to the treatment strategies, patients were randomly divided into DEX and ranibizumab combination therapy group (initial combination therapy group), DEX monotherapy group and ranibizumab monotherapy group, with 29 eyes, 26 eyes and 23 eyes respectively. Different types of RVO were divided into different treatment groups of BRVO and CRVO. Best corrected visual acuity (BCVA) and frequency domain optical coherence tomography were performed. The BCVA examination was carried out using the international standard visual acuity chart, which was converted into the logarithmic minimum angle of resolution (logMAR) visual acuity during statistics. There were no significant differences in logMAR BCVA ( χ2 =2.376) and central retinal thickness (CRT) ( F=0.052) among the three groups ( P>0.05). After treatment, the patients were followed up every month for 6 months. The changes of BCVA, CRT and the incidence of adverse reactions were observed during follow-up. One-way ANOVA and Kruskal-Wallis H test were used to compare the differences. Results:During the follow-up period, compared with the baseline, the BCVA of the eyes in the initial combination treatment group, DEX treatment group and ranibizumab treatment group were significantly improved ( Z=110.970, 90.359, 207.303), and CRT was significantly decreased ( F=107.172, 88.418, 61.040), the difference was statistically significant ( P<0.01). At 1, 2, 3, 4, 5, and 6 months after treatment, there were significant differences in the mean changes in BCVA between the initial combined treatment group, DEX treatment group, and ranibizumab treatment group ( χ2=34.522, 29.570, 14.199, 7.000, 6.434, 6.880; P<0.05); 1, 2, 3, and 6 months after treatment, the differences were statistically significant ( F=4.313, 7.520, 3.699, 3.152; P<0.05). The time required to improve BCVA by 0.1 logMAR units in the initial combination treatment group, DEX treatment group, and ranibizumab treatment group was 5.73 (3.21, 8.48), 9.97 (6.29, 18.78), and 20.00 (9.41, 37.89) d, respectively; The time required for CRT to drop to 300 μm was 24.31 (21.32, 26.15), 29.42 (25.65, 31.37), and 29.17 (25.28, 36.94) d, respectively. The BCVA improvement of 0.1 logMAR unit and the time required for CRT to decrease to 300 μm in the eyes of initial combined treatment group were shorter than those in the eyes of DEX treatment group and the ranibizumab treatment group, and the differences were statistically significant ( Z=-3.533, -4.445, -3.670, -4.030; P<0.01). Different BRVO treatment groups: 1, 2, 3, 5, and 6 months after treatment, the mean BCVA changes were significantly different ( χ 2=24.989, 21.652, 11.627, 7.054, 9.698; P<0.05); CRVO was different treatment group: 1 and 2 months after treatment, there were significant differences in mean BCVA changes ( χ 2=11.137, 9.746; P<0.05). Two months after treatment, there were significant differences in CRT changes between BRVO and CRVO groups with different treatment regimens ( F=3.960, 3.722; P<0.01). The time required to improve BCVA by 0.1 logMAR unit in the eyes of BRVO and CRVO combined treatment group was shorter than that in the eyes of BRVO, CRVO DEX treatment group and the BRVO, CRVO ranibizumab treatment group, and the differences were statistically significant (BRVO: Z=-2.687, -3.877; P<0.05; CRVO: Z=-2.437, -3.575; P<0.05). The time required for CRT to drop to 300 μm in the CRVO combined treatment group was significantly shorter than that in the CRVO DEX treatment group and the CRVO ranibizumab treatment group, and the difference was statistically significant ( F=6.910, P<0.010); there was no statistically significant difference between the different BRVO treatment groups ( F=1.786, P>0.05). The number of re-treated eyes in the initial combined treatment group and DEX treatment group was less than that in the ranibizumab treatment group, and the difference was statistically significant ( χ 2=18.330, 7.224; P<0.05). The retreatment interval of the eyes in the initial combined treatment group was significantly longer than that in the DEX treatment group and the ranibizumab treatment group, and the difference was statistically significant ( P <0.01). There was no significant difference in the incidence of intraocular hypertension among the initial combined treatment group, DEX treatment group and ranibizumab treatment group ( χ2=0.058, P>0.05). Conclusions:The new strategy of initial combination therapy with DEX and ranibizumab in the treatment of RVO-ME has a better short-term effect. Compared with the monotherapy group, the retreatment interval is shorter, the visual and anatomical benefits are faster, the efficacy lasts longer, and the safety is better.

Application of a new strategy of initial combination therapy with intravitreal dexamethasone intravitreal implant and ranibizumab in macular edema secondary to retinal vein occlusion / 中华眼底病杂志

Objective:To observe the short-term efficacy and safety of a new strategy of dexamethasone intravitreal implant (DEX) combined with ranibizumab in the treatment of retinal vein occlusion (RVO) secondary to macular edema (ME) (RVO-ME).Methods:A prospective clinical interventional study. From May 2020 to September 2021, 78 RVO-ME patients with 78 eyes diagnosed in the eye examination of Department of Ophthalmology of The First Affiliated Hospital of Anhui University of Science&Technology were included in the study. Among them, there were 35 males and 43 females, all with monocular disease. Branch retinal vein occlusion (BRVO) was found in 40 patients with 40 eyes; central retinal vein occlusion (CRVO) was found in 38 patients with 38 eyes. According to the treatment strategies, patients were randomly divided into DEX and ranibizumab combination therapy group (initial combination therapy group), DEX monotherapy group and ranibizumab monotherapy group, with 29 eyes, 26 eyes and 23 eyes respectively. Different types of RVO were divided into different treatment groups of BRVO and CRVO. Best corrected visual acuity (BCVA) and frequency domain optical coherence tomography were performed. The BCVA examination was carried out using the international standard visual acuity chart, which was converted into the logarithmic minimum angle of resolution (logMAR) visual acuity during statistics. There were no significant differences in logMAR BCVA ( χ2 =2.376) and central retinal thickness (CRT) ( F=0.052) among the three groups ( P>0.05). After treatment, the patients were followed up every month for 6 months. The changes of BCVA, CRT and the incidence of adverse reactions were observed during follow-up. One-way ANOVA and Kruskal-Wallis H test were used to compare the differences. Results:During the follow-up period, compared with the baseline, the BCVA of the eyes in the initial combination treatment group, DEX treatment group and ranibizumab treatment group were significantly improved ( Z=110.970, 90.359, 207.303), and CRT was significantly decreased ( F=107.172, 88.418, 61.040), the difference was statistically significant ( P<0.01). At 1, 2, 3, 4, 5, and 6 months after treatment, there were significant differences in the mean changes in BCVA between the initial combined treatment group, DEX treatment group, and ranibizumab treatment group ( χ2=34.522, 29.570, 14.199, 7.000, 6.434, 6.880; P<0.05); 1, 2, 3, and 6 months after treatment, the differences were statistically significant ( F=4.313, 7.520, 3.699, 3.152; P<0.05). The time required to improve BCVA by 0.1 logMAR units in the initial combination treatment group, DEX treatment group, and ranibizumab treatment group was 5.73 (3.21, 8.48), 9.97 (6.29, 18.78), and 20.00 (9.41, 37.89) d, respectively; The time required for CRT to drop to 300 μm was 24.31 (21.32, 26.15), 29.42 (25.65, 31.37), and 29.17 (25.28, 36.94) d, respectively. The BCVA improvement of 0.1 logMAR unit and the time required for CRT to decrease to 300 μm in the eyes of initial combined treatment group were shorter than those in the eyes of DEX treatment group and the ranibizumab treatment group, and the differences were statistically significant ( Z=-3.533, -4.445, -3.670, -4.030; P<0.01). Different BRVO treatment groups: 1, 2, 3, 5, and 6 months after treatment, the mean BCVA changes were significantly different ( χ 2=24.989, 21.652, 11.627, 7.054, 9.698; P<0.05); CRVO was different treatment group: 1 and 2 months after treatment, there were significant differences in mean BCVA changes ( χ 2=11.137, 9.746; P<0.05). Two months after treatment, there were significant differences in CRT changes between BRVO and CRVO groups with different treatment regimens ( F=3.960, 3.722; P<0.01). The time required to improve BCVA by 0.1 logMAR unit in the eyes of BRVO and CRVO combined treatment group was shorter than that in the eyes of BRVO, CRVO DEX treatment group and the BRVO, CRVO ranibizumab treatment group, and the differences were statistically significant (BRVO: Z=-2.687, -3.877; P<0.05; CRVO: Z=-2.437, -3.575; P<0.05). The time required for CRT to drop to 300 μm in the CRVO combined treatment group was significantly shorter than that in the CRVO DEX treatment group and the CRVO ranibizumab treatment group, and the difference was statistically significant ( F=6.910, P<0.010); there was no statistically significant difference between the different BRVO treatment groups ( F=1.786, P>0.05). The number of re-treated eyes in the initial combined treatment group and DEX treatment group was less than that in the ranibizumab treatment group, and the difference was statistically significant ( χ 2=18.330, 7.224; P<0.05). The retreatment interval of the eyes in the initial combined treatment group was significantly longer than that in the DEX treatment group and the ranibizumab treatment group, and the difference was statistically significant ( P <0.01). There was no significant difference in the incidence of intraocular hypertension among the initial combined treatment group, DEX treatment group and ranibizumab treatment group ( χ2=0.058, P>0.05). Conclusions:The new strategy of initial combination therapy with DEX and ranibizumab in the treatment of RVO-ME has a better short-term effect. Compared with the monotherapy group, the retreatment interval is shorter, the visual and anatomical benefits are faster, the efficacy lasts longer, and the safety is better.

Comparison of Safety and Efficacy of Glimepiride-Metformin and Vildagliptin- Metformin Treatment in Newly Diagnosed Type 2 Diabetic Patients.

OBJECTIVE: To compare the safety and efficacy of glimepiride and vildagliptin as add-on therapy to metformin in newly diagnosed patients with type 2 diabetes mellitus (T2DM). METHODS: This 24-week, prospective, comparative, observational study was conducted among newly diagnosed patients with T2DM. The primary endpoint was a change in fasting plasma glucose (FPG), postpradinal glucose (PPG), and HbA1c from the baseline to week 24. The key secondary endpoints were monitoring treatment-emergent adverse events such as hypoglycemia, overall gastrointestinal symptoms and weight gain, and electrocardiogram (ECG) findings. RESULTS: A total of 100 eligible patients were divided into two groups: group A (n = 50) received vildagliptin plus metformin and group B (n = 50) received glimepiride plus metformin. The mean age of the patients was 49.98 years and 52.12 years in group A and group B, respectively. Electrocardiographic findings were within normal limits in all the patients from group A, whereas 47 patients from group B showed normal ECG findings. A significant decrease in HbA1c, fasting and post-prandial plasma glucose was observed with group A and group B from the baseline to week-24. However, at week-24, reduction in HbA1c and blood glucose parameters were comparable between the groups. Safety outcomes did not show any events of hypoglycemia with vildagliptin. Mild hypoglycemia was reported with glimepiride in five patients. CONCLUSION: Vildagliptin-metformin appeared to be equally effective to glimepiride-metformin in reducing HbA1c level and blood glucose parameters, however, resulted in better adverse event profiles with lower risks of hypoglycemia.

[Initial combination therapy for primary open-angle glaucoma]. / 'Startovaia' kombinirovannaia terapiia pervichnoi otkrytougol'noi glaukomy.

PURPOSE: To study the efficacy and safety of initial combination therapy in patients with primary open-angle glaucoma (POAG). MATERIAL AND METHODS: The study included 111 patients (161 eyes) with stages II-III b-c of POAG aged 46 to 89 years (mean age 70.8±8.5 years). In the test group, therapy began with a fixed combination of prostaglandin (PG) (latanoprost) and beta-blocker (BB) (timolol). In patients of the control group, POAG therapy began with administration of the analogue of prostaglandin (latanoprost). When the target IOP was not achieved, a second drug was added to the treatment - instillations of 0.5% solution of timolol maleate 2 times a day. RESULTS: In patients of the test group the treatment started with a combination of BB + PG, the target IOP in the 'worst' eyes was achieved in 33 cases (64%) in 1.5±0.6 visits, and in the 'best' eyes - in 17 cases (81%), in 1.2±0.4 visits. In the control group with a 'step-by-step' selection of antihypertensive therapy, the target IOP in the 'worst' eyes was achieved in 35 cases (59%), in 2.5±0.7 visits, and in the 'best' eyes - in 22 cases (76%), in 2.2±0.5 visits (p<0.05). In both study groups, there were no cases of drug withdrawal attributed to their side effects. Patients noted conjunctival hyperemia in 5% (4 eyes) and 7% (6 eyes) of cases in the test group and the control group, respectively (p>0.05). Hyperemia decreased significantly in 2 weeks of latanoprost administration or fixed combination and did not cause withdrawal. CONCLUSION: Initial combination therapy is possible in patients with newly diagnosed POAG in some clinical situations, namely in stages II-III POAG with high IOP, unavailability of regular observation of patients for various social and economic reasons, absence of somatic and local contraindications to individual components of the combined treatment, etc.

New Drugs, Therapeutic Strategies, and Future Direction for the Treatment of Pulmonary Arterial Hypertension.

Despite recent advances in Pulmonary Arterial Hypertension (PAH) treatment, this condition is still characterized by an extremely poor prognosis. In this review, we discuss the use of newly-approved drugs for PAH treatment with already known mechanisms of action (macitentan), innovative targets (riociguat and selexipag), and novel therapeutic approaches with initial up-front combination therapy. Secondly, we describe new potential signaling pathways and investigational drugs with promising role in the treatment of PAH.

Initial combination therapy with vildagliptin plus metformin in drug-naïve patients with T2DM: a 24-week real-life study from Asia.

AIMS: To assess the effectiveness and safety of vildagliptin/metformin initial combination therapy in drug-naïve patients with type 2 diabetes mellitus (T2DM). METHODS: INITIAL was a 24-week prospective, observational study in T2DM patients with glycated hemoglobin (HbA1c) ≥ 7.5%, and prescribed vildagliptin/metformin as initial combination therapy. The primary endpoint was change in HbA1c from baseline to week 24. Key secondary endpoints were HbA1c change from baseline to week 12, proportion of patients achieving HbA1c ≤7.0%, change in body weight at 12 and 24 weeks, change in HbA1c by sub-groups (baseline HbA1c, age, body mass index [BMI], dosage strength, co-morbidities) from baseline to week 24, and safety. RESULTS: A total of 532 patients were enrolled. The mean age, HbA1c, and BMI were 49.6 ± 11.27 years, 9.3 ± 1.57%, and 26.7 ± 4.50 kg/m2, respectively. Cardiovascular risk factors present at baseline were dyslipidemia (30.1%), hypertension (29.7%), and obesity (20.9%). The mean reductions in HbA1c from baseline to week 12 (-1.6 ± 1.59%) and 24 (-1.9 ± 1.70%) were statistically significant (p < .001). At 24 weeks, 39.6% of patients achieved HbA1c ≤ 7.0%, and the mean body weight reduction was -1.1 ± 2.62 kg. HbA1c reductions were consistently seen from baseline to weeks 12 and 24 in the various sub-groups. Overall, 48 (9.0%) patients reported adverse events, including one hypoglycemic episode. There were no serious adverse events or deaths. CONCLUSIONS: Overall, in a relatively young drug-naïve T2DM Asian study population with high baseline HbA1c and often associated with cardiovascular risk factors, vildagliptin/metformin combination therapy was associated with significant and clinically relevant HbA1c reduction from baseline. This effect was seen at week 12, was maintained over 24 weeks, and was accompanied by good tolerability.

Apparent subadditivity of the efficacy of initial combination treatments for type 2 diabetes is largely explained by the impact of baseline HbA1c on efficacy.

AIM: To explain the subadditive efficacy typically observed with initial combination treatments for type 2 diabetes. METHODS: Individual subject data from 1186 patients with type 2 diabetes [mean glycated haemoglobin (HbA1c) = 8.8%] treated with metformin, canagliflozin or canagliflozin + metformin were used. The baseline HbA1c versus ΔHbA1c relationships for monotherapy arms were determined using analysis of covariance and then used to predict efficacy in the combination arms by modelling how applying one treatment lowers the 'effective baseline HbA1c' for a second treatment. The model was further tested using data from several published combination studies. RESULTS: The mean ΔHbA1c levels were -1.25, -1.33, -1.37, -1.77 and -1.81% with metformin, canagliflozin 100 mg, canagliflozin 300 mg, canagliflozin 100 mg/metformin and canagliflozin 300 mg/metformin, respectively. Using the monotherapy results, the predicted efficacy for the canagliflozin/metformin arms was within 10% of the observed values using the new model, whereas assuming simple additivity overpredicted efficacy in the combination arms by nearly 50%. For 10 other published initial combination studies, predictions from the new model [mean (standard error) predicted ΔHbA1c = 1.67% (0.14)] were much more consistent with observed values [ΔHbA1c = 1.72% (0.12)] than predictions based on assuming additivity [predicted ΔHbA1c = 2.19% (0.21)]. CONCLUSIONS: The less-than-additive efficacy commonly seen with initial combination treatments for type 2 diabetes can be largely explained by the impact of baseline HbA1c on the efficacy of individual treatments. Novel formulas have been developed for predicting the efficacy of combination treatments based on the efficacy of individual treatments and the baseline HbA1c of the target patients.

Safety and efficacy of initial combination of linagliptin and metformin in patients with type 2 diabetes: A subgroup analysis of Indian patients from a randomized, double-blind, placebo-controlled study.

CONTEXT AND OBJECTIVES: The number of people with diabetes is increasing exponentially in India. Owing to a unique "Asian Indian Phenotype," Indians develop diabetes a decade earlier and have an earlier onset of complications than Western populations. Therefore, it is essential to evaluate more effective treatment strategies at an earlier stage of disease progression, such as initial combination therapy, in Indian patients. In this study, we evaluated the efficacy and safety of initial combination therapy with linagliptin plus metformin in comparison to linagliptin or metformin monotherapy in Indian patients with type 2 diabetes mellitus. METHODS: This is a subgroup analysis of Indian patients who participated in a Phase III, 24-week, double-blind, placebo-controlled, trial. Overall, 249 Indian patients were randomized to one of six treatment arms (Two free combination therapy arms: Linagliptin 2.5 mg twice daily [bid] + either low [500 mg, n = 36] or high [1000 mg, n = 44] dose metformin bid and four monotherapy arms: Linagliptin 5 mg once daily [qd, n = 40], metformin 500 mg [n = 49] or 1000 mg bid [n = 45], or placebo [n = 23]). RESULTS: The placebo-corrected mean change in glycated hemoglobin from baseline (8.9%) to week 24 was -1.83% for linagliptin + metformin 1000 mg bid; -1.46% for linagliptin + metformin 500 mg bid; -1.30% for metformin 1000 mg bid; -1.00% for metformin 500 mg bid; and -0.77% for linagliptin 5 mg qd. None of the patients in the combination therapy arms had hypoglycemia, whereas there was one event in the metformin 1000 mg bid arm. Rates of adverse event were similar across various treatments. CONCLUSIONS: In this subgroup analysis of Indian patients, initial combination therapy with linagliptin + metformin was more efficacious in improving glycemic control than the monotherapy arms, with a comparable tolerability profile. The results were comparable to the overall population.