In T2DM requiring insulin initiation, icodec titrated with an app safely reduced HbA1c vs. daily basal insulin analogues at 52 wk.

SOURCE CITATION: Bajaj HS, Aberle J, Davies M, et al. Once-weekly insulin icodec with dosing guide app versus once-daily basal insulin analogues in insulin-naive type 2 diabetes (ONWARDS 5): a randomized trial. Ann Intern Med. 2023;176:1476-1485. 37748181.

Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

AIMS/HYPOTHESIS: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. METHODS: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. RESULTS: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA1c (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. CONCLUSIONS/INTERPRETATION: Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. REGISTRATION: PROSPERO registration no. CRD42022382594.

Efficacy of pharmacologic interventions on magnetic resonance imaging biomarkers in patients with nonalcoholic fatty liver disease: systematic review and network meta-analysis.

BACKGROUND AND AIM: Several agents are under investigation for nonalcoholic fatty liver disease (NAFLD). We assessed the comparative efficacy of pharmacologic interventions for patients with NAFLD focusing on magnetic resonance imaging (MRI) biomarkers. METHODS: We searched Medline, Embase, and CENTRAL. We included randomized controlled trials of more than 12 weeks of intervention that recruited patients with biopsy-confirmed or MRI-confirmed NAFLD and assessed the efficacy of interventions on liver fat content (LFC) and fibrosis by means of MRI. We performed random-effects frequentist network meta-analyses and assessed confidence in our estimates using the CINeMA (Confidence in Network Meta-Analysis) approach. RESULTS: We included 47 trials (8583 patients). Versus placebo, thiazolidinediones were the most efficacious for the absolute change in LFC, followed by vitamin E, fibroblast growth factor (FGF) analogs, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with mean differences ranging from -7.46% (95% confidence interval [-11.0, -3.9]) to -4.36% (-7.2, -1.5). No differences between drug classes were evident. Patients receiving GLP-1 RAs or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs were more likely to achieve ≥30% relative reduction in LFC. Among agents, efruxifermin produced the largest reduction in LFC compared to placebo [-13.5% (-18.5, -8.5)], followed by pioglitazone, while being superior to most interventions. The effect of interventions on magnetic resonance elastography assessed fibrosis was small and insignificant. The confidence in our estimates was low to very low. CONCLUSIONS: Several drug classes may reduce LFC in patients with NAFLD without a significant effect on fibrosis; nevertheless, trial duration was small, and confidence in the effect estimates was low.

Reporting of adverse events of treatment interventions in multiple myeloma: an overview of systematic reviews.

The present study is an overview of systematic reviews focusing on adverse events of antimyeloma treatments. It provides a systematic description of adverse events as they are reported in the systematic reviews as well as a critical appraisal of included reviews. We conducted a comprehensive literature search in the most widely used electronic databases looking for systematic reviews that had an adverse event of an antimyeloma treatment intervention as primary outcome. Two independent reviewers conducted selection of included studies and data extraction on predesigned online forms and assessed study quality using AMSTAR 2. Overall corrected covered area (CCA) was calculated to examine the overlap of primary studies across systematic reviews. After screening eligible studies, 23 systematic reviews were included in this overview. Seven reviews with overall CCA of 14.7% examined cardiovascular adverse events of different drugs, including immunomodulatory drugs and proteasome inhibitors (mainly carfilzomib). Nine focused on infections, presenting with overall CCA of 5.8%, each one focused on a different drug or drug class. Three studied thromboembolism in patients treated either with lenalidomide, any immunomodulatory drug, or with daratumumab and had an overall CCA equal to 1.5%. Four more reviews focused on bortezomib-associated neurotoxicity, carfilzomib-associated renal toxicity, or second primary malignancies as an adverse event of lenalidomide or anti-CD38 monoclonal antibody treatment. The quality of included studies as judged by AMSTAR 2 was mostly critically low. Absence of a priori registered protocol and formal assessment of risk of bias of included primary studies were the most common shortcomings. Reporting of antimyeloma drug-associated toxicity is supported by multiple systematic reviews; nevertheless, methodological quality of existing reviews is mostly low.

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes. METHODS: We searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly tirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was change in HbA1c from baseline. Secondary efficacy outcomes included change in body weight, proportion of individuals reaching the HbA1c target of <53 mmol/mol (<7.0%), ≤48 mmol/mol (≤6.5%) or <39 mmol/mol (<5.7%), and proportion of individuals with body weight loss of at least 5%, 10% or 15%. Safety outcomes included hypoglycaemia, gastrointestinal adverse events, treatment discontinuation due to adverse events, serious adverse events, and mortality. We used version 2 of the Cochrane risk-of-bias tool for randomised trials to assess risk of bias for the primary outcome. RESULTS: Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from -17.71 mmol/mol (-1.62%) to -22.35 mmol/mol (-2.06%) vs placebo, -3.22 mmol/mol (-0.29%) to -10.06 mmol/mol (-0.92%) vs GLP-1 RAs, and -7.66 mmol/mol (-0.70%) to -12.02 mmol/mol (-1.09%) vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin. Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15 mg (OR 5.60 [95% CI 3.12, 10.06]), associated with higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). Odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51 [95% CI 1.07, 2.15]). Tirzepatide 15 mg led to higher discontinuation rate of study medication due to adverse events regardless of comparator, while all tirzepatide doses were safe in terms of serious adverse events and mortality. CONCLUSIONS/INTERPRETATION: A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA1c and body weight, assessment of risk of bias solely for the primary outcome, and generalisation of findings mainly to individuals who are overweight or obese and already on metformin-based background therapy. PROSPERO registration no. CRD42021283449.

Sotagliflozin for patients with type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed three secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). RESULTS: We included 11 RCTs comprising 16 411 subjects in the meta-analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD -0.42%, 95% CI -0.56 to -0.29), body weight (WMD -1.33 kg, 95% CI -1.57 to -1.09), and systolic blood pressure (WMD -2.44 mmHg, 95% CI -2.81 to -2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all-cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding the incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with an increased incidence of diarrhoea, genital infections, and volume depletion events. CONCLUSIONS: Sotagliflozin reduces blood glucose, body weight, and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable with other sodium-glucose co-transporter-2 inhibitors.

Comparative efficacy and safety of glucose-lowering drugs as adjunctive therapy for adults with type 1 diabetes: A systematic review and network meta-analysis.

AIM: To assess the efficacy and safety of glucose-lowering drugs used as an adjunct to insulin therapy in adults with type 1 diabetes. METHODS: We searched Medline, Embase and the Cochrane Central Register of Controlled Trials up to 24 January 2020 for randomized controlled trials. Our primary outcome was change in HbA1c. We additionally assessed eight efficacy and six safety secondary endpoints. We performed random effects frequentist network meta-analysis to estimate mean differences (MDs) and odds ratios (ORs), alongside 95% confidence intervals (CIs). We assessed risk of bias and evaluated confidence in the evidence for the primary outcome. RESULTS: We included 58 trials comprising 13 216 participants. Overall, sodium-glucose co-transporter (SGLT) inhibitors, liraglutide, glibenclamide, acarbose and metformin reduced HbA1c compared with placebo (MDs ranging from -0.46% [95% CI -0.64% to -0.29%] for empagliflozin to -0.20% [-0.35% to -0.06%] for metformin). SGLT inhibitors, exenatide daily, liraglutide and metformin reduced body weight and total daily insulin dose, while liraglutide and SGLT inhibitors reduced blood pressure. Diabetic ketoacidosis and genital infections were more frequent with SGLT inhibitors, while exenatide, liraglutide, pramlintide and metformin increased the incidence of nausea. No drug increased the incidence of severe hypoglycaemia. Confidence in evidence was mainly moderate to very low. CONCLUSIONS: Specific drugs may improve glycaemic control and reduce body weight, blood pressure and total daily insulin dose in patients with type 1 diabetes. However, low quality of evidence and an increased risk of diabetic ketoacidosis, genital infections or gastrointestinal adverse events should be taken into consideration by healthcare providers and patients. Future long-term trials are needed to clarify their benefit-to-risk profile and elucidate their role in clinical practice.

Ultra-rapid-acting insulins for adults with diabetes: A systematic review and meta-analysis.

We performed a systematic review and meta-analysis of randomized controlled trials to assess the efficacy and safety of the novel, ultra-rapid-acting insulins aspart and lispro in adults with type 1 or type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed eight efficacy and six safety endpoints. We calculated weighted mean differences (WMD) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, alongside 95% confidence intervals (CIs). We additionally assessed statistical heterogeneity among studies with the I2 statistic, considering values greater than 60% as indicative of substantial heterogeneity. Nine studies comprising 5931 patients were included in the systematic review; eight active-controlled studies could be synthesized in terms of a meta-analysis. Treatment with ultra-rapid-acting insulins had a similar effect on change in HbA1c compared with rapid-acting insulins (WMD -0.02%, 95% CI -0.08 to 0.05, I2  = 61% for patients with type 1 diabetes and -0.02%, 95% CI -0.09 to 0.04, I2  = 19% for patients with type 2 diabetes). Similarly, no difference was evident in terms of change in fasting plasma glucose, self-measured plasma glucose, body weight, basal or bolus insulin dose, incidence of serious adverse events and hypoglycaemia. Compared with rapid-acting insulins, ultra-rapid-acting insulins reduced 1- and 2-hour postprandial glucose (PPG) increment based on a liquid meal test, both in patients with type 1 and type 2 diabetes (WMD -0.94 mmol/L, 95% CI -1.17 to -0.72, I2  = 0% and -0.56 mmol/L, 95% CI -0.79 to -0.32, I2  = 0%, respectively, for change in 1-hour PPG increment). In conclusion, ultra-rapid-acting insulins were as efficacious and safe as rapid-acting insulins, showing a favourable effect solely on PPG control.

Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: A systematic review and network meta-analysis.

AIM: To compare the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library, and grey literature sources until 29 September 2020 for randomized controlled trials of at least 24 weeks' duration assessing the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. We performed frequentist network meta-analyses and calculated weighted mean differences and 95% confidence intervals combining trial arms of different approved doses of a given intervention into a single group. We evaluated the confidence in pooled estimates using the CINeMA (Confidence In Network Meta-Analysis) framework. RESULTS: In total, 424 trials (276 336 patients) assessing 21 antidiabetic medications from nine drug classes were included. Subcutaneous semaglutide was the most efficacious in reducing body weight followed by oral semaglutide, exenatide twice-daily, liraglutide, and the sodium-glucose co-transporter-2 (SGLT-2) inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. The same agents also conferred the greatest reductions in systolic blood pressure. Metformin had a modest effect in reducing body weight and systolic blood pressure. Diastolic blood pressure was reduced with the SGLT-2 inhibitors pioglitazone, exenatide twice-daily and semaglutide. In subgroup analyses of trials with over 52 weeks' duration, semaglutide and SGLT-2 inhibitors reduced both body weight and systolic blood pressure. CONCLUSIONS: Semaglutide and SGLT-2 inhibitors conferred reductions both in body weight and blood pressure that were sustainable for over 1 year of treatment. These agents may be preferable treatment options for patients with type 2 diabetes who are overweight/obese and/or hypertensive.

Some glucose-lowering drugs reduce risk for major adverse cardiac events.

SOURCE CITATION: Zhu J, Yu X, Zheng Y, et al. Association of glucose-lowering medications with cardiovascular outcomes: an umbrella review and evidence map. Lancet Diabetes Endocrinol. 2020;8:192-205. 32006518.

In type 2 diabetes, SGLT2 inhibitors were linked to diabetic ketoacidosis vs. DPP-4 inhibitors.

SOURCE CITATION: Douros A, Lix LM, Fralick M, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic ketoacidosis: a multicenter cohort study. Ann Intern Med. 2020;173:417-25. 32716707.

Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

BACKGROUND: Several pharmacologic options for type 2 diabetes are available. PURPOSE: To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. DATA SOURCES: Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020. STUDY SELECTION: English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes. DATA EXTRACTION: Pairs of reviewers extracted data and appraised risk of bias. DATA SYNTHESIS: 453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively. LIMITATION: Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk. CONCLUSION: In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes. PRIMARY FUNDING SOURCE: European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043).

Patients' and Clinicians' Preferences on Outcomes and Medication Attributes for Type 2 Diabetes: a Mixed-Methods Study.

BACKGROUND: Patients' views on the relative importance of treatment outcomes and medication attributes for type 2 diabetes may differ from clinicians' perceptions. OBJECTIVE: To assess which treatment outcomes and medication attributes are considered important by patients and clinicians for therapeutic decisions in type 2 diabetes. DESIGN: Exploratory, sequential, mixed-methods design comprising a qualitative (focus groups) and a quantitative (survey) phase. PARTICIPANTS: Patients in the focus groups (n = 33) and the survey study (n = 656) were recruited from 4 and 9 diabetes clinics across Greece, respectively. Clinicians in the survey study (n = 363) were identified from Greek registries for healthcare professionals. MEASUREMENTS: We conducted 6 focus groups to obtain patients' views regarding the impact of type 2 diabetes on their lives. Identified themes informed the development of a survey, which aimed to assess which outcomes and medication attributes are considered most important by patients and clinicians. We calculated odds ratios to compare patients' and clinicians' responses. RESULTS: The focus groups identified 6 main themes and 15 subthemes. In the survey study, patients were more likely than clinicians to rate prevention of amputation (odds ratio, 9.32; 95% CI, 6.51 to 13.35), diabetic eye disease (6.16; 4.63 to 8.21), sexual dysfunction, and stroke as important, while clinicians were more likely than patients to choose risk for hypoglycemia, and reduction of all-cause mortality, HbA1c, and body weight. Compared with clinicians, patients were less concerned about drug cost (0.16; 0.11 to 0.23), but more concerned about route of administration and need for less frequent glucose self-monitoring. CONCLUSIONS: Patients and clinicians differ in the perception of the relative importance of treatment outcomes and drug characteristics. Individual patient preferences should be explored and implemented in the therapeutic decision-making for type 2 diabetes.

Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of combination therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and a sodium-glucose co-transporter-2 inhibitor (SGLT2i) in patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library and grey literature sources up to 2 December 2019 for randomized controlled trials in adults with type 2 diabetes assessing the combination of GLP-1RA and SGLT2i, either as co-initiation therapy or as add-on to each other, against placebo or an active comparator. The primary outcome was change in HbA1c . Secondary outcomes included change in body weight, blood pressure and estimated glomerular filtration rate, and incidence of severe hypoglycaemia, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke and hospitalization for heart failure. We pooled data using random effects meta-analyses. RESULTS: Seven trials (1913 patients) were eligible. Compared with GLP-1RA, GLP-1RA/SGLT2i combination therapy was associated with a greater reduction in HbA1c (weighted mean difference -0.61%, 95% CI -1.09% to -0.14%, four studies), body weight (-2.59 kg, -3.68 to -1.51 kg, three studies) and systolic blood pressure (-4.13 mmHg, -7.28 to -0.99 mmHg, four studies). Compared with SGLT2i, GLP-1RA/SGLT2i combination therapy reduced HbA1c (-0.85%, -1.19% to -0.52%, six studies) and systolic blood pressure (-2.66 mmHg, -5.26 to -0.06 mmHg, six studies), but not body weight (-1.46 kg, -2.94 to 0.03 kg, five studies). After excluding data for one trial that had a considerably longer duration than the remaining studies, body weight was also reduced versus SGLT2i (-1.79 kg, -2.99 to -0.59 kg, five studies). Combination therapy did not increase the incidence of severe hypoglycaemia. Data for mortality and cardiovascular outcomes were scarce. CONCLUSIONS: GLP-1RA/SGLT2i combination therapy seems to reduce HbA1c , body weight and systolic blood pressure without increasing the risk of severe hypoglycaemia compared with either GLP-1RA or SGLT2i. No conclusions can be made regarding long-term effectiveness or the effect on cardiovascular outcomes.

Oral semaglutide for type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of oral semaglutide, a novel glucagon-like peptide-1 receptor agonist, for patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library and grey literature sources up to July 1, 2019 for randomized controlled trials (RCTs) comparing oral semaglutide with placebo or other antidiabetic agents. The primary outcome was change from baseline in HbA1c. Secondary outcomes included change from baseline in body weight and blood pressure, cardiovascular endpoints, severe hypoglycaemia, gastrointestinal adverse events and diabetic retinopathy. We synthesized results using weighted mean differences (WMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, along with 95% confidence intervals (CIs). RESULTS: We included 11 RCTs with 9890 patients in the systematic review. Compared with placebo, oral semaglutide reduced HbA1c and body weight (WMD -0.89%, 95% CI -1.07 to -0.71 and - 2.99 kg, 95% CI -3.69 to -2.30, respectively). Oral semaglutide was also superior to other active comparators (including liraglutide, empagliflozin and sitaglipitin) in terms of lowering HbA1c (WMD -0.35%, 95% CI -0.43 to -0.26) and reduction of body weight (WMD -1.48 kg, 95% CI -2.28 to -0.67), and had a favourable effect on systolic blood pressure. Compared with placebo, oral semaglutide reduced all-cause mortality (OR 0.58, 95% CI 0.37 to 0.92) and cardiovascular mortality (OR 0.55, 95% CI 0.31 to 0.98), and had a neutral effect on myocardial infarction, stroke, severe hypoglycaemia and diabetic retinopathy. However, treatment with oral semaglutide increased the incidence of nausea, vomiting and diarrhea, while events of acute pancreatitis were rare. CONCLUSIONS: Oral semaglutide can effectively and safely reduce blood glucose, body weight and systolic blood pressure. Nevertheless, it is associated with increased incidence of gastrointestinal adverse events. Further research is needed to clarify its long-term safety and comparative effectiveness against other antidiabetic agents.

Glucagon-like peptide-1 receptor agonists and microvascular outcomes in type 2 diabetes: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on microvascular endpoints in adult patients with type 2 diabetes. We included 60 studies with 60 077 patients. GLP-1 RAs marginally reduced urinary albumin-to-creatinine ratio compared with placebo or other antidiabetic agents (weighted mean difference - 2.55 mg/g; 95% confidence interval [CI] -4.37 to -0.73 and -5.52; -10.89 to -0.16, respectively) and had no clinically relevant effect on change in estimated glomerular filtration rate. Treatment with GLP-1 RAs did not increase incidence of diabetic retinopathy, macular oedema, retinal detachment and retinal haemorrhage, irrespective of comparator. Nevertheless, incidence of vitreous haemorrhage was higher in subjects treated with GLP-1 RAs compared with placebo (odds ratios 1.93; 95% CI 1.09 to 3.42). In conclusion, GLP-1 RAs are safe regarding nephropathy- and retinopathy-related outcomes. Caution may be warranted for incidence of vitreous haemorrhage. The low overall quality of evidence highlights the need for consistent assessment and reporting of microvascular endpoints in future trials.

Effect of liraglutide on ambulatory blood pressure in patients with hypertension and type 2 diabetes: A randomized, double-blind, placebo-controlled trial.

AIMS: To assess the effect of liraglutide on 24-hour ambulatory blood pressure and heart rate in patients with hypertension (pre- and stage 1 hypertension) and inadequately controlled Type 2 diabetes (glycated haemoglobin 7%-10% [53-86 mmol/mol]). MATERIALS AND METHODS: Eligible patients for this investigator-initiated, parallel-group, randomized, double-blind trial were on stable background antihyperglycaemic therapy excluding insulin, glucagon-like peptide-1 receptor agonists and dipeptidyl-peptidase-4 inhibitors. Participants were centrally randomized in a 1:1 ratio to daily liraglutide 0.6 mg, titrated to 1.2 mg after the first week, or placebo for 5 weeks. The primary outcome was change in 24-hour ambulatory systolic blood pressure (SBP), and secondary outcomes included change in ambulatory diastolic blood pressure (DBP) and heart rate. We also assessed renal sodium handling. RESULTS: Of 87 patients assessed for eligibility, 62 (66.1% men) with a mean age of 60.2 years were randomized to liraglutide (n = 31) or placebo (n = 31). All participants received background therapy with metformin, whilst 35.5% were treated concomitantly with sulphonylureas and 14.5% with pioglitazone. Compared with placebo, liraglutide reduced 24-hour SBP by -5.73 mm Hg (95% confidence interval [CI] -9.81 to -1.65) and had a neutral effect on 24-hour DBP (mean difference - 1.42 mm Hg; 95% CI -4.25 to 1.40), whilst increasing 24-hour heart rate by 6.16 beats/min (95% CI 3.25 to 9.07). Findings were consistent for daytime and night-time measurements. Liraglutide did not increase urine sodium excretion. CONCLUSION: Based on 24-hour ambulatory measurements, short-term treatment with liraglutide had a favourable effect on SBP whilst increasing heart rate.

Semaglutide for type 2 diabetes mellitus: A systematic review and meta-analysis.

AIMS: To assess the efficacy and safety of semaglutide, a recently approved glucagon-like peptide 1 receptor agonist (GLP-1 RA) for type 2 diabetes. MATERIALS AND METHODS: We searched major electronic databases and grey literature sources for randomized controlled trials comparing semaglutide with placebo or other antidiabetic agents. Primary outcome was change from baseline in HbA1c. Secondary endpoints included change from baseline in body weight, blood pressure, heart rate and incidence of hypoglycaemia, gastrointestinal adverse effects, pancreatitis and diabetic retinopathy. RESULTS: A total of 6 placebo-controlled and 7 active-controlled studies with subcutaneous semaglutide were included. We identified only 1 trial with oral semaglutide. Compared with placebo, subcutaneous semaglutide 0.5 and 1 mg reduced HbA1c by 1.01% (95% CI, 0.56-1.47) and 1.38% (1.05-1.70), respectively. Both doses demonstrated superior glycaemic efficacy compared to other antidiabetic agents, including sitagliptin, exenatide, liraglutide, dulaglutide and insulin glargine. Semaglutide also had a beneficial effect on body weight (mean difference vs placebo -4.11 kg, 95% CI -4.85 to -3.37 for semaglutide 1 mg) and systolic blood pressure. We did not observe increased hypoglycaemia rates with semaglutide; nevertheless, we noted an increased incidence of nausea, vomiting and diarrhoea. Cases of pancreatitis were infrequent and the odds ratio for diabetic retinopathy compared with placebo was 1.32 (95% CI, 0.98-1.77). CONCLUSIONS: Semaglutide is a potent once-weekly GLP-1 RA, significantly reducing HbA1c, body weight and systolic blood pressure. However, it is associated with increased incidence of gastrointestinal adverse events. Results for pancreatitis and retinopathy require further assessment in post-approval pharmacovigilance studies.

Evaluation of the Greek TranQol: a novel questionnaire for measuring quality of life in transfusion-dependent thalassemia patients.

The aim of our study was to evaluate the Greek version of the transfusion-dependent quality of life (TranQol) questionnaire and report our experience of using this novel disease-specific quality of life (QoL) measure in patients with transfusion-dependent thalassemia (TDT). The TranQol and SF-36v2 questionnaires were administered to 94 adult TDT patients with a mean age of 32.1 years (SD = 7, range = 19-58), recruited from the Adult Thalassemia Unit of Hippokration General Hospital of Thessaloniki, Greece. The TranQol was evaluated in terms of construct validity, reliability, and responsiveness. There was a moderately strong correlation between the TranQol summary and both the SF-36v2 physical and mental component summaries (r = 0.4, p < 0.001 and r = 0.5, p < 0.001, respectively). There was also a moderately strong correlation between the physical health scale of TranQol and the relevant SF-36v2 scales, including physical functioning (r = 0.4, p < 0.001), role-physical (r = 0.6, p < 0.001), and bodily pain (r = 0.5, p < 0.001). TranQol also exhibited good internal consistency (Cronbach's alpha coefficient = 0.9) and excellent test-retest reliability (intra-class correlation coefficient = 0.9). The subgroup of patients that reported a better QoL 1 week after transfusion also demonstrated a significant improvement in their TranQol score. These are the first data regarding the administration of the Greek TranQol in a single thalassemia unit. The psychometric properties of the Greek TranQol confirmed it is a valid, reliable, and responsive to change questionnaire, which can be incorporated into future clinical trials.