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Aim: To explore whether the beneficial cardiovascular (CV) effect of sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease. Methods: We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs). Results: We included 12 trials comprising 83 804 patients. SGLT‐2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor‐neprilysin inhibitors (ARNIs), b‐blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b‐blocker plus MRA, or an ARNI plus b‐blocker plus MRA (HRs ranged from 0.61 to 0.83; P >.1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all‐cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate. Conclusions: The benefit of SGLT‐2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified. [ABSTRACT FROM AUTHOR]

Eligibility criteria We included large-scale (>1000 patients), randomized, CVOTs comparing antidiabetic drugs versus placebo or active comparator in patients with type 2 diabetes regardless of background treatment or duration. Compared with the overall representation of women within the US population of patients with type 2 diabetes (47.8% of all patients), female participants were underrepresented (PPR = 0.73). Keywords: systematic review; antidiabetic drug; cardiovascular disease; type 2 diabetes EN systematic review antidiabetic drug cardiovascular disease type 2 diabetes 618 622 5 01/04/23 20230201 NES 230201 INTRODUCTION Representation of minority groups in clinical trials serves as a metric of social equity allowing for generalizability of research findings. For CVOTs assessing antidiabetic drugs in patients with or without type 2 diabetes, we utilized data only for the subgroup of patients with type 2 diabetes. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim To assess the efficacy and safety of recently approved once-weekly glucagon-like peptide 1 receptor agonists ( GLP-1 RAs) in patients with type 2 diabetes. Methods We conducted a systematic review and meta-analysis of randomized controlled trials comparing any GLP-1 RA licensed for once-weekly dosing (albiglutide, dulaglutide or exenatide extended release) with placebo or other antidiabetic agents. We searched Medline, Embase, the Cochrane Library and grey literature for articles published up to December 2014 and extracted data in duplicate. Results In our systematic review we included 33 trials with a total of 16 003 participants. Compared with placebo the change in glycated haemoglobin ( HbA1c) concentration was −0.66% [six studies; 95% confidence interval ( CI) −1.14 to −0.19; I2 = 88%] with albiglutide, and −1.18% (seven studies; 95% CI −1.34 to −1.02; I2 = 65%) with dulaglutide. Based on data from placebo-controlled trials, we did not detect statistically significant weight-sparing benefits for albiglutide or dulaglutide. Compared with other antidiabetic agents, once-weekly GLP-1 RAs outperformed sitagliptin, daily exenatide and insulin glargine in terms of HbA1c-lowering (mean differences −0.40%; 95% CI −0.66 to −0.14; I2 = 85%, −0.44%; 95% CI −0.58 to −0.29; I2 = 40% and −0.28; 95% CI −0.45 to −0.10; I2 = 81%, respectively). The main adverse effects of treatment included gastrointestinal and injection site reactions. Conclusions Given their dosing scheme and overall efficacy and safety profile, once-weekly GLP-1 RAs are a convenient therapeutic option for use as add-on to metformin. [ABSTRACT FROM AUTHOR]

Aim To assess the efficacy and safety of the novel sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin compared with placebo or other antidiabetic agents in patients with type 2 diabetes. Methods We conducted a systematic review and meta-analysis of randomized controlled trials. We searched Medline, Embase and the Cochrane Library through December 2013 and grey literature. Two reviewers working independently extracted relevant data and carried out risk-of-bias assessments. We synthesized results using random-effects models and computed weighted mean differences (WMDs) and odds ratios (ORs). Results We included 10 studies with 6203 participants. Compared with placebo, mean changes in haemoglobin A1c were −0.62% [95% confidence interval (CI) −0.68 to −0.57%] for empagliflozin 10 mg and −0.66% (−0.76 to −0.57%) for empagliflozin 25 mg. Empagliflozin 25 mg daily had glycaemic efficacy similar to metformin or sitagliptin (WMD −0.11%; 95% CI −0.25 to 0.03%), without increasing risk for hypoglycaemia. It was also associated with body weight loss (WMD −1.84; 95% CI −2.30 to −1.38 kg vs. placebo) and had a favourable effect on blood pressure. Incidence of hypoglycaemia with empagliflozin was similar to placebo (OR 1.10; 95% CI 0.87 to 1.39); nevertheless we noted an increased risk for genital tract infections (OR 3.31; 95% CI 1.55 to 7.09). Findings were similar for the 10-mg dosing regimen. Conclusions Empagliflozin effectively lowers blood glucose and provides additional clinical benefits including body weight and blood pressure reduction. Ongoing trials will elucidate the long-term safety and effect of empagliflozin on cardiovascular outcomes. [ABSTRACT FROM AUTHOR]