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

Abstract

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.

Strategically Playing with Fire: SGLT Inhibitors as Possible Adjunct to Closed-Loop Insulin Therapy

“…29 Glucagon-like Peptitde-1 (GLP1)-receptor agonists have demonstrated conflicting outcomes in benefits as adjunct to T1D care, both with and without HCL. 24-27,30-33 The effect of dipeptitdyl peptidase-4 inhibitors is not as significant compared to other adjunctive agents in T1D, 34 with one inpatient study demonstrating reduced post-prandial glycemia with sitagliptin using HCL. 27 While pramlintide has been studied as an injectable pharmacotherapy adjunct to routine insulin therapy or integrated into HCL, 19,24,25 and has shown benefits, 22,24 its clinical application is limited by the lack of an existing co-formulation with insulin and the need for separate injections or infusion systems.…”

Liraglutide changes body composition and lowers added sugar intake in overweight persons with insulin pump‐treated type 1 diabetes

“…[4][5][6][7][8] A number of add-ons to insulin with the potential to improve glucose levels while sustaining or even reducing body weight has been investigated in open-and closed-loop therapies. [9][10][11][12] In particular, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide has been the target of study in clinical trials in different subgroups of persons with T1D. [13][14][15][16][17][18][19][20][21] A recent meta-analysis of randomized controlled trials of at least 4 weeks' duration showed that when liraglutide is added to insulin therapy, persons with T1D on average achieve a decrease in HbA1c of 2 mmol/mol (0.2%) and a 3.85-kg weight loss.…”

“…A number of add‐ons to insulin with the potential to improve glucose levels while sustaining or even reducing body weight has been investigated in open‐ and closed‐loop therapies 9‐12 . In particular, the glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide has been the target of study in clinical trials in different subgroups of persons with T1D 13‐21 .…”

“…In particular, the glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide has been the target of study in clinical trials in different subgroups of persons with T1D 13‐21 . A recent meta‐analysis of randomized controlled trials of at least 4 weeks' duration showed that when liraglutide is added to insulin therapy, persons with T1D on average achieve a decrease in HbA1c of 2 mmol/mol (0.2%) and a 3.85‐kg weight loss 12 …”

“…[13][14][15][16][17][18][19][20][21] A recent meta-analysis of randomized controlled trials of at least 4 weeks' duration showed that when liraglutide is added to insulin therapy, persons with T1D on average achieve a decrease in HbA1c of 2 mmol/mol (0.2%) and a 3.85-kg weight loss. 12 Currently, liraglutide is only approved for the treatment of type 2 diabetes, overweight and obesity, and its off-label use for the management of T1D is relatively limited. 2 Nevertheless, the combination of even a modest reduction of HbA1c and a moderate weight loss makes liraglutide an attractive therapeutic option for persons with T1D who struggle with glucose values and a body weight above the recommended levels despite dietary guidance, diabetes education and diabetes technology use.…”