<scp>GLP</scp>‐1 receptor agonist added to insulin versus basal‐plus or basal‐bolus insulin therapy in type 2 diabetes: A systematic review and meta‐analysis

Aim: To compare the efficacy and safety of a glucagon-like peptide-1 receptor agonist (GLP1RA) plus basal insulin versus basal-bolus insulin treatment in patients with very uncontrolled type 2 diabetes. Materials and methods:The SIMPLE study was a 6-month pragmatic, randomized, open-label trial testing the effectiveness of two approaches to treat patients with type 2 diabetes and HbA1c ≥10%. We randomized patients to detemir plus liraglutide or detemir plus aspart (before each meal). The primary endpoint was change in HbA1c; changes in body weight, insulin dose, hypoglycaemia and diabetes-related quality-of-life were secondary outcomes.Results: We randomized 120 participants aged 47.4 ± 9.5 years, Hispanic 40%, African American 42%, diabetes duration 10 [25th-75th percentile (6 to 15)] years, body mass index 37.2 ± 10.3 kg/m 2 . HbA1c decreased more with GLP1RA plus basal insulin [12.2% (95% CI 11.8% to 12.6%) to 8.1% (95% CI 7.4% to 8.7%)] compared with basal-bolus insulin [11.8% (95% CI 11.5% to 12.2%) to 8.8% (95% CI 88.1% to 9.55%)]; estimated treatment difference (ETD) of −1.1% (95% CI −2.0% to −0.1%) (non-inferiority margin 0.4% and P = .0001, superiority P = .026). Compared with basal-bolus insulin, treatment with GLP1RA plus basal insulin led to a body weight ETD of −3.7 kg (95% CI −5.8 to −1.5; P = .001), fewer patients experiencing hypoglycaemia [66.1% vs 35.2% (P = .002)], and greater improvements in general/current health perception, treatment satisfaction, and fear of hypoglycaemia, while taking a lower total daily dose of insulin [estimated treatment ratio 0.68 (95% CI 0.55 to 0.84)].Conclusions: In patients with HbA1c ≥10% treatment with GLP1RA plus basal insulin, compared with basal-bolus insulin, resulted in better glycaemic control and body weight, lower insulin dosage and hypoglycaemia, and improved quality of life. This treatment strategy is an effective and safe alternative to a basal-bolus insulin regimen.

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A randomized trial comparing the efficacy and safety of treating patients with type 2 diabetes and highly elevated HbA1c levels with basal‐bolus insulin or a glucagon‐like peptide‐1 receptor agonist plus basal insulin: The SIMPLE study

Abreu

Tumyan

Elhassan

et al. 2019

“…BI and GLP‐1RAs potentiate each other by acting through different mechanisms in different tissues . Addition of GLP‐1RAs to a basal oral therapy is as effective as addition of bolus insulin with respect to glycaemic control, but with lower risk of hypoglycaemia and weight gain, and lower insulin doses . Therapeutic inertia in treating patients with uncontrolled T2D can worsen cardiovascular outcomes, and intensification of a basal oral regimen is often delayed in clinical practice while timely addition of a GLP‐1RA to BI could improve clinical and economic outcomes …”

Section: Introductionmentioning

confidence: 99%

“…7,8 Addition of GLP-1RAs to a basal oral therapy is as effective as addition of bolus insulin with respect to glycaemic control, but with lower risk of hypoglycaemia and weight gain, and lower insulin doses. 9 Therapeutic inertia in treating patients with uncontrolled T2D can worsen cardiovascular outcomes, 10 and intensification of a basal oral regimen is often delayed in clinical practice 11 13 However, many patients in clinical practice do not receive high doses of BI, implying that the GLP-1RA dose in the FRC may be under-titrated. Compared with FRCs, flexible combinations of BI and GLP-1RA are burdened by the higher numbers of injections and regimen complexity, but have the advantage of being able to combine any BI with any GLP-1RA, each at the desired dose.…”

Section: Introductionmentioning

confidence: 99%

Fixed versus flexible combination of GLP‐1 receptor agonists with basal insulin in type 2 diabetes: A retrospective multicentre comparative effectiveness study

Morieri

Rigato

Frison³

et al. 2019

Background and Aims The combination of basal insulin (BI) and GLP‐1 receptor agonists (GLP‐1RAs) is a rational and effective therapy for patients with uncontrolled type 2 diabetes (T2D). We compared the effectiveness of fixed and flexible BI/GLP‐1RA combinations using routinely accumulated clinical data. Methods This was a retrospective, multicentre, real‐world study concerning T2D patients initiating a fixed or flexible BI/GLP‐1RA combination (NCT03959865). The primary endpoint was change in HbA1c. Secondary endpoints were changes in body weight, fasting plasma glucose (FPG) and systolic blood pressure (SBP). Confounding was addressed by propensity score matching (PSM) or multivariable adjustment (MVA). Results A total of 609 patients were included in the study, 131 in the fixed group and 478 in the flexible group. The two groups differed in terms of diabetes duration, body weight and concomitant medications. After 5.7 months, observed HbA1c reductions were 0.6% and 0.8%, and body weight reductions were 2.8 kg and 1.2 kg in the flexible and fixed groups, respectively. Following PSM, HbA1c declined similarly in the two groups, whereas reduction in body weight was significantly in favour of the flexible combination. Findings were robust in sensitivity analyses, with the exception that, with MVA, a significantly higher reduction in HbA1c was detected in the fixed group. Final doses of BI were higher in the fixed group, whereas those of GLP‐1RA were higher in the flexible group. Conclusions In routine specialist care, initiation of the fixed or flexible BI/GLP‐1RA combination allowed similar improvement in glycaemic control, but greater weight loss was observed with the flexible combination. This difference reflected dosages of BI and GLP‐1RAs.

“…25 Among the reported 13 studies, AWARD-4 and AWARD-7 26 were the only studies evaluating the combination of a GLP-1 RA with up-titrated prandial insulin. However, results from the AWARD-4 study are in line with results from the combination of GLP-1 RAs with insulin that was evaluated in a recent meta-analysis in comparison to a basal-bolus or basal-plus regimen (mean body weight difference, −3.72 kg).…”

Section: Discussionmentioning

confidence: 99%

Weight loss in patients with type 2 diabetes receiving once‐weekly dulaglutide plus insulin lispro or insulin glargine plus insulin lispro: A post‐hoc analysis of the AWARD‐4 study across baseline body mass index subgroups

Fuechtenbusch¹,

Aberle

Heitmann

et al. 2019

Aims: Insulin-treated patients with type 2 diabetes (T2D) and obesity are challenged in achieving body weight stability or reduction, in addition to glycaemic control. Post-hoc analyses of body weight and insulin dose data from the AWARD-4 trial involved comparison of treatment with once-weekly dulaglutide 1.5 mg (N = 295) or 0.75 mg (N = 293) and treatment with daily insulin glargine (N = 296), each with prandial insulin lispro (± metformin).Materials and methods: Changes in weight and in the proportion of patients without weight gain or with weight loss of at least 3%, 5% or 10% or composites of HbA1c less than 7% without weight gain and weight loss of at least 3% after 52 weeks were compared between the dulaglutide (either dose) groups and the insulin glargine group, overall and by baseline BMI (<30, 30-<35, ≥35 kg/m 2 ), using analysis of covariance and logistic regression, including interaction terms. Results:The following parameters were statistically significant (P < 0.01) in favour of the dulaglutide-treated groups, at lower mean total daily insulin doses, vs the insulin glargine group.The achieved targets were more pronounced with dulaglutide 1.5 mg than with insulin glargine: LSM weight change difference, −3.23 kg; proportion of patients without weight gain, 49.0% vs 19.0%; proportion of patients with weight loss ≥3%, 21.7% vs 5.7% or with weight loss ≥5%, 10.5% vs 2.4%; proportion of patients with HbA1c <7% without weight gain, 26.2% vs 7.9%;proportion of patients with HbA1c <7% and weight loss ≥3%, 11.9% vs 1.4%, respectively. Treatment effect for these parameters was not significantly different across BMI categories.Conclusions: Larger proportions of patients in late-stage T2D needing treatment intensification achieved glycemic control without weight gain or with weight loss at lower insulin doses with once-weekly dulaglutide plus daily prandial insulin than with a basal-bolus insulin regimen, overall and across all three BMI subgroups.