Comparison of cardiovascular and metabolic outcomes in people with type 2 diabetes on insulin versus non-insulin glucose-lowering therapies (GLTs): A systematic review and meta-analysis of clinical trials

Abstract

Objectives: To compare the cardiovascular and metabolic outcomes of Insulin versus noninsulin glucose lowering therapy (GLT).Methods: We included randomised control trials (RCTs) which randomised patients aged >18 years with Type 2 Diabetes (T2D) to insulin vs non-insulin GLT. We used risk ratios (RR), risk difference (RD) and odds ratios (OR) with 95% confidence interval (95%CI) to analyse the treatment effects of dichotomous outcomes and mean differences (with 95% CI) for continuous outcomes.Results: We included 18 RCTs with 19,300 participants. There was no significant difference in the risk of all-cause mortality and CV events between the groups (RR= 1.01; 95%CI: 0.96 -1.06; p = 0.69). In 16 trials, insulin showed greater efficacy in glycaemic control (mean diff= -0.20; 95%CI: -0.28 to -0.11 but the proportion achieving HbA1c level of either ≤7.0% or 7.4% (53 or 57mmol/mol) was similar in both (OR=1.55; 95%CI= 0.92 to 2.62). The non-insulin group had a significant reduction in weight (mean diff = -3.41; 95%CI: -4.50 to -2.32) and an increase in the proportion of adverse events (54.7% vs 45.3%, p= 0.044), but the insulin group showed an (RR= 1.90; 95%CI: 1.44 to 2.51) increased risk of hypoglycaemia.Conclusion: There was no difference in the risk of all-cause mortality and adverse cardiovascular (CV) events between Insulin and non-insulin GLTs. Insulin was associated with superior reduction in HbA1c; least reduction in weight and higher risk of hypoglycaemia. Both showed similar proportion of patients achieving HbA1c target. Noninsulin GLTs were associated with a higher risk in reported adverse drug events.3 | P a g e Introduction:For many patients with type 2 diabetes (T2D), treatment intensification using additional antihyperglycaemic agents is required in order to achieve optimal glycaemic control and prevent long-term vascular complications.[1, 2] A variety of antihyperglycaemic agents are available but questions regarding the long term safety and efficacy of some of these agents have been raised. In addition, recent focus by international regulatory agencies on the cardiovascular (CV) safety profile of commonly used antihyperglycaemic agents [3,4] have led to debate about the most appropriate choice of therapy for treatment intensification.Amidst this, exogenous insulin remains to be one of the most established glucose lowering therapies available [5][6][7][8][9][10] and its use in people with T2D has grown markedly over recent years. More recently however, the effectiveness and safety of insulin therapy has been a subject of intense discussion.[11-13] Moreover, recent large epidemiological studies have reported adverse cardiovascular CV outcome and increase mortality with insulin compared with non-insulin therapy. [13, 14] While the possible mechanism behind the observed the association between insulin and adverse cardiovascular and metabolic outcomes and mortality remains unclear, it is hypothesized that these may include, but not limited to, hypoglycaemia and weight gain. Although insulin the...

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

“…Early insulin did not significantly alter a composite CV outcome of CV death, non-fatal MI and stroke, revascularization and hospitalization for heart failure compared with standard care (HR 1.04; 95% CI 0.97-1.11; P = 0.27).P = 0.71) and CV mortality (RR 0.99, 95% CI 0.90-1.09; P = 0.94) versus patients treated with other glucose-lowering medications, and similar rates versus those treated with diet or placebo (RR 0.92, 95% CI 0.80-1.07; P = 0.31, and RR 0.95, 95% CI 0.77-1.18; P = 0.64, respectively] 51. Consistent with these findings, another meta-analysis of 18 randomized trials in a total of 19 300 people with type 2 diabetes found no significant difference in the risk of all-cause mortality and CV events between groups treated with insulin compared with other glucose-lowering agents (RR 1.01, 95% CI 0.96-1.06; P = 0.69) 52. Extensive evidence from type 1 diabetes, especially with the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, indicates that insulin therapy does not increase CV risk 53.…”

“…A meta‐analysis of 20 randomized trials involving 18 599 patients with type 2 diabetes found that those treated with insulin had similar rates of all‐cause mortality (relative risk [RR] 0.99; 95% CI 0.92‐1.06; P = 0.71) and CV mortality (RR 0.99, 95% CI 0.90‐1.09; P = 0.94) versus patients treated with other glucose‐lowering medications, and similar rates versus those treated with diet or placebo (RR 0.92, 95% CI 0.80‐1.07; P = 0.31, and RR 0.95, 95% CI 0.77‐1.18; P = 0.64, respectively] . Consistent with these findings, another meta‐analysis of 18 randomized trials in a total of 19 300 people with type 2 diabetes found no significant difference in the risk of all‐cause mortality and CV events between groups treated with insulin compared with other glucose‐lowering agents (RR 1.01, 95% CI 0.96‐1.06; P = 0.69) …”

Effects on clinical outcomes of intensifying triple oral antidiabetic drug (OAD) therapy by initiating insulin versus enhancing OAD therapy in patients with type 2 diabetes: A nationwide population‐based, propensity‐score‐matched cohort study

“…Favourable cardiovascular outcomes of intensive glycaemic control using sulphonylureas or insulin versus conventional therapy using diet control were documented in the 10‐year follow‐up UK Prospective Diabetes Study; however, other RCTs either showed no significant benefits of insulin therapy on cardiovascular outcomes or revealed a link between insulin‐based therapy and a greater number of non‐fatal cardiovascular events . Recently, two meta‐analyses of RCTs suggested a neutral effect of insulin therapy on cardiovascular outcomes . These study findings should be interpreted with caution, however, because the studies included a limited number of cardiovascular events and shorter follow‐up periods, the sulphonylureas used might also have had detrimental effects on cardiovascular disease (CVD), and the study populations were specific to either patients at an early stage of diabetes or those with existing CVD .…”

“…13 Recently, two meta-analyses of RCTs suggested a neutral effect of insulin therapy on cardiovascular outcomes. 14,15 These study findings should be interpreted with caution, however, because the studies included a limited number of cardiovascular events and shorter follow-up periods, the sulphonylureas used 10,12 might also have had detrimental effects on cardiovascular disease (CVD), 16 and the study populations were specific to either patients at an early stage of diabetes 11 or those with existing CVD. 12,13 Conversely, longitudinal cohort studies have shown an association between insulin therapy and increased risk of CVD and all-cause mortality in patients with T2DM, but the effects of insulin therapy were only assessed in patients at an early stage of the antidiabetic treatment course, with insulin being used as monotherapy, or as second-line or third-line antidiabetic treatment.…”

Specialist Advice Does Not Modify the Risk of Death of Diabetic 2 Patients

“…The role of insulin should be considered carefully, turning out to be an important predictor of death. A meta-analysis of RCTs found no difference in the risk of all-cause mortality [RR= 1.00 (0.93 -1.08)] between Insulin and non-insulin glucose-lowering therapies in diabetes2 patients but at the same time it found an increased risk of hypoglycemia: RR= 1.90 (1.44 -2.51) [21]. In our observational approach the identification of the precise role of insulin as an independent predictor of death should have required other adjustments for clinical indicators of severity and for complications of diabetic disease and its treatment, but this was not the purpose of this research.…”