Progression of glucose‐lowering diabetes therapy in TECOS

Abstract

Summary Aims TECOS was a randomized, double‐blind, placebo‐controlled trial assessing the impact of sitagliptin vs. placebo on cardiovascular outcomes when added to usual care in patients with type 2 diabetes. We report the use of concomitant diabetes medications and the risk for progression to insulin during follow‐up. Materials and Methods TECOS enrolled 14 671 participants with HbA1c 6.5%‐8.0% on monotherapy with metformin, pioglitazone, sulfonylurea (SU), or dual therapy with two oral agents or insulin with or without metformin. Subsequent diabetes management was by the participant's usual care physician. Time to initiation of insulin and risk of hypoglycaemia were estimated using Cox proportional hazards models. Results The most common glucose‐lowering regimens at baseline were metformin monotherapy (30.2%), SU monotherapy (8.5%), metformin/SU therapy (35.1%), and insulin with or without metformin (13.9% and 8.6%, respectively). Over a median 3.0 years’ follow‐up, diabetes therapy was intensified in 25.2% of participants (sitagliptin 22.0%, placebo 28.3%). Medications most commonly added were SU (8.3%) or insulin (8.8%). Insulin initiation in the usual care setting occurred at mean (standard deviation) HbA1c of 8.5 (1.5)%. Sitagliptin did not impact rates of severe hypoglycaemia, but delayed progression to insulin when added to metformin or metformin/SU regimens. Conclusion Consistent with the trial's pragmatic design, TECOS participants underwent typical progression of diabetes medications. Sitagliptin was associated with lower HbA1c, without increased risk for severe hypoglycaemia and was associated with delayed progression to insulin when added to metformin with or without SU.

Lower risk of death and cardiovascular events in patients with diabetes initiating glucagon‐like peptide‐1 receptor agonists or sodium‐glucose cotransporter‐2 inhibitors: A real‐world study in two Italian cohorts

“…A sensitivity analysis with first‐time users of DPP‐4 inhibitors as a comparator cohort was also carried out. This comparison allowed assessment of the effects of GLP‐1RAs and SGLT2 inhibitors versus a drug class—DPP‐4 inhibitors—known to exhibit neutral effects on major CV outcomes in T2D patients 33–36 ; moreover, GLP‐1RAs, SGLT2 inhibitors and DPP‐4 inhibitors are prescribed only by diabetes specialists in Italy.…”

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“…However, treating blood glucose levels is not going to prevent the development of vascular pathology in diabetes. This was confirmed in seven multinational, multi-center, randomized controlled trials of tight blood glucose control with medications (ACCORD, ADVANCE, VADT, ORIGIN, ELIXA, TECOS and SAVOR) [10][11][12][13][14][15][16]. They all failed to demonstrate reductions in heart disease, the major cause of death of persons with diabetes [17].…”

Association between glycated haemoglobin levels and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the TECOS randomized clinical trial

“…Sixth, although some may argue that the outcome differences may have been driven by differences in concomitant medication use, we adjusted for use of aspirin, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statin, and glucose-lowering therapies in our multivariate models, <2.5% of patients were on thiazolidinediones or glucagon-like peptide-1 receptor agonists during the trial, none were taking a sodium-glucose co-transporter 2 inhibitor, and up-titration of glycaemic therapies largely occurred in patients with marked hyperglycaemia during follow-up (the mean HbA 1c when agents were added was 8.5%). 13 Thus, it would not alter our finding of a HbA 1c nadir of 7% but may have underestimated the magnitude of excess risk for patients with markedly elevated HbA 1c . In the same vein, given a prior TECOS sub-study demonstrated a U-shaped association between baseline blood pressure assessments and cardiovascular outcomes, 24 we adjusted for systolic blood pressure in our multivariable analyses.…”

“…It is important to note that the association between HbA 1c levels and outcomes that we observed is not due to use of glucose-lowering therapies known to modify HF risk independent of glycaemic effects: less than 2.4% of TECOS participants were taking a thiazolidinedione or a glucagon-like peptide-1 receptor agonist, and none a sodium-glucose co-transporter 2 inhibitor. 4,13,14 While the meta-analysis of 12 cardiovascular outcome trials in T2D discussed in our Introduction reported no correlation between HbA 1c values and risk of HF events, 2 none of those trials specifically targeted HbA 1c reduction. For at least some of the agents with demonstrated cardiovascular efficacy in T2D, their impacts appear to be independent of their glucose-lowering effects.…”