Type 2 diabetes subgroups and response to glucose‐lowering therapy: Results from the EDICT and Qatar studies

Abstract

Aim To examine the efficacy of glucose‐lowering medications in subgroups of patients with type 2 diabetes mellitus (T2DM). Research design and methods Cluster analysis was performed in participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study and the Qatar study using age, body mass index (BMI), glycated haemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA‐IR) and beta‐cell function (HOMA‐β). Participants also underwent an oral glucose tolerance test with measurement of plasma glucose, insulin and C‐peptide concentrations to derive independent measures of insulin secretion and insulin sensitivity. The response to glucose‐lowering therapies (change in HbA1c) was measured in each participant cluster for 3 years. Results Three distinct and comparable clusters/groups of T2DM patients were identified in both the EDICT and Qatar studies. Participants in Group 1 had the highest HbA1c and manifested severe insulin deficiency. Participants in Group 3 had comparable insulin sensitivity to those in Group 1 but better beta‐cell function and better glucose control. Participants in Group 2 had the highest BMI with severe insulin resistance accompanied by marked hyperinsulinaemia, which was primarily attributable to decreased insulin clearance. Unexpectedly, participants in Group 1 had better response to combination therapy with pioglitazone plus exenatide than with insulin therapy or metformin sequentially followed by glipizide and basal insulin, while participants in Group 2 responded equally well to both therapies despite very severe insulin resistance. Conclusion Distinct metabolic phenotypes characterize different T2DM clusters and differential responses to glucose‐lowering therapies. Participants with severe insulin deficiency respond better to agents that preserve beta‐cell function, while, surprisingly, patients with severe insulin resistance did not respond favourably to insulin sensitizers.

Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study

“…This is confirmed by the many metabolites discussed above that are related to insulin resistance. Results from Qatari patients with severe insulin resistance showed that these patients did not respond adequately to insulin sensitizers such as metformin [ 75 ]. This may explain the low efficacy of metformin in the case of severe insulin resistance.…”

Treatment responses to basal insulin glargine 300 U/ml and glargine 100 U/ml in newly defined subphenotypes of type 2 diabetes: A post hoc analysis of the EDITION 3 randomized clinical trial

“…4,10 FCP has been shown to be an equivalent cluster variable to originally used HOMA2 parameters for the assignation of participants into the four T2D subphenotypes. 6,9 All clinical outcomes (HbA1c, FPG, glycaemic outcome achievement, insulin dose, hypoglycaemia, body weight) were assessed at baseline and over the 26-week study period following the introduction of either IGlar-300 or IGlar-100, administered once-daily before bedtime, and titrated once-weekly to achieve a target FPG of <5.6 mmol/L (<100 mg/dl). Hypoglycaemia was determined according to the international consensus on definition as agreed by ADA/ EASD 12 using a confirmed plasma glucose (PG) value of ≤3.9 mmol/L (level 1) and <3.0 mmol/L (level 2) (≤70 or <54 mg/dl).…”

“…Variables that included age at onset of known diabetes, HbA1c, body mass index (BMI) and fasting C‐peptide (FCP) at baseline were scaled and centred for each participant and then assigned to one of the four T2D subphenotypes to which they were most similar, as estimated by the smallest Euclidean distance to subphenotype centroids derived from ANDIS coordinates 4,10 . FCP has been shown to be an equivalent cluster variable to originally used HOMA2 parameters for the assignation of participants into the four T2D subphenotypes 6,9 …”

“…The SIDD subphenotype responded better to basal insulin than to standard‐of‐care (OADs only) treatment as shown in the ORIGIN trial 8 . One study indicated that the SIRD subphenotype may benefit more from treatment with pioglitazone, 7 although this finding has not been replicated 9 . Results from a large, pooled analysis of insulin‐naïve study participants with T2D who were above glycated haemoglobin (HbA1c) targets with OADs showed that basal insulin glargine 100 U/ml (IGlar‐100) treatment achieved similar reductions in HbA1c and fasting plasma glucose (FPG) at 6 months in all T2D subphenotypes.…”

“…8 One study indicated that the SIRD subphenotype may benefit more from treatment with pioglitazone, 7 although this finding has not been replicated. 9 Results from a large, pooled analysis of insulin-naïve study participants with T2D who were above glycated haemoglobin (HbA1c) targets with OADs showed that basal insulin glargine 100 U/ml (IGlar-100) treatment achieved similar reductions in HbA1c and fasting plasma glucose (FPG) at 6 months in all T2D subphenotypes. Optimal glycaemic control was only achieved in MARD, whereas in the SIDD subphenotype the HbA1c levels failed to reach target levels.…”