Durability of glycaemic control in patients with type 2 diabetes after metformin failure: Prognostic model derivation and validation using the DISCOVER study

Abstract

Aim: To develop and internally validate prognostic models on the long-term durability of glycaemic control in patients with type 2 diabetes after metformin failure.Materials and Methods: DISCOVER is a 3-year, prospective observational study across six continents investigating second-line glucose-lowering therapies. In this analysis from 35 countries, we included patients on metformin initiating secondline glucose-lowering medication(s) because of physician-defined lack of efficacy.The outcome was durability of glycaemic control, defined as three consecutive levels of HbA1c at 6-, 12-and 24-month follow-up at target (HbA1c equal to or lower than the level when the physician initiated the second-line therapy in patients with baseline HbA1c ≤7% [53 mmol/mol]; and equal to or lower than 7% in those with baseline HbA1c >7%). We developed and internally validated two prognostic models: a base model, which included age, sex, ethnicity, country income group, baseline HbA1c and second-line therapy, and an advanced model, established through statistical variable selections from a model including base variables and 13 additional predictors selected from a literature review. We used logistic regression to develop and 500 bootstrapping samples to internally validate the models; discrimination and calibration were used to assess model performance.Results: Overall, 896 out of 2995 participants (29.9%) had sustained glycaemic control. The base model performed well: Nagelkerke R 2 was 0.13, C-index 0.70 (95% CI: 0.68, 0.71) and bias-corrected C-index 0.69 after internal validation. Diabetes duration, insurance type, estimated glomerular filtration rate and glucose self-monitoring were additionally selected in the advanced model, which had only a slightly better performance compared with the base model: Nagelkerke R 2 0.20, C-index 0.71 (95% CI: 0.69, 0.73) and bias-corrected C-index 0.70. Calibration plots showed good calibrations of both validated models.

Durability of glycaemic control in type 2 diabetes: A systematic review and meta‐analysis for its association with body weight changes

“…For diabetes treatment, the main issue is not the achievement of glycaemic control but the long‐term maintenance of therapeutic efficacy. However, studies evaluating the long‐term effects of diabetes medications are scarce 7–10,17,18,29,42,43 ; hence, no meta‐analysis has compared treatment durability among therapies, and few studies have focused on the reasons for poor glycaemic control 3,44 …”

“…However, studies evaluating the long-term effects of diabetes medications are scarce [7][8][9][10]17,18,29,42,43 ; hence, no meta-analysis has compared treatment durability among therapies, and few studies have focused on the reasons for poor glycaemic control. 3,44 In current clinical studies, the time frame for evaluation of treatment durability is controversial. Follow-up longer than 26 weeks was recommended in DUAL VIII, 10 but 2 years was recommended in the A Diabetes Outcome Progression Trial (ADOPT) study.…”

“…Antidiabetic therapy durability is evaluated by the treatment failure rate, goal‐achievement (HbA1c <7.0%) rate, treatment intensification rate and coefficient of failure (CoF, annual increase in HbA1c). However, comparing durability among different studies is difficult as neither accepted uniform evaluation criteria nor optimal time frames have been established, and many clinical trials regarding the efficacy of hypoglycaemic therapies are not sufficiently long to assess therapeutic durability 3 …”

“…However, comparing durability among different studies is difficult as neither accepted uniform evaluation criteria nor optimal time frames have been established, and many clinical trials regarding the efficacy of hypoglycaemic therapies are not sufficiently long to assess therapeutic durability. 3 Decreased beta-cell function is principally responsible for the loss of glycaemic control and largely explains the difficulty of maintaining target HbA1c levels. 4 Loss of glucose-lowering efficacy over time has commonly been found in existing long-term studies regardless of monotherapy, [5][6][7][8] combination therapy 9 or insulin treatment.…”