Treatment intensification for patients with type 2 diabetes and poor glycaemic control.

To identify the time to and patient characteristics associated with treatment intensification in patients with type 2 diabetes (T2D) and poor glycaemic control. Using a large US insurance claims database, we conducted a retrospective cohort study among adult patients with T2D and glycated haemoglobin (HbA1c) ≥8% (index date) after ≥3 months of therapy including metformin. Patients were required to have continuous enrolment for at least 12 months before (baseline) and after index date, and no injectable antidiabetes medications. We defined treatment intensification as prescription fill for injectable or additional oral antidiabetic drugs (OADs). Cox modelling was performed to identify factors associated with time to treatment intensification. For the 11 525 patients meeting the inclusion criteria, the mean age at index date was 57 years, 40% were female and the mean index HbA1c was 9.1%. Overall, 37% of patients had their treatment intensified <6 months after, 11% had their treatment intensified 6-12 months after, and 52% did not have their treatment intensified <12 months after the index date. A higher index HbA1c was associated with early intensification [hazard ratio (HR) 1.18 for HbA1c ≥9 to <10% and HR 1.41 for HbA1c ≥10% compared with HbA1c ≥8 to <9%; p < 0.0001), and later line of therapy was associated with late intensification (HR 0.78 for metformin with one OAD and HR 0.68 for metformin with ≥2 OADs compared with metformin monotherapy; p < 0.0001). Fewer than half of patients with T2D and treatment failure received intensification within 12 months in a real-world US population. Factors associated with treatment inertia can be used to target clinical care for these patients.

Fu AZ ，Sheehan JJ 《-》

Long-term sustainability of glycaemic achievements with second-line antidiabetic therapies in patients with type 2 diabetes: A real-world study.

To inform patients and their carers about both the probability of reducing glycated haemoglobin (HbA1c) to clinically desirable levels and the sustainability of such control over 2 years with major second-line antidiabetic therapies, in individual risk scenarios, with and without third-line intensification. From US Centricity Electronic Medical Records, 163 081 patients with type 2 diabetes aged 18 to 80 years, who had initiated metformin, intensified their treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), sulphonylureas (SUs), insulin or thiazolidinediones (TZDs), and continued second-line treatment for ≥6 months, were selected. Treatment groups were balanced with regard to baseline characteristics, and glycaemic achievements were estimated using logistic regression analysis. With HbA1c concentrations of 58-63.9 mmol/mol (7.5-7.9%) at second-line treatment initiation, the adjusted probabilities of achieving HbA1c <53 mmol/mol (<7%) at 6 months were 32%, 38%, 39%, 26% and 38% in the SU, DPP-4 inhibitor, GLP-1RA, insulin and TZD groups, respectively, while with baseline HbA1c concentrations of 64-75 mmol/mol (8-9%), the corresponding probabilities of reducing HbA1c to <58 mmol/mol (<7.5%) were 38%, 44%, 40%, 34% and 42%, respectively. In these baseline HbA1c categories, the adjusted probabilities of sustaining HbA1c achievements over 2 years were higher in the GLP-1RA and TZD groups, compared with the SU and insulin groups (P < .01). With baseline HbA1c concentrations of 75.1-108 mmol/mol (9.1-12%) 38% of patients achieved an HbA1c concentration <58 mmol/mol (<7.5%) at 6 months. The adjusted probability of sustaining this control over 2 years was higher in the incretin and TZD groups (range 62%-75%), while insulin and SUs offered lower chances of sustainable control (range 54%-56%). Patients treated with second-line incretins and TZDs had a significantly higher probability of achieving and sustaining glycaemic control over 2 years without further intensification, compared with those treated with SUs or insulin.

Montvida O ，Shaw JE ，Blonde L ，Paul SK ... -  《-》

Change in glycated haemoglobin levels after initiating second-line therapy in type 2 diabetes: a primary care database study.

The aim of the present study was to compare the absolute reduction in glycated haemoglobin (HbA1c) levels at 6 months after initiating second-line glucose-lowering therapy in patients with type 2 diabetes treated with metformin monotherapy in general practices. A total of 7009 patients were identified (Disease Analyser Germany: January 2004 to December 2014). The patients' mean ± standard deviation (s.d.) age was 63 ± 11 years, 55.5% were male and their mean ± s.d. HbA1c level was 8.0 ± 1.6%. The initiated second-line therapies included: dipeptidyl peptidase-4 (DPP-4) inhibitors (38.7%); sulphonylureas (36.3%); insulin (13.3%); glucagon-like peptide-1 receptor agonists (GLP-1RAs; 2.5%); thiazolidinediones (5%); and other agents (glinides, aldose-reductase inhibitors; 4.1%). The mean absolute HbA1c change from baseline was -0.9% (DPP-4 inhibitors, -0.9%; sulphonylureas, -0.9%; insulin, -1.1%; GLP-1RAs, -0.7%; thiazolidinediones, -0.9%; and other, -0.7%; all p < 0.001). Overall, 58% of patients reached the HbA1c target of <7% (DPP-4 inhibitors, 61.7%; sulphonylureas, 56.7%; insulin, 45.6%; GLP-1RAs, 62.2%; thiazolidinediones, 69.7%; and other, 57.5%). Compared with sulphonlyureas, DPP-4 inhibitors, GLP-1RAs and thiazolidinediones were associated with an increased odds of reaching HbA1c <7% [odds ratio (OR) 1.24, 95% confidence interval (CI) 1.09-1.40; OR 1.43, 95% CI 1.01-2.04; and OR 1.70, 95% CI 1.30-2.23, respectively], whereas insulin was related to a lower odds (0.66, 95% CI 0.55-0.78). In conclusion, in patients with type 2 diabetes very similar reductions in HbA1c after 6 months of second-line therapy were achieved regardless of the type of therapy.

Rathmann W ，Bongaerts B ，Kostev K 《-》

Comparative cardiovascular safety of glucagon-like peptide-1 receptor agonists versus other antidiabetic drugs in routine care: a cohort study.

To evaluate the comparative cardiovascular disease (CVD) safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in head-to-head comparisons with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulphonylureas or insulin, when added to metformin, as used in 'real-world' patients with type 2 diabetes mellitus (T2DM). Within a large US commercial health plan database linked to laboratory test results, we identified three pairwise 1 : 1 propensity-score-matched cohorts of patients with T2DM aged ≥18 years treated with metformin who initiated a GLP-1 RA or a comparator, i.e. DPP-4 inhibitor (n = 35 534), second-generation sulphonylureas (n = 28 138) or insulin (n = 47 068), between 2005 and 2013. We examined the association between drug initiation and a composite CVD endpoint, comprising hospitalizations for acute myocardial infarction, unstable angina, stroke or coronary revascularization. During the course of 1 year, there were 13.9 and 13.7 CVD events per 1000 person-years among propensity-score-matched initiators of GLP-1 RAs versus DPP-4 inhibitors [hazard ratio (HR) 1.02; 95% confidence interval (CI) 0.84-1.24]; and 12.1 versus 14.0 events among initiators of GLP-1 RAs versus sulphonylureas (HR 0.86; 95% CI 0.69-1.08). The effect estimates for GLP-1 RAs versus insulin were sensitive to the adjustment for glycated haemoglobin, after which the HR was 1.01 (95% CI 0.73-1.41). Results were robust across several sensitivity analyses, including an as-treated analysis considering up to 8.7 years of follow-up. This large study, performing head-to-head comparisons of GLP-1 RAs with other antidiabetic agents in real-world patients, provides estimates of relative safety precise enough to exclude large differences in CVD risk and adds further understanding to results from recent clinical trials.

Patorno E ，Everett BM ，Goldfine AB ，Glynn RJ ，Liu J ，Gopalakrishnan C ，Kim SC ... -  《-》

Factors Associated with Type 2 Diabetes Mellitus Treatment Choice Across Four European Countries.

The aim of this analysis was to identify factors associated with the choice of type 2 diabetes mellitus (T2DM) therapy at the time of intensification of antidiabetic treatment across 4 European countries. Antidiabetic drug prescription/dispensing records and patients' characteristics were obtained from the electronic health care records of patients with T2DM from the Netherlands (NL), Italy, and Spain (ES) (all, 2007-2011); and the United Kingdom (UK; 2008-2012). Oral monotherapy was defined as first-line; oral dual therapy, as second-line; >2 oral treatments or oral combined with an injectable, as third-line; and injectables only, as fourth-line treatment. Treatment intensification was defined as the start of a higher line of treatment. Comedication, comorbidities, clinical parameters, and other factors associated with treatment choice were identified using multivariate relative risk estimation by Poisson regression with robust error variance. In the 5-year study period, 485,120 patients (79% of the treated T2DM population) underwent treatment intensification. Changes in treatment choice were clearly visible over the study period, such as a decline in the use of thiazolidinediones (NL, ES, UK) and increases in the use of dipeptidyl peptidase-4 inhibitors (DPP4i) (NL, ES, UK) and glucagon-like peptide-1 receptor agonists (UK). With first-line treatment, advanced age and renal comorbidity were associated with the use of sulfonylureas (SUs; all countries), whereas high body mass index (BMI) was inversely associated with SU use in the United Kingdom and Spain. With second-line treatment, advanced age was associated with metformin + SU use (all countries); and renal comorbidity with SU + DPP4i use in the United Kingdom and the Netherlands. High BMI was associated with metformin + thiazolidinedione (TZD) use in the United Kingdom and Spain, and with metformin + DPP4i in the United Kingdom. With third-line treatment, advanced age and renal comorbidity were associated with the use of SU + insulin (NL, ES, UK). Hemoglobin A1c >8.5% was positively associated, and high BMI was inversely associated, with the use of any third-line combination containing insulin. Across treatment lines TZD and metformin were negatively associated with renal and cardiac morbidity. Second and third line treatment choices strongly depended on prior treatments. With fourth-line treatment, women were more likely to receive glucagon-like peptide-1 receptor agonists than were men in the United Kingdom and Spain. The results suggest that the main factors driving treatment choice at any stage of intensification were age, hemoglobin A1c, BMI, renal and cardiac morbidity, and treatment history. These drivers were consistent with guidelines on, and contraindications of, specific medications. Differences between countries were generally consistent with, but not solely attributable to, differences in local guidelines and reimbursement policies.

Heintjes EM ，Overbeek JA ，Hall GC ，Prieto-Alhambra D ，Lapi F ，Hammar N ，Bezemer ID ... -  《-》