Sodium-glucose co-transporter-2 inhibitors, the latest residents on the block: Impact on glycaemic control at a general practice level in England.

To determine, using published general practice-level data, how differences in Type 2 diabetes mellitus (T2DM) prescribing patterns relate to glycaemic target achievement levels. Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of different classes of medication in 2015/2016 and changes between that year and the year 2014/2015 in medication to proportion of patients achieving target glycaemic control (glycated haemoglobin A1c [HbA1c] ≤58 mmol/mol [7.5%]) and proportion of patients at high glycaemic risk (HbA1c >86 mmol/mol [10.0%]) for practices in the National Diabetes Audit with >100 people with T2DM on their register. Overall, HbA1c outcomes were not different between the years studied. Although, in percentage terms, most practices increased their use of sodium-glucose co-transporter-2 (SGLT2) inhibitors (96%), dipeptidyl peptidase-4 (DPP-4) inhibitors (76%) and glucagon-like peptide 1 (GLP-1) analogues (53%), there was wide variation in the use of older and newer therapies. For example, 12% of practices used >200% of the national average for some newer agents. In cross-sectional analysis, greater prescribing of metformin and analogue insulin were associated with a higher proportion of patients achieving HbA1c ≤58 mmol/mol; the use of SGLT2 inhibitors and metformin was associated with a reduced proportion of patients with HbA1c >86 mol/mol; otherwise associations for sulphonylureas, GLP-1 analogues, SGLT2 inhibitors and DPP-4 inhibitors were neutral or negative. In year-on-year analysis there was ongoing deterioration in glycaemic control, which was offset to some extent by increased use of SGLT2 inhibitors and GLP-1 analogues, which were associated with a greater proportion of patients achieving HbA1c levels ≤58 mmol/mol and a smaller proportion of patients with HbA1c levels >86 mmol/mol. SGLT2 inhibitor prescribing was associated with significantly greater improvements than those found for GLP-1 analogues. Greater use of newer agents was associated with improvement in glycaemic outcomes but was not sufficient to compensate for the prevailing decline. This may reflect wide variability in the prescribing of newer agents. We found that SGLT inhibitors may be superior to other oral agents in relation to HbA1c outcome. Serious consideration should be given to their use.

Heald AH ，Fryer AA ，Anderson SG ，Livingston M ，Lunt M ，Davies M ，Moreno GYC ，Gadsby R ，Young RJ ，Stedman M ... -  《-》

Improving type 2 diabetes mellitus glycaemic outcomes is possible without spending more on medication: Lessons from the UK National Diabetes Audit.

To determine the factors at general practice level that relate to glycaemic control outcomes in people with type 2 diabetes (T2DM). Data were accessed from 4050 general practices (50% of total) covering 1.6 million patients with T2DM in the UK National Diabetes Audit 2013 to 2014 and 2014 to 2015. This audit reported characteristics, services and outcomes in the T2DM population, including percentage of patients who had total glycaemic control (TGC), defined as glycated haemoglobin (HbA1c) ≤7.5% (58 mmol/mol), and the percentage who were at higher glycaemic risk (HGR), defined as HbA1c >10% (86 mmol/mol); the respective figures were 67.2% and 6.2%. The medication data were examined in terms of annual defined daily doses (DDDs). Multivariate linear regression analysis was used to identify associations between DDD and patient and practice characteristics. Over the period 2012/2013 to 2015/2016, patient numbers grew 4% annually and annual medication expenditure by 8%, but glycaemic control outcomes did not improve. The main findings were that practices with better outcomes: had a higher percentage of patients aged >65 years; provided more effective diabetes services (including case identification, care checks, patient education, percentage of patients with blood pressure and cholesterol under control and more patients with type 1 diabetes achieving target HbA1c levels); spent less overall on prescribing per patient with T2DM; and on average, prescribed fewer sulphonylureas, less insulin (for patients with T2DM), fewer glucagon-like peptide-1 agonists, more metformin, more dipeptidyl peptidase-4 inhibitors, and more blood glucose monitoring strips. Ethnicity and social disadvantage and levels of thiazolidinedione (glitazone) prescribing had no significant impact on outcomes. Sodium-glucose co-transporter-2 inhibitor use was too low for an effect to be observed in the period examined. If all practices brought their service and medication to the level of the top decile practices, they could achieve 74.7% compared with the median of 67.3% of patients achieving TGC, showing an increase of 213 000 in patients achieving TGC, while reducing the number at HGR to 3.8% compared with 6.1%, benefiting 62 000 patients. This could have a major impact on the overall consequent healthcare costs of managing diabetes complications with their attendant mortality risks.

Heald AH ，Livingston M ，Malipatil N ，Becher M ，Craig J ，Stedman M ，Fryer AA ... -  《-》

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 ... -  《-》

Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data.

To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice. Cohort study emulating a comparative effectiveness trial (target trial). Linked primary care, hospital, and death data in England, 2015-21. 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin. Primary outcome was absolute change in glycated haemoglobin A1c (HbA1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures. 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA1c change between baseline and one year were -2.5 mmol/mol (95% confidence interval (CI) -3.7 to -1.3) for SGLT-2 inhibitors versus sulfonylureas and -3.2 mmol/mol (-4.6 to -1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking-the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43). This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (v DPP-4 inhibitors) and kidney disease progression (v sulfonylureas), with no evidence of differences in other clinical endpoints.

Bidulka P ，Lugo-Palacios DG ，Carroll O ，O'Neill S ，Adler AI ，Basu A ，Silverwood RJ ，Bartlett JW ，Nitsch D ，Charlton P ，Briggs AH ，Smeeth L ，Douglas IJ ，Khunti K ，Grieve R ... -  《BMJ-British Medical Journal》

Development of a treatment selection algorithm for SGLT2 and DPP-4 inhibitor therapies in people with type 2 diabetes: a retrospective cohort study.

Current treatment guidelines do not provide recommendations to support the selection of treatment for most people with type 2 diabetes. We aimed to develop and validate an algorithm to allow selection of optimal treatment based on glycaemic response, weight change, and tolerability outcomes when choosing between SGLT2 inhibitor or DPP-4 inhibitor therapies. In this retrospective cohort study, we identified patients initiating SGLT2 and DPP-4 inhibitor therapies after Jan 1, 2013, from the UK Clinical Practice Research Datalink (CPRD). We excluded those who received SGLT2 or DPP-4 inhibitors as first-line treatment or insulin at the same time, had estimated glomerular filtration rate (eGFR) of less than 45 mL/min per 1·73 m2, or did not have a valid baseline glycated haemoglobin (HbA1c) measure (<53 or ≥120 mmol/mol). The primary efficacy outcome was the HbA1c value reached 6 months after drug initiation, adjusted for baseline HbA1c. Clinical features associated with differential HbA1c outcome on the two therapies were identified in CPRD (n=26 877), and replicated in reanalysis of 14 clinical trials (n=10 414). An algorithm to predict individual-level differential HbA1c outcome on the two therapies was developed in CPRD (derivation; n=14 069) and validated in head-to-head trials (n=2499) and CPRD (independent validation; n=9376). In CPRD, we further explored heterogeneity in 6-month weight change and treatment discontinuation. Among 10 253 patients initiating SGLT2 inhibitors and 16 624 patients initiating DPP-4 inhibitors in CPRD, baseline HbA1c, age, BMI, eGFR, and alanine aminotransferase were associated with differential HbA1c outcome with SGLT2 inhibitor and DPP-4 inhibitor therapies. The median age of participants was 62·0 years (IQR 55·0-70·0). 10 016 (37·3%) were women and 16 861 (62·7%) were men. An algorithm based on these five features identified a subgroup, representing around four in ten CPRD patients, with a 5 mmol/mol or greater observed benefit with SGLT2 inhibitors in all validation cohorts (CPRD 8·8 mmol/mol [95% CI 7·8-9·8]; CANTATA-D and CANTATA-D2 trials 5·8 mmol/mol [3·9-7·7]; BI1245.20 trial 6·6 mmol/mol [2·2-11·0]). In CPRD, predicted differential HbA1c response with SGLT2 inhibitor and DPP-4 inhibitor therapies was not associated with weight change. Overall treatment discontinuation within 6 months was similar in patients predicted to have an HbA1c benefit with SGLT2 inhibitors over DPP-4 inhibitors (median 15·2% [13·2-20·3] vs 14·4% [12·9-16·7]). A smaller subgroup predicted to have greater HbA1c reduction with DPP-4 inhibitors were twice as likely to discontinue SGLT2 inhibitors than DPP-4 inhibitors (median 26·8% [23·4-31·0] vs 14·8% [12·9-16·8]). A validated treatment selection algorithm for SGLT2 inhibitor and DPP-4 inhibitor therapies can support decisions on optimal treatment for people with type 2 diabetes. BHF-Turing Cardiovascular Data Science Award and the UK Medical Research Council.

Dennis JM ，Young KG ，McGovern AP ，Mateen BA ，Vollmer SJ ，Simpson MD ，Henley WE ，Holman RR ，Sattar N ，Pearson ER ，Hattersley AT ，Jones AG ，Shields BM ，MASTERMIND consortium ... -  《The Lancet Digital Health》