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
Authors: Bidulka Patrick , Lugo-Palacios David G , Carroll Orlagh , O’Neill Stephen , Adler Amanda I , Basu Anirban , Silverwood Richard J , Bartlett Jonathan W , Nitsch Dorothea , Charlton Paul , Briggs Andrew H , Smeeth Liam , Douglas Ian J , Khunti Kamlesh , Grieve Richard 
Published: May 2024

Abstract

Objective
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.

Design
Cohort study emulating a comparative effectiveness trial (target trial).

Setting
Linked primary care, hospital, and death data in England, 2015-21.

Participants
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.

Main outcome measures

Primary outcome was absolute change in glycated haemoglobin A
1c
(HbA
1c
) 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 HbA
1c
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.

Results

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 HbA
1c
values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA
1c
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).

Conclusions

This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA
1c
, 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.