Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach

MASTERMIND consortium; Laura M. Güdemann; Katie G. Young; Nicholas J.M. Thomas; Rhian Hopkins; Robert Challen; Angus G. Jones; Andrew T. Hattersley; Ewan R. Pearson; Beverley M. Shields; Jack Bowden; John M. Dennis; Andrew P. McGovern

doi:10.1007/s00125-024-06190-9

Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach

MASTERMIND consortium, Laura M. Güdemann (Lead / Corresponding author), Katie G. Young, Nicholas J.M. Thomas, Rhian Hopkins, Robert Challen, Angus G. Jones, Andrew T. Hattersley, Ewan R. Pearson, Beverley M. Shields, Jack Bowden, John M. Dennis, Andrew P. McGovern

Diabetes Endocrinology and Reproductive Biology

Research output: Contribution to journal › Article › peer-review

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Abstract

Aims/hypothesis: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis.

Methods: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013–2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument.

Results: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA_1c reduction was similar between SGLT2i and DPP4i (−0.3 mmol/mol [−1.6, 1.1], −0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (−4 mmol/mol [4.8, −3.1], −0.4% [−0.4, −0.3]).

Conclusions/interpretation: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes.

Original language	English
Number of pages	11
Journal	Diabetologia
DOIs	https://doi.org/10.1007/s00125-024-06190-9
Publication status	Published - 5 Jun 2024

Keywords

Causal analysis
Effectiveness
Older adults
Safety
SGLT2 inhibitors

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00125-024-06190-9Licence: CC BY

Final Published VersionFinal published version, 1.24 MBLicence: CC BY

Cite this

MASTERMIND consortium, Güdemann, L. M., Young, K. G., Thomas, N. J. M., Hopkins, R., Challen, R., Jones, A. G., Hattersley, A. T., Pearson, E. R., Shields, B. M., Bowden, J., Dennis, J. M., & McGovern, A. P. (2024). Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach. Diabetologia. https://doi.org/10.1007/s00125-024-06190-9

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abstract = "Aims/hypothesis: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis. Methods: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013–2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument. Results: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA1c reduction was similar between SGLT2i and DPP4i (−0.3 mmol/mol [−1.6, 1.1], −0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (−4 mmol/mol [4.8, −3.1], −0.4% [−0.4, −0.3]). Conclusions/interpretation: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes.",

keywords = "Causal analysis, Effectiveness, Older adults, Safety, SGLT2 inhibitors",

author = "{MASTERMIND consortium} and G{\"u}demann, {Laura M.} and Young, {Katie G.} and Thomas, {Nicholas J.M.} and Rhian Hopkins and Robert Challen and Jones, {Angus G.} and Hattersley, {Andrew T.} and Pearson, {Ewan R.} and Shields, {Beverley M.} and Jack Bowden and Dennis, {John M.} and McGovern, {Andrew P.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = jun,

day = "5",

doi = "10.1007/s00125-024-06190-9",

language = "English",

journal = "Diabetologia",

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MASTERMIND consortium, Güdemann, LM, Young, KG, Thomas, NJM, Hopkins, R, Challen, R, Jones, AG, Hattersley, AT, Pearson, ER, Shields, BM, Bowden, J, Dennis, JM & McGovern, AP 2024, 'Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach', Diabetologia. https://doi.org/10.1007/s00125-024-06190-9

TY - JOUR

T1 - Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years

T2 - an instrumental variable approach

AU - MASTERMIND consortium

AU - Güdemann, Laura M.

AU - Young, Katie G.

AU - Thomas, Nicholas J.M.

AU - Hopkins, Rhian

AU - Challen, Robert

AU - Jones, Angus G.

AU - Hattersley, Andrew T.

AU - Pearson, Ewan R.

AU - Shields, Beverley M.

AU - Bowden, Jack

AU - Dennis, John M.

AU - McGovern, Andrew P.

PY - 2024/6/5

Y1 - 2024/6/5

N2 - Aims/hypothesis: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis. Methods: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013–2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument. Results: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA1c reduction was similar between SGLT2i and DPP4i (−0.3 mmol/mol [−1.6, 1.1], −0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (−4 mmol/mol [4.8, −3.1], −0.4% [−0.4, −0.3]). Conclusions/interpretation: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes.

AB - Aims/hypothesis: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis. Methods: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013–2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument. Results: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA1c reduction was similar between SGLT2i and DPP4i (−0.3 mmol/mol [−1.6, 1.1], −0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (−4 mmol/mol [4.8, −3.1], −0.4% [−0.4, −0.3]). Conclusions/interpretation: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes.

KW - Causal analysis

KW - Effectiveness

KW - Older adults

KW - Safety

KW - SGLT2 inhibitors

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U2 - 10.1007/s00125-024-06190-9

DO - 10.1007/s00125-024-06190-9

M3 - Article

C2 - 38836934

AN - SCOPUS:85195273123

SN - 0012-186X

JO - Diabetologia

JF - Diabetologia

ER -

Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

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MASTER MIND - MRC ABPI Stratification and Extreme Response Mechanism in Type 2 Diabetes (Joint with University of Exeter, Newcastle University, Kings College London, University of Oxford and University of Glasgow)

Cite this

Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

MASTER MIND - MRC ABPI Stratification and Extreme Response Mechanism in Type 2 Diabetes (Joint with University of Exeter, Newcastle University, Kings College London, University of Oxford and University of Glasgow)

Cite this