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. 2020 Sep;22(9):1537-1547.
doi: 10.1111/dom.14063. Epub 2020 May 18.

Validation of distinct type 2 diabetes clusters and their association with diabetes complications in the DEVOTE, LEADER and SUSTAIN-6 cardiovascular outcomes trials

Anna R Kahkoska  1 , Milan S Geybels  2 , Klara R Klein  1 , Frederik F Kreiner  2 , Nikolaus Marx  3 , Michael A Nauck  4 , Richard E Pratley  5 , Benjamin O Wolthers  2 , John B Buse  1
Affiliations

Validation of distinct type 2 diabetes clusters and their association with diabetes complications in the DEVOTE, LEADER and SUSTAIN-6 cardiovascular outcomes trials

Anna R Kahkoska et al. Diabetes Obes Metab. 2020 Sep.

Abstract

Aims: To validate the clusters of Swedish individuals with recent-onset diabetes at differential risk of complications, which were identified in a previous study, in three global populations with long-standing type 2 diabetes (T2D) who were at high cardiovascular risk, and to test for differences in the risk of major diabetes complications and survival endpoints.

Materials and methods: We assigned participants from recent global outcomes trials (DEVOTE [n = 7637], LEADER [n = 9340] and SUSTAIN-6 [n = 3297]) to the previously defined clusters according to age at diabetes diagnosis, baseline glycated haemoglobin (HbA1c) and body mass index (BMI). Outcomes were assessed using Kaplan-Meier analysis and log-rank tests.

Results: The T2D clusters were consistently replicated across the three trial cohorts. The risk of major adverse cardiovascular events and cardiovascular death differed significantly, in all trials, across clusters over a median follow-up duration of 2.0, 3.8 and 2.1 years, respectively, and was highest for the cluster of participants with high HbA1c and low BMI (P < 0.05 in DEVOTE and LEADER). In LEADER and SUSTAIN-6, the risk of nephropathy differed across clusters (P < 0.0001 and P = 0.003, respectively). The risk of severe hypoglycaemia differed in DEVOTE (P = 0.006).

Conclusions: Previously identified clusters can be replicated in three geographically diverse cohorts of long-standing T2D and are associated with cluster-specific risk profiles for additional clinical and survival outcomes, providing further validation of the clustering methodology. The external validity and stability of clusters across cohorts provides a premise for future work to optimize the clustering approach to yield T2D subgroups with maximum predictive validity who may benefit from subtype-specific treatment paradigms.

Keywords: GLP-1; cardiovascular disease; diabetes complications; hypoglycaemia; insulin analogues; type 2 diabetes.

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Conflict of interest statement

A.R.K. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number F30DK113728. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.R.K. has received financial support from Novo Nordisk for travel to present data. M.S.G. is an employee of Novo Nordisk. K.R.K. declares no competing interests. F.F.K. is an employee of Novo Nordisk. N.M. has given lectures for Amgen, Boehringer Ingelheim, Sanofi‐Aventis, MSD, BMS, AstraZeneca, Lilly and Novo Nordisk, has received unrestricted research grants from Boehringer Ingelheim, and has served as an advisor for Amgen, Bayer, Boehringer Ingelheim, Sanofi‐Aventis, MSD, BMS, AstraZeneca and Novo Nordisk. In addition, N.M. served in trial leadership for Boehringer Ingelheim and Novo Nordisk. N.M. declines all personal compensation from pharmaceutical or device companies. M.A.N. has received fees for serving on advisory boards and for lecturing from AstraZeneca, Berlin‐Chemie/Menarini, Boehringer Ingelheim, Eli Lilly, Genentech, GSK, Medscape, MSD, Novo Nordisk, Sanofi‐Aventis, Sun Pharma and Takeda, grant support for clinical studies from AstraZeneca, Eli Lilly, GSK, MSD and Novo Nordisk, and travel support in connection with the above‐mentioned activities. R.E.P. has received speaker fees from AstraZeneca, Novo Nordisk and Takeda, consulting fees from AstraZeneca, Boehringer‐Ingelheim, Eisai, Eli Lilly, GSK, Glytec, Janssen, Ligand Pharmaceuticals, Merck, Mundipharma, Novo Nordisk, Pfizer, Sanofi and Takeda, grants from Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Lilly, Merck, Novo Nordisk, Sanofi and Takeda, and personal consulting fees from Sanofi US Services, Inc., outside the submitted work. Except for consulting fees in February 2018 and June 2018 from Sanofi US Services, Inc., services were paid for directly to Advent Health, a non‐profit organisation. B.O.W. is an employee of Novo Nordisk. J.B.B.'s contracted consulting fees are paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Dexcom, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, vTv Therapeutics and Zafgen. J.B.B. reports grant support from AstraZeneca, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Sanofi, Theracos, Tolerion and vTv Therapeutics, is a consultant to Cirius Therapeutics Inc, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics, and Stability Health, holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio and Stability Health, and is supported by grants from the NIH (UL1TR002489, U01DK098246, UC4DK108612, U54DK118612), PCORI and ADA.

Figures

FIGURE 1
FIGURE 1
Clustering parameters (glycated haemoglobin and body mass index at baseline, and age at diabetes diagnosis) by cluster assignment in the DEVOTE, LEADER and SUSTAIN‐6 trials. Boxes are the median, and 25th and 75th percentiles; whiskers are the 1st and 99th percentiles. Values outside these percentiles are represented by open circles. Cluster labels correspond to the ANDIS labels as follows: Cluster A, severe insulin‐deficient diabetes; Cluster B, severe insulin‐resistant diabetes; Cluster C, mild obesity‐related diabetes; and Cluster D, mild age‐related diabetes. Baseline was defined as trial entry
FIGURE 2
FIGURE 2
Cumulative risk of a major adverse cardiovascular event (MACE), cardiovascular (CV) death and all‐cause death by cluster in the DEVOTE, LEADER and SUSTAIN‐6 trials. First occurrence of a MACE was the three‐component primary outcome in each trial; components comprised CV death, non‐fatal myocardial infarction and non‐fatal stroke. All outcomes had been confirmed by adjudication performed by external, independent medical experts. Full lines represent analyses based on all eligible participants; dashed lines represent analyses based on all except the 20% of the participants who were most difficult to assign to a single cluster (see text). P values are from a log‐rank test for the analysis of all participants. Participants at risk, shown in the tables, are for the full analysis. The median follow‐up time was 2.0, 3.8 and 2.1 years in DEVOTE, LEADER and SUSTAIN‐6 respectively. N, number of participants; %, proportion of participants
FIGURE 3
FIGURE 3
Cumulative risk of severe hypoglycaemia and new or worsening of nephropathy by cluster in the DEVOTE, LEADER and SUSTAIN‐6 trials. New or worsening of nephropathy was defined as occurrence of one of the following: new onset of persistent macroalbuminuria or doubling of the serum creatine concentration or of creatine clearance; continuous renal replacement therapy; death attributable to renal disease. Hypoglycaemic episodes were classified as severe according to contemporaneous American Diabetes Association criteria. All outcomes had been confirmed by adjudication performed by external, independent medical experts. Full lines represent analyses based on all eligible participants; dashed lines represent analyses based on all except the 20% of the participants who were most difficult to assign to a single cluster (see text). P values are from a log‐rank test for the analysis of all participants. Participants at risk, shown in the tables, are for the full analysis. The median follow‐up time was 2.0, 3.8 and 2.1 years in DEVOTE, LEADER and SUSTAIN‐6, respectively. N, number of participants; %, proportion of participants
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