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How conclusive is the CONCLUDE trial?

Abstract

The development of basal insulin analogues has reduced the risk of hypoglycaemia in insulin-treated individuals with type 2 diabetes. Insulin degludec and insulin glargine 300 U/ml (glargine U300) represent an evolution of basal insulin analogues, both of them reducing the risk of hypoglycaemia as compared with that associated with glargine U100. However, whether degludec and glargine U300 are equivalent with respect to glycaemic control and risk of hypoglycaemia remains to be fully ascertained. In the CONCLUDE trial, 1609 individuals with type 2 diabetes were randomised to either degludec 200 U/ml (degludec U200) or glargine U300. In this issue of Diabetologia (https://doi.org/10.1007/s00125-019-05080-9) the investigators report that during the maintenance period, HbA1c improved to a similar extent in the two groups with no significant difference in the rate of overall hypoglycaemia (the primary endpoint of the study), while rates of nocturnal symptomatic and severe hypoglycaemia (secondary endpoints) were lower with degludec U200 than with glargine U300. These results, although of great interest to the clinician, need to be carefully interpreted as they cannot be considered as conclusive. First, the primary endpoint was not met and, therefore, analyses of secondary endpoints remain exploratory. Even assuming that degludec is superior to glargine in reducing the risk of hypoglycaemia, the mechanism(s) accounting for such an advantage remain elusive and potential differences in pharmacokinetics and pharmacodynamics difficult to appreciate because of methodological issues. The study design had to be amended because of lack of reliability of the glucometers initially used in the trial, particularly in the low blood glucose ranges, so the potential implications of these changes in the subsequent conduct of the trial cannot be excluded. Finally, comparison with the BRIGHT trial, the only other available head-to-head study, is complicated by differences between the two studies in the primary endpoint (HbA1c reduction vs reduction of the risk of hypoglycaemia), study population (insulin-experienced vs insulin-naive) and concomitant glucose-lowering medications. In spite of all this, CONCLUDE teaches us an important lesson regarding the need, particularly in the clinical setting, to monitor the reliability of the glucometers the diabetic individual uses to adjust his/her insulin dose. Insufficient precision or inappropriate use of the glucometer can easily offset any minute advantage a new insulin can offer with respect to glycaemic control and risk of hypoglycaemia.

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Abbreviations

CONFIRM:

Clinical Outcome assessmeNt of the eFfectiveness of Insulin degludec in Real-life Medical practice

Degludec U200:

Insulin degludec 200 U/ml

EMA:

European Medicines Agency

Glargine U300:

Insulin glargine 300 U/ml

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Acknowledgements

I am indebted to the EASD for giving me the task of delivering an independent commentary on the occasion of the presentation of the results of the CONCLUDE trial at the 55th Annual Meeting of the EASD. This paper is largely based on that commentary. I am also grateful to G. Bolli (University of Perugia, Perugia, Italy), T Heise (Profil, Neuss, Germany), J. Rosenstock (Dallas Diabetes Research Center at Medical City, Dallas, TX, USA) and the CONCLUDE trial investigators A. Philis-Tsimikas (Scripps Whittier Diabetes Institute, San Diego, CA, USA) and T. R. Pieber (Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria) for constructive discussion and for sharing their views, some of which I have reported in the paper.

Funding

This work was funded by the University of Pisa, Department of Clinical and Experimental Medicine.

Author information

The author is the sole contributor to this paper.

Correspondence to Stefano Del Prato.

Ethics declarations

The author has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis Pharmaceuticals Co., and Merck Sharpe & Dohme; and is a consultant for or has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Merck Sharp & Dohme, Novartis Pharmaceuticals Co., Novo Nordisk, Sanofi and Takeda.

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Del Prato, S. How conclusive is the CONCLUDE trial?. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05086-8

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Keywords

  • Basal insulin analogues
  • Degludec
  • Glargine U300
  • Glucometer
  • Hierarchical statistical analysis
  • Home blood glucose monitoring
  • Hypoglycaemia
  • Pharmacodynamics
  • Pharmacokinetics
  • Type 2 diabetes