Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Commentary

How Valid Are the New Hypoglycemia Definitions for Use in Clinical Trials?

  1. Philip Home⇑
  1. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K.
  1. Corresponding author: Philip Home, philip.home{at}newcastle.ac.uk
Diabetes Care 2020 Feb; 43(2): 272-274. https://doi.org/10.2337/dci19-0056
PreviousNext
  • Article
  • Info & Metrics
  • PDF
Loading

The recent changes to hypoglycemia definitions, as proposed by the International Hypoglycaemia Study Group (IHSG) and widely accepted by some regulators and major diabetes associations, were poorly evidence-based, relying on pathophysiological studies and small clinical studies (1). In this issue of Diabetes Care, Heller et al. (2) attempt to remedy this, and they present some useful information on the effect of choice of level for hypoglycemia on statistical power and effect size when comparing insulins. The definitions are for use in clinical trials, as the IHSG emphasizes, and not for application to individual people with diabetes seen in clinical practice (1).

Broadly, using data from the SWITCH 1 (type 1 diabetes [T1D]) and SWITCH 2 (type 2 diabetes [T2D]) studies of insulin degludec versus insulin glargine 100 units/mL (3,4), the difference in event rates declines below the earlier American Diabetes Association (ADA) threshold of <3.9 mmol/L (<70 mg/dL), increasing in inverse proportion to the absolute decline in event rates, at least down to 2.8–2.9 mmol/L (50–52 mg/dL) where the number of events leads to uncertainty. This is best espoused in the authors' Fig. 2A, where for SWITCH 2 the central estimate for difference in rate of confirmed symptomatic events between insulins falls with each 0.1 mmol/L drop in threshold from 3.9 to 3.0 mmol/L (70 to 54 mg/dL). More importantly, the upper confidence limit also falls despite the overall confidence interval (CI) widening, meaning higher certainty that the difference is real. Below 3.0 mmol/L, the lower event rate leads to increasing uncertainty, with loss of statistical difference by 2.7 mmol/L (49 mg/dL).

The T1D study, where the majority of hypoglycemia events will be influenced by mealtime and not basal insulin but in which the event rate is much higher, appears confirmatory of the T2D study (authors' Fig. 2B), with a small improvement in hypoglycemia compared with control appearing when using a progressively lower threshold below 3.9 mmol/L down to 2.5 mmol/L (45 mg/dL). No similar data analysis for nocturnal hypoglycemia, which might be influenced more by a difference between two basal insulins, is given.

Notable also from Fig. 2 is that exclusion of asymptomatic hypoglycemia appears to improve discrimination at any threshold with no detriment to the upper confidence limit despite lower event rates.

Other data are available in the literature but can be difficult to integrate because symptomatic confirmed hypoglycemia is often combined with severe hypoglycemia (making sense from the patient perspective) and the threshold is sometimes 3.1 mmol/L (56 mg/dL), although that is perhaps not materially different from 3.0 mmol/L. However, the EDITION series of studies of insulin glargine 300 units/mL do present equivalent data using <3.0 and ≤3.9 mmol/L for documented symptomatic hypoglycemia. In T1D, no material effect on the central estimate versus control can be discerned, but the CIs are wider at the lower cutoff of <3.0 mmol/L (5). However, in a very small study, central estimates were lower using <3.0 mmol/L, and despite widening CIs the upper limit for nocturnal hypoglycemia then fell to 0.82, having been 1.11 at ≤3.9 mmol/L (6). In the same article, continuous glucose monitoring (CGM) numbers of values below the two cutoffs fell by 40%, but so did difference between insulins; power thus seems similar, but estimates and CIs are not given.

In a primary composite analysis of the T2D EDITION studies, the effect on overall event rate is dramatic, with an 83% drop in number of events using the lower cutoff (data for both insulins combined) and a halving of proportion of people affected (53% to 24%) (7). For documented symptomatic hypoglycemia, data are available for 1 year of exposure (8), and for incidence (proportion of people affected) as well as event rate, the former a more powerful statistic in people with T2D. Overall, however, in the two articles, whether for incidence or rates, and whether including asymptomatic or not, there are no consistent effects on central estimates, but statistical power is adversely affected by a lower hypoglycemia definition with wider CIs.

The BRIGHT study also presents data for ≤3.9 and <3.0 mmol/L thresholds in T2D (9). Underpowering for hypoglycemia is a problem for that study but particularly for the lower threshold where the CIs are about double (in logarithmic terms) those for ≤3.9 mmol/L, with the data presented being for all biochemically confirmed hypoglycemia.

Novo Nordisk's U.S. Food and Drug Administration prescribing information for insulin degludec (last revised November 2018) notes that the primary definition of hypoglycemia used in its registration trials was of episodes “with or without the presence of hypoglycemic symptoms” (10). While the IHSG article was not clear as to whether asymptomatic hypoglycemia should be included as “events” (1), and while the current article gives data both with and without such episodes, the authors here use “IHSG level 2” to mean all episodes, with and without symptoms (2). Presently, the U.S. Food and Drug Administration is not happy to accept comparative hypoglycemia data based on studies with variation in “intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors” (10). Accordingly, the SWITCH studies are not included in the current U.S. insulin degludec label. The subjective nature of self-measured plasma glucose, in particular in open-label studies, is also understood to be an issue, not least because the frequency of self-measurement will affect the frequency of detection of nonsymptomatic episodes and thus the proportions of data contributed by symptomatic events and biochemical detections.

Use of biochemically confirmed symptoms as given in the current report would appear to bring the definition closer to the patient experience, at a cost of missing possible “clinically significant” hypoglycemia, and, in some studies, losing useful statistical power. The IHSG is nevertheless further motivated to consider inclusion of nonsymptomatic detection by the need to give a definition for CGM-detected hypoglycemia (<3.0 mmol/L [<54 mg/dL] for 20 min) (1). Some other studies have addressed the issue of symptomatic and asymptomatic episodes by presenting data on both all documented hypoglycemia and documented symptomatic hypoglycemia (5,7,8), and going forward and with increasing use of CGM in randomized controlled trials (RCTs), this seems wise. Similarly, it seems sensible, as in the study by Heller et al., to present both a primary composite (clinically significant confirmed hypoglycemia or severe hypoglycemia) and its components (2).

The IHSG has not advised changing the long-established ADA definition of severe hypoglycemia (requiring assistance), though it is now referred to as “IHSG level 3” (1). The presentation of DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events) data in the current article does not then add new information (11). This is also true of severe hypoglycemia/level 3 in the SWITCH studies, where in T2D the number of episodes is too small (SWITCH 2, n = 53) to do more than indicate there is not a safety issue compared with insulin glargine 100 units/mL (4).

The present article does not help with the underlying issue of what is “clinically important” hypoglycemia (and is not intended to) (2), except insofar as supporting symptomatic/severe hypoglycemia as an adequate measure compared with the addition of self-measured asymptomatic episodes. That is likely to change with increasing use of CGM. While the DEVOTE and CAROLINA studies both failed to show any reduction in cardiovascular events when hypoglycemia event rate is reduced (11,12), levels of 3.0 mmol/L (54 mg/dL) are also important with regard to reduced hypoglycemia awareness, with asymptomatic cognitive impairment, defective counterregulation, and increased risk of severe hypoglycemia (1).

The issue of study power from the change in definition, while not found to be real in the SWITCH studies, might be further addressed by applying the approach used by Heller et al. (analysis by 0.1 mmol/L intervals from 3.9 down to 2.5 mmol/L) in other studies, most obviously other published insulin RCTs including other studies on insulin degludec and insulin glargine 300 units/mL. Indeed, data might be available from insulin studies going back a couple of decades. But, as noted above, the advent of valid CGM is changing the approach used in RCTs (6), and the emphasis then becomes asymptomatic hypoglycemia, albeit at the same “clinically significant” level. Because CGM detects more hypoglycemia than intermittent self-measurement of plasma glucose, the issue of statistical power is more easily addressed, and data collection is more objective. Current CGM metrics often use time in range of 3.9–10.0 mmol/L (40–180 mg/dL), but analysis at additional levels (time below 3.0 mmol/L, events as defined above) is computationally easy. Methodological traps related to validity of measurements with CGM at lower levels, and statistical analysis of repeated measures, require careful attention with this technology.

Lastly, these discussions have little relevance to observational pharmacoepidemiological (“real-life”) studies, where the recording of symptomatic hypoglycemia is invariably too erratic to be useful, indeed even for severe hypoglycemia/IHSG level 3. Here, only hospitalization for the primary indication of management of hypoglycemia seems valid and is thus independent of cutoffs for measured glucose level.

In summary, the deeper analysis of data from the well-powered SWITCH studies does support that the new IHSG level 2 definition compared with the previous ADA definition can result in statistically more robust findings when comparing insulins. However, other similar analyses on lower-power studies may not support that conclusion. Exclusion of asymptomatic events may not be detrimental. We can look forward to future data from studies using CGM that may add to our understanding of different cutoff levels as applied to clinical trials.

Article Information

Duality of Interest. P.H. or institutions with which he is associated have received direct or indirect financial support from AntriaBio, Boehringer Ingelheim, GlaxoSmithKline, Hanmi, Janssen, Merck, Novo Nordisk, and Sanofi for his advisory, research, or speaking activities. No other potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying article, p. 398.

  • © 2020 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

References

  1. ↵
    1. International Hypoglycaemia Study Group
    . Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017;40:155–157
    OpenUrlFREE Full Text
  2. ↵
    1. Heller SR,
    2. Buse JB,
    3. Ratner R, et al
    . Redefining hypoglycemia in clinical trials: validation of definitions recently adopted by the American Diabetes Association/European Association for the Study of Diabetes. Diabetes Care 2020;43:398–404
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Lane W,
    2. Bailey TS,
    3. Gerety G, et al.; Group Information; SWITCH 1
    . Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes: the SWITCH 1 randomized clinical trial. JAMA 2017;318:33–44
    OpenUrl
  4. ↵
    1. Wysham C,
    2. Bhargava A,
    3. Chaykin L, et al
    . Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA 2017;318:45–56
    OpenUrlPubMed
  5. ↵
    1. Home PD,
    2. Bergenstal RM,
    3. Bolli GB, et al
    . New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 1 diabetes: a randomized, phase 3a, open-label clinical trial (EDITION 4). Diabetes Care 2015;38:2217–2225
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Bergenstal RM,
    2. Bailey TS,
    3. Rodbard D, et al
    . Comparison of insulin glargine 300 units/mL and 100 units/mL in adults with type 1 diabetes: continuous glucose monitoring profiles and variability using morning or evening injections. Diabetes Care 2017;40:554–560
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Ritzel R,
    2. Roussel R,
    3. Bolli GB, et al
    . Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab 2015;17:859–867
    OpenUrlCrossRefPubMed
  8. ↵
    1. Ritzel R,
    2. Roussel R,
    3. Giaccari A,
    4. Vora J,
    5. Brulle-Wohlhueter C,
    6. Yki-Järvinen H
    . Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the EDITION clinical studies in people with type 2 diabetes. Diabetes Obes Metab 2018;20:541–548
    OpenUrlPubMed
  9. ↵
    1. Rosenstock J,
    2. Cheng A,
    3. Ritzel R, et al
    . More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: the randomized head-to-head BRIGHT Trial. Diabetes Care 2018;41:2147–2154
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Novo Nordisk Inc
    . Prescribing information (U.S.): Tresiba. Accessed 29 October 2019. Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203314s010lbl.pdf
  11. ↵
    1. Marso SP,
    2. McGuire DK,
    3. Zinman B, et al.; DEVOTE Study Group
    . Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017;377:723–732
    OpenUrlCrossRefPubMed
  12. ↵
    1. Rosenstock J,
    2. Kahn SE,
    3. Johansen OE, et al.; CAROLINA Investigators
    . Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 2019;322:1155–1166
    OpenUrl
PreviousNext
Back to top
Diabetes Care: 43 (2)

In this Issue

February 2020, 43(2)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
How Valid Are the New Hypoglycemia Definitions for Use in Clinical Trials?
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
How Valid Are the New Hypoglycemia Definitions for Use in Clinical Trials?
Philip Home
Diabetes Care Feb 2020, 43 (2) 272-274; DOI: 10.2337/dci19-0056

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

How Valid Are the New Hypoglycemia Definitions for Use in Clinical Trials?
Philip Home
Diabetes Care Feb 2020, 43 (2) 272-274; DOI: 10.2337/dci19-0056
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Article Information
    • Footnotes
    • References
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Taking the Air Out of Oxygen Supplementation in Individuals With Diabetes and Acute Coronary Syndromes
  • The Cardiovascular Legacy of Good Glycemic Control: Clues About Mediators From the DCCT/EDIC Study
Show more Commentary

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.