Beyond HbA1c.

It can scarcely be denied that the supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience. The diaTribe Foundation convened a meeting on the topic of glycemic outcomes beyond HbA1c on 21 July 2017, in Bethesda (MD, USA), focusing on potential uses of continuous glucose monitoring (CGM). Understanding patterns of glycemia in people with diabetes has long been a focus of approaches to improving treatment, and over the past few years this has become an available modality for clinical practice. Glucose levels are not the only biologic parameters affecting HbA1c levels; HbA1c changes with anemia or, more subtly, with changes in rates of erythrocyte turnover not reflected in hemoglobin levels outside the normal range. Renal disease often is associated with lower HbA1c than would be predicted based on an individual's glycemic levels. Furthermore, HbA1c levels tend to increase with age and are higher in some ethnic groups; for example, people of African ethnicity have higher HbA1c levels than people of Northern European descent. Indeed, we have argued that even as a measure of mean glycemia HbA1c is inherently imprecise. Overall, for some 20% of people with diabetes, HbA1c levels are substantially higher, or substantially lower, than those that would be predicted from mean blood glucose levels. If one recognizes that HbA1c is, at best, a partial measure of mean glycemic exposure, one must surely accept that HbA1c does not reflect variability within a day, from day to day, and from period to period. Many glucose-lowering medicines, particularly the sulfonylureas and insulin, cause hypoglycemia, with consequent negative effects on quality of life and patient-reported outcomes, as well as association with weight gain and adverse macrovascular outcome; hypoglycemia will, of course, not be captured by HbA1c measurement. Based on these considerations, HbA1c may be more limited than generally recognized as a surrogate marker of optimal diabetes treatment, leading the European Medicines Agency to consider relying less on this measure, with the implication that novel approaches will be required for clinical practice and for clinical trials in developing future medicines. In surveys performed by a market research company (dQ&A Market Research, San Francisco, CA, USA) and reported at the Bethesda meeting, among >3000 people with type 1 (T1D) or type 2 (T2D) diabetes both receiving and not receiving insulin, the majority reported a sense that their diabetes care is not very successful and that too much of their time was spent outside the 70-180 mg/dL (3.9-10.0 mEq/L) range. Although self-monitoring of capillary blood glucose (SMBG) is an important tool for patients to use in understanding glycemic excursions, CGM offers a far superior technology in this regard and can avoid the erroneous conclusions often accompanying the use of the inherently indirect measurement of HbA1c. Duration and severity of hypoglycemia may come to be considered important medication efficacy measures, rather than just being considered safety outcomes. Glucose cut-off levels suggested at the meeting may be: <54 mg/dL (3.0 mEq/L) for severe hypoglycemia, <70 mg/dL (3.9 mEq/L) for low blood glucose levels, >180 mg/dL (10.0 mEq/L) for high blood glucose levels, and >240 mg/dL (13.3 mEq/L) for serious high blood glucose levels. An important part of both SMBG and CGM technologies will be the development of data transmission and storage modalities to better provide feedback to people with diabetes and health care providers in adjusting a variety of treatments, as well as their growing use in insulin dose adjustment algorithms; important in such approaches will be the integration of SMBG with CGM to recognize potential measurement errors and to improve the accuracy and assurance of patients and providers that the CGM results are accurate, a particular concern for readings in the hypoglycemia range, but remaining an issue throughout the clinical glycemia range. However, one must recognize that many commercially available SMBG instruments also fail to exhibit required accuracy, and that the indirect relationship between HbA1c and blood glucose suggests that HbA1c is at best limited in its portrayal of glycemic exposure. All these modalities play a role, but the use of CGM appears crucial to the development of better approaches to clinical treatment with multiple views allowing understanding of patterns of glycemic exposure. We look forward to further improvements in this methodology.

Bloomgarden Z 《-》

Effects of real-time continuous glucose monitoring in type 1 diabetes: a meta-analysis of randomized controlled trials.

Dicembrini I ，Cosentino C ，Monami M ，Mannucci E ，Pala L ... -  《-》

Integrated sensor-augmented pump therapy systems [the MiniMed® Paradigm™ Veo system and the Vibe™ and G4® PLATINUM CGM (continuous glucose monitoring) system] for managing blood glucose levels in type 1 diabetes: a systematic review and economic evaluatio

Riemsma R ，Corro Ramos I ，Birnie R ，Büyükkaramikli N ，Armstrong N ，Ryder S ，Duffy S ，Worthy G ，Al M ，Severens J ，Kleijnen J ... -  《-》

Methods for insulin delivery and glucose monitoring in diabetes: summary of a comparative effectiveness review.

Golden SH ，Sapir T 《-》

The Association Between HbA(1c) and Time in Hypoglycemia During CGM and Self-Monitoring of Blood Glucose in People With Type 1 Diabetes and Multiple Daily Insulin Injections: A Randomized Clinical Trial (GOLD-4).

According to recent guidelines, individuals with type 1 diabetes should spend <4.0% of time per day with glucose levels <3.9 mmol/L (<70 mg/dL) and <1.0% per day with glucose levels <3.0 mmol/L (<54 mg/dL). In the GOLD randomized crossover trial, 161 individuals with type 1 diabetes treated with multiple daily insulin injections (MDI) were randomized to continuous glucose monitoring (CGM) or conventional therapy with self-monitoring of blood glucose (SMBG) and evaluated over 16 months. We estimated the association between time spent in hypoglycemia and various mean glucose and HbA1c levels. Time spent in hypoglycemia (<3.9 mmol/L and <3.0 mmol/L) increased significantly with lower mean HbA1c and mean glucose levels during both CGM and conventional therapy. During CGM, 24 (57.1%) individuals with HbA1c <7.5% (<58 mmol/mol) had <1.0% time spent in hypoglycemia <3.0 mmol/L and 23 (54.8%) had <4.0% time spent in hypoglycemia <3.9 mmol/L. During CGM, mean time spent in hypoglycemia for individuals with mean HbA1c 7.0% (52 mmol/mol) was estimated to be 5.4% for <3.9 mmol/L and 1.5% for <3.0 mmol/L. The corresponding values during SMBG were 9.2% and 3.5%, respectively. Individuals with mean glucose levels of 8 mmol/L spent 4.9% units more time with glucose levels <3.9 mmol/L and 2.8% units more time <3.0 mmol/L during SMBG compared with CGM. Reaching current targets for time in hypoglycemia while at the same time reaching HbA1c targets is challenging for patients with type 1 diabetes treated with MDI both with CGM and SMBG monitoring. However, CGM is associated with considerably less time in hypoglycemia than SMBG at a broad range of HbA1c levels and is crucial for patients with MDI treatment if they are to have a chance to approach hypoglycemia targets.

Seyed Ahmadi S ，Westman K ，Pivodic A ，Ólafsdóttir AF ，Dahlqvist S ，Hirsch IB ，Hellman J ，Ekelund M ，Heise T ，Polonsky W ，Wijkman M ，Schwarcz E ，Lind M ... -  《-》