Project objectives

 After change in oral antidiabetic medication type or dose, HbA1c can identify patients in whom further dose adjustment would be safe and beneficial at intervals of 4 to 8 weeks.

Aims

• to determine how rapidly HbA1c levels change in response to treatment, and
• to develop a protocol for monitoring the titration of oral medication by frequent HbA1c measurements that could be tested against usual care in a randomised controlled trial.

Research questions

• after a change in medication how do HbA1c levels at 2, 4 and 8 weeks correlate with HbA1c levels at 12 weeks?
• can change in HbA1c levels at 2, 4 or 8 weeks after change in medication be used to predict overall change in HbA1c levels at 12 weeks?

This study aims to understand whether HbA1c testing at more frequent intervals could be used to titrate medication earlier to attain the optimal dose more quickly.

We will recruit 100 patients with non-insulin treated diabetes who are starting or changing their oral medication in response to poor glycaemic control into a 12-week observational study. HbA1c will be measured at 0, 2, 4, 8 and 12 weeks after a medication change by routine laboratory measurement using blood samples obtained through venepuncture. We will calculate mean (standard error) of change in HbA1c at 2, 4, 8 and 12 weeks, and the predictive value of 2, 4 or 8 week HbA1c for 12 week HbA1c in a linear model.

Results will be used to design an intervention study of titration with frequent HbA1c testing versus usual care. Faster or more accurate titration of medication would have benefits to patients and hence indirect economic benefit to the NHS.

The team includes an academic GP with expertise in diabetes and clinical trials, a senior statistician with expertise in monitoring and diagnostic accuracy studies, and a researcher with experience in biomedical devices.

Brief summary

Abstract from recent PLOS ONE publication (Hirst JA, Stevens RJ, Farmer AJ. PLoS One. 2014;9(3):e92458):

Background

Current guidance about the interval needed before retesting HbA1c when monitoring for glycaemic control is based on expert opinion rather than well-powered studies. The aim of our work was to explore how fast HbA1c changes after a change in glucose-lowering medication. This has implications for whether routine HbA1c testing intervals before 12 weeks could inform diabetes medication adjustments.

Methods

This 12-week cohort study recruited patients from 18 general practices in the United Kingdom with non-insulin treated diabetes who were initiating or changing dose of oral glucose-lowering medication. HbA1c was measured at baseline and 2, 4, 8 and 12 weeks after recruitment. HbA1c levels at earlier time intervals were correlated with 12-week HbA1c. A ROC curve analysis was used to identify the 8-week threshold above which medication adjustment may be clinically appropriate.

Results

Ninety-three patients were recruited to the study. Baseline characteristics for 79 patients with no change in medication and full 12-week follow-up were: mean±standard deviation age was 61.3±10.8 years, 33% were female with diabetes duration of 6.0±4.3 years. Mean HbA1c at baseline, 2, 4, 8 and 12 weeks was 8.7±1.5%, (72.0±16.8mmol/mol) 8.6±1.6% (70.7±17.0mmol/mol), 8.4±1.5% (68.7±15.9mmol/mol), 8.2±1.4% (66.3±15.8mmol/mol) and 8.1±1.4% (64.8±15.7mmol/mol) respectively. At the end of the study 61% of patients had sub-optimal glycaemic control (HbA1c>7.5% or 59mmol/mol). The 8-week change correlated significantly with the 12-week change in HbA1c and an HbA1c above 8.2% (66mmol/mol) at 8 weeks correctly classified all 28 patients who had not achieved glycaemic control by 12 weeks.

Conclusions/interpretation

This is the first study designed with sufficient power to examine short-term changes in HbA1c. The 12-week change in HbA1c can be predicted 8 weeks after a medication change. Many participants who had not achieved glycaemic control after 12 weeks may have benefitted from an earlier review of their HbA1c and medication.

Key findings

Our study has provided evidence that earlier and more frequent measurement of HbA1c after a change in medication has potential to inform adjustments of medication in patients with diabetes. In addition, this is the first study on this scale designed and powered specifically to explore the course of HbA1c change over the weeks following a change in medication dose and suggest a testing interval based on evidence from patient data. In this cohort of patients we found that 79% of the change in HbA1c had occurred within the first 8 weeks of a medication change and that this result remained robust in sensitivity analyses. The results of our study show that the HbA1c level 8 weeks after a change in medication was strongly predictive of HbA1c 12 weeks after the change in diabetes medication and that patients with HbA1c greater than 8.2% (66 mmol/mol) at 8 weeks did not achieve glycaemic control at 12 weeks.

Plain English summary

People with diabetes and their doctors use HbA1c, a blood test, to assess whether their level of blood glucose (sugar) is well-controlled by their medication. Current guidance suggests that HbA1c tests cannot usefully be repeated within three months, but although widely accepted, this notion is derived from very few, somewhat small studies, and contradicted by some recent studies. If HbA1c could be tested more frequently, it could be used when starting new treatment (or changing dose) to guide adjustment to the optimal dose as fast as possible. Achieving blood glucose control reduces the risk of developing complications, and the earlier a patient and their doctor can understand how the patient is responding to their medication; the earlier this control can be achieved. In this project, we investigated the role of HbA1c measurement in people changing their type or combination of pills for diabetes by measuring changes in HbA1c over 0, 2, 4, 8 and 12 weeks to determine how quickly HbA1c changes in response to treatment.

Ninety-three patients with diabetes who were not taking insulin and were having a change to their diabetes medicine were recruited from 18 general practices in the United Kingdom. Their HbA1c was measured five times over 12 weeks. The HbA1c levels at earlier time intervals were compared with the12-week HbA1c.

Seventy-nine patients with average age of 61 years, 33% of whom were female were included in the final analysis. At the end of the study 61% of patients had HbA1c above 7.5% or 59mmol/mol. We found that the 8-week change in HbA1c could be used to predict the 12-week change in HbA1c and all patients with HbA1c above 8.2% (66mmol/mol) at 8 weeks had HbA1c of 7.5% (59mmol/mol) or above at the end of the study.

Our study found that the change in HbA1c 8 weeks after changing medicines can be used to predict the final change in HbA1c. Many patients may therefore benefit from an having an earlier review of their HbA1c and medicines.

Dissemination

Published articles

1. Hirst JA, Stevens RJ, Farmer AJ. How quickly do HbA1c levels respond to a change in oral glucose lowering therapy? Results from a cohort study. Diabetologia. September 2013, Volume 56, Issue 1 Supplement, S446.
   http://link.springer.com/journal/125/56/1/suppl/page/1
2. Hirst JA, Stevens RJ, Farmer AJ. Changes in HbA1c Level over a 12-Week Follow-up in Patients with Type 2 Diabetes following a Medication Change. PLoS One. 2014 Mar 25;9(3):e92458.
   http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092458

Public involvement

A PPI representative assisted with the wording on the patient information sheet. Overall experience of working with the representative was helpful and positive.

Impact

Taken from PLOS ONE publication (Hirst JA, Stevens RJ, Farmer AJ. PLoS One. 2014;9(3):e92458):

Clinical implications

In our cohort of 79 patients with uncontrolled diabetes we have demonstrated that the majority of the change in HbA1c has taken place within the first 8 weeks of a medication change. We have shown from our analysis that twenty-eight patients who had an HbA1c at 8 weeks of greater than 8.2% (66 mmol/mol) would have safely benefitted from an adjustment in their medication 8 weeks after their medication change. In addition our work has shown that people with uncontrolled diabetes could have their HbA1c re-tested after 8 weeks to identify those who are non-adherent or non-responders to their medication type. We recognise that any medication changes would need to be assessed in a case-by-case basis and need to be dependent on individual patients, their HbA1c level and combinations of medications which they are taking. A randomised trial to test an 8-week testing interval compared with usual care in people with uncontrolled diabetes is now needed.

This project was funded by the National Institute for Health Research School for Primary Care Research (project number 151)

Department of Health Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR School for Primary Care Research, NIHR, NHS or the Department of Health.