Outcome measures for type 1 diabetes – A consensus report

The disease burden of type1 diabetes can negatively impact quality of life, including finances and careers.

Hba1c is a well-accepted measurement for evaluating the efficacy of diabetes therapies and technologies in clinical practice and research. However, as a measure of mean glucose over 2-3 months, Hba1c does not capture glucose variability or exposure to hypoglycaemia and hyperglycaemia. In addition, it does not capture the impact of glucose variability on individual’s quality of life.

In 2017 Diabetes Care Published a Consensus report of a decision- making body for the Type 1 Diabetes Outcomes Program.

This Steering Committee comprised of representatives from:

• The American Association of Clinical Endocrinologists
• The American Association of Diabetes Educators
• The American Diabetes Association
• The Endocrine Society
• JDRF International
• The Leona M and Harry B Helmsley Charitable Trust
• The Paediatric Endocrine Society
• The T1D Exchange

The Objective: Define clinically meaningful type1 diabetes outcomes beyond HbA1c based on the evidence, consensus from clinical experts, and input from researchers, people with Type 1 diabetes, and industry.

These outcomes include:

• Hypoglycaemia
• Hyperglycaemia
• Time in Range [ TIR]
• Diabetic Ketoacidosis [ DKA]
• Patient reported outcomes [ POR]

The definitions reflect the committee’s assessment of the outcome’s short – term and long-term clinical impact on people with type1 diabetes.

Below is a summary of the consensus definitions

Hypoglycaemia

Level 1: glucose < 3.9 mmol/L and glucose ≥3mmol/L

Level 2: glucose < 3.0 mmol/L

Level 3:  a severe event characterised by altered mental and/or physical status requiring assistance

Hyperglycaemia

Level 1: elevated glucose- glucose >10 mmol/L and ≤13.9 mmol/L 

Level 2: very elevated glucose- glucose >13.9 mmol/L

Time in range: Percentage of readings in the range of 3.9-10 mmol/L per unit of time.

DKA: Elevated serum or urine ketones (greater than the upper limit of the normal range) and serum bicarbonate < 15mmol/L or blood PH <7.3

For Patient reported outcomes, the group referred to the US  FDA guidance in 2009, defining PRO as “any report of the status of patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else” .    Furthermore, it advises PRO be used to gather information “best known by the patient or best measured from the patient perspective.”

Time in Range

The steering committee considered it important to keep the time in range definition wide in order to accommodate variations across the population with Type1 diabetes including different age groups – but not precluding the possibility of negative outcomes.

Normal glycaemic range for people without diabetes is 3.9-7.8mmol/L. however, people with type 1 diabetes do not have the physiological insulin secretion and therefore spending most of the day in the same range as those without diabetes is generally not achievable. Because the current post prandial upper limit is 10.0 mmol/L for people with type 1 diabetes, this was the limit applied to the time in range definition.

CGM

To measure of time in range, CGM or similar technologies are required to generate the data needed.

“The Steering Committee felt that these technologies were at a point of development in which they could and should be used safely and effectively to capture time in range data “

Recognition of gaps in evidence and measurement

The group recognised that further research needs to be done to

• Better understanding the connection between hyperglycaemia and macrovascular disease and other chronic complications 
• Demonstrate correlation or a direct causative relationship between time in range for patients with type 1 diabetes and positive health outcomes
• Develop standard PROs for type1 diabetes, including assessments of burden to patients 
• Develop new surveillance methods that provide consistent ways of reporting hypoglycaemia and more work needs to be done on the links between level 1and level 2 hypoglycaemia to long term outcomes.

RESULT: “The Steering Committee recommends use of the defined clinically meaningful outcomes beyond HbA1c in the research , development and evaluation of type 1 diabetes therapies .” 

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