Section 1 – Shona

Shona, a 38-year-old lady of South Asian ethnicity, contacts the surgery to discuss the results of her annual blood test, which she undergoes because of a previous history of gestational diabetes. Results are as follows:

• HbA_1c 44 mmol/mol (6.2%).
• eGFR 86 mL/min/1.73 m².
• Total cholesterol 5.6 mmol/L; non-HDL cholesterol 3.2 mmol/L.

 
Shona has a strong family history of type 2 diabetes. Her blood pressure is 138/79 mmHg and a recent BMI was 29.3 kg/m².

How would you interpret these results?

Section 2

Shona’s renal function and blood pressure are satisfactory, but her lipid profile is adverse. For an individual of Asian ethnicity, her BMI is within the obese range.

Shona’s HbA_1c now falls within the range of non-diabetic hyperglycaemia (NDH). NDH is a term that embraces various states of hyperglycaemia that fall short of reaching the criteria for diabetes. Prediabetes (the term used in this case study), intermediate hyperglycaemia and impaired glucose regulation are alternative terms.

How is prediabetes defined?

Section 3

The most convenient method for defining prediabetes is an HbA_1c in the range of 42–47 mmol/mol (6.0–6.4%), the diagnostic threshold for diabetes being 48 mmol/mol (NICE, 2017).

Fasting plasma glucose is an alternative means of diagnosis. Less commonly, an oral glucose tolerance test may be used (Table 1).

There is not, however, a universal consensus on the definition of prediabetes. Thus, the American Diabetes Association (2024) has set a lower HbA_1c threshold of 39–47 mmol/mol (5.7–6.5%).

A review of data collected by the Health Survey for England found that by 2011, the prevalence of prediabetes in England had risen rapidly to around a third of the adult population, using HbA_1c between 5.7–6.4% as criteria (Mainous et al, 2014).

What risk factors does Shona have for developing prediabetes (or type 2 diabetes)?

Section 4

Shona’s previous gestational diabetes, raised BMI, ethnicity and family history of diabetes all contribute to an increased risk of diabetes. A more detailed list of risk factors is listed below:

• Increasing age.
• Increasing BMI.
• Sedentary lifestyle.
• Family history of type 2 diabetes (especially first-degree relatives).
• Ethnicity – South Asian, African, African–Caribbean, Chinese.
• Gestational diabetes.
• Polycystic ovarian syndrome.
• Medical conditions such as Cushing’s syndrome.
• Medication such as corticosteroids and antipsychotics.
• Severe mental health conditions (e.g. schizophrenia).

 
Why is it important to identify prediabetes?

Section 5

First, people with prediabetes are at high risk of progression to type 2 diabetes. The annual conversion rate from prediabetes to type 2 diabetes has been estimated to be around 5–10%, with a similar proportion reverting to normoglycaemia (Tabák et al, 2012).

In addition, people with prediabetes are at increased risk of developing macrovascular and microvascular complications (Palladino et al, 2020).

Which individuals do you think are more likely to progress from prediabetes to type 2 diabetes?

Section 6

In a retrospective cohort study of 400 000 people in the UK with prediabetes (HbA_1c 42–47 mmol/mol) between 2005 and 2017, Gardner et al (2023) identified higher progression rates to type 2 diabetes for:

• South Asian (hazard ratio [HR] 1.31) and mixed-race (HR 1.22) but not Black populations (HR 0.98) compared to those with white European ethnicity.
• Greater levels of socioeconomic deprivation.
• Overweight/obesity versus normal/underweight.
• Age 40–65 years versus younger or older populations.

 
Similar findings have become apparent in the NHS Diabetes Prevention Programme annual audits. Overall, following an initial diagnosis of prediabetes, 5.4%, 10% and 13% were diagnosed with diabetes after 1, 2 and 3 years, respectively (NHS England, 2022).

What diabetes complications can arise in prediabetes?

Section 7

Prediabetes is not in itself a benign state. A recent meta-analysis demonstrated that, compared to people with normoglycaemia, prediabetes is associated with an increased risk of cardiovascular disease and all-cause mortality (Cai et al, 2020).

A study using UK Biobank data showed that people with an HbA_1c in the range of 39–47 mmol/mol were at increased risk of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), heart failure and overall mortality when compared to people with an HbA_1c <39 mmol/mol. There was a steady gradient of risk seen with HbA_1c levels below the diagnostic threshold for diabetes. In this study, 13.8% of individuals with prediabetes developed ASCVD or CKD over 11 years (Honigberg et al, 2021).

A recent review of 95 meta-analyses concluded that prediabetes is associated with increased risk of all-cause mortality, ASCVD, CKD, heart failure, atrial fibrillation, total cancers and all-cause dementia compared to people with normoglycaemia (Schlesinger et al, 2022).

Whilst microvascular problems are a less clearly documented problem in prediabetes, the UKPDS (UK Prospective Diabetes Study) found evidence of these at the time of diagnosis of diabetes in a quarter of individuals (UKPDS Group, 1998). One review found that, based on eGFR criteria and/or the presence of albuminuria, diabetic kidney disease can develop in the prediabetic stages (Branda et al, 2019). A recent systematic review found a 6.6% prevalence of retinopathy in people with prediabetes versus 3.2% in those with normal glucose tolerance (Kirthi et al, 2022).

Are you aware of any evidence supporting interventions that reduce the progression of prediabetes to diabetes?

Section 8 – Preventing the progression of prediabetes to diabetes: The evidence

Several large randomised controlled trials in a variety of countries have investigated the effect of lifestyle intervention on prevention of type 2 diabetes. The Finish Diabetes Prevention Study was one of the first to demonstrate that intensive lifestyle intervention based on dietary change and exercise effectively reduced the risk of developing diabetes in people with impaired glucose tolerance (Tuomilehto et al, 2001).

The US Diabetes Prevention Program achieved a 58% relative risk reduction of developing type 2 diabetes through intensive lifestyle measures versus standard advice (Knowler et al, 2002). In follow-up studies, both the Finnish and the US interventions demonstrated persistence of benefits after the end of the trials.

Metformin has been the most frequently studied medication in diabetes prevention trials. Compared with no pharmacological treatment, metformin achieved a 31% relative risk reduction in onset of type 2 diabetes in the US Diabetes Prevention Program (Knowler et al, 2002).

Summarising the available evidence, a meta-analysis concluded that lifestyle interventions based on diet and exercise can achieve around a 50% relative risk reduction of type 2 diabetes in those at high risk of diabetes (Gillies et al, 2007). Medication, notably metformin, can also be effective, but lifestyle intervention appears to be superior.

A recent network meta-analysis of 63 real-world studies of lifestyle intervention for diabetes prevention in a cohort with prediabetes or diabetes risk factors found a 9% cumulative incidence of type 2 diabetes with intervention versus 12% in the control group: a 29% relative risk reduction (Galaviz et al, 2021).

How would you manage Shona’s prediabetes?

Section 9

You could start by explaining to Shona what prediabetes means and the potential problems associated with it. You could then move on to discuss the importance of dietary adjustment, regular exercise and weight loss.

Shona should be offered referral to the appropriate local provider of a lifestyle programme for prediabetes. In Shona’s case, this would be the Healthier You NHS Diabetes Prevention Programme, which runs in England (see later). Other options, depending on local resources, might include referral to a dietitian or a health and wellbeing coach.

A cardiovascular risk assessment can be performed using the QRISK®3 tool (available at: https://qrisk.org) to allow a decision as to whether statin therapy should be offered. Blood pressure control, smoking cessation and moderation of alcohol consumption are all, where appropriate, important interventions.

In Shona’s case, the QRISK3 score comes out at around 3.5%, and so statin therapy would not currently be indicated (the recommended threshold for treatment being 10%), although it is worth noting that prediabetes is not factored in as a risk factor in the QRISK3 model.

The Healthier You NHS Diabetes Prevention Programme has been rolled out across England. What are the eligibility criteria for referral?

Section 10

Healthier You is an evidence-based lifestyle change programme consisting of at least 13 sessions run over 9 months, which can be delivered face to face or remotely via a digital service with group support. The aim is to empower people to eat healthily, increase physical exercise and manage their weight (Bakhai, 2021; NHS England, 2023).

All individuals over the age of 18 years with an HbA_1c of 42–47 mmol/mol (6.0–6.4%) or a fasting plasma glucose of 5.5–6.9 mmol/L in the last 12 months can be referred by GP practices in England to the Healthier You programme. Additionally, women with previous gestational diabetes who are subsequently normoglycaemic are eligible for the programme (Bakhai, 2021).

If availability of places is limited then priority for the programme should be given to those with HbA_1c 44–47 mmol/mol and fasting plasma glucose 6.5–6.9 mmol/L. If HbA_1c is 48 mmol/mol or more, or if fasting glucose is 7.0 mmol/L or more, then the type 2 diabetes pathway should be followed.

Outside England, lifestyle change programmes for those with prediabetes should be offered by Health Boards and Public Health organisations.

What lifestyle advice could you suggest to Shona?

Section 11

In line with NICE PH38 recommendations (NICE, 2017), you could encourage Shona to:

• Increase consumption of foods that are high in dietary fibre (e.g. whole grains, vegetables, fruit, beans, lentils, cereals).
• Reduce the total amount of fat, particularly saturated fat, in her diet; for example, by consuming low-fat dairy products and fish and lean meats rather than fatty and processed meats.
• Aim for a minimum of 150 minutes of moderate-intensity physical activity per week.
• Aim to gradually lose weight, to reach and maintain a BMI within the healthy range.

 
Bear in mind, however, that any changes should be agreed with Shona and be achievable and sustainable within the context of her daily life.

What follow-up would you arrange for Shona?

Section 12

If Shona takes up the invitation to attend a diabetes prevention programme, she will receive follow-up from here. Without this, it would be supportive to offer Shona a follow-up appointment with the Practice Nurse to review how she is managing her lifestyle change after a couple of months.

If Shona required treatment for blood pressure and dyslipidaemia, follow-up with appropriate measurements should be arranged. Shona should have a repeat BMI, blood pressure, HbA_1c, renal function and lipid profile on an annual basis.

When might you consider offering medication to Shona?

Section 13

If Shona had a blood pressure persistently above 140/90 mmHg, she should be offered antihypertensive medication. If her QRISK3 score was 10% or more, she could be offered atorvastatin 20 mg once daily.

In terms of prediabetes management, if Shona was unresponsive (in terms of glycaemic control improvement) or unable to undertake lifestyle change, then metformin could be considered as an evidence-based treatment option (NICE, 2017). The dose of metformin should be gradually titrated up to 2 g daily, re-checking HbA_1c after 3 months or so. If gastrointestinal problems arise, there is the option of using modified-release metformin.

NICE suggests to consider the use of orlistat in those individuals with a BMI of 28.0 kg/m² or more, in conjunction with a low-fat diet. Review progress after 12 weeks to decide whether orlistat is effective (aim for a loss of 5% of original body weight) and tolerated (NICE, 2017).

Any consideration for medication should, of course, take account of Shona’s future plans for a further pregnancy.

Are you aware of any newer treatments for weight loss that could be used in people who have not progressed to type 2 diabetes?

Section 14

The injectable GLP-1 receptor agonists liraglutide and semaglutide have both gained a licence for weight loss alongside lifestyle management in obese/overweight people without type 2 diabetes.

NICE recommends liraglutide 3 mg once daily (Saxenda®), alongside a reduced-calorie diet and increased physical activity, for individuals with prediabetes (defined as an HbA_1c 42–47 mmol/mol or fasting glucose 5.5–6.9 mmol/L) who have a BMI of ≥35 kg/m² (or ≥32.5 kg/m² in a higher-risk ethnic minority group) and are at high risk of cardiovascular disease (hypertension, hyperlipidaemia). Treatment should be initiated from a Tier 3 weight management service (NICE, 2020; NICE, 2023a).

NICE also recommends semaglutide 2.4 mg once weekly (Wegovy®) to treat obesity in people with at least one weight-related comorbidity, which would include prediabetes, for a maximum treatment duration of 2 years, again within the context of a specialist weight management service (NICE, 2023a; NICE, 2023b).

It should be mentioned that, at the time of writing, availability of GLP-1 RAs is severely restricted. The GIP/GLP-1 receptor agonist tirzepatide has gained a licence for obesity management; however, NICE guidance on its use has yet to be published.

Who else would you test for prediabetes?

Section 15

Consider opportunistic HbA_1c or fasting plasma glucose testing in people with risk factors for type 2 diabetes (described earlier) to identify those with prediabetes, who should then be offered referral to a lifestyle programme.

NICE (2017) has recommended a two-stage process of identifying people at high risk of type 2 diabetes. The first step enables people to perform a risk assessment using either a validated questionnaire or a computer-based assessment, such as the Diabetes UK “Know your risk” tool (available at: https://riskscore.diabetes.org.uk/). Such an assessment could be performed by the individual themselves or offered at a GP surgery, pharmacy or other health facility.

High-risk individuals from the first step can then undergo a blood test for hyperglycaemia, and management then depends on whether this result is normal or indicates prediabetes or diabetes.

This ends the case study. The final section includes supplemental information on the effectiveness of the Healthier You NHS Diabetes Prevention Programme.

Section 16: Early outcome data from the NHS Diabetes Prevention Programme

Nearly 325 000 people were referred during the first 2.5 years of the NHS Diabetes Prevention Programme. Just over half of those referred attended at least the initial assessment, achieving a mean weight loss of 2.3 kg and an HbA_1c reduction of 1.26 mmol/mol. Of those who completed the programme (defined as attending >60% of sessions), reductions of 3.3 kg and 2.04 mmol/mol in weight and HbA_1c, respectively, were attained (Valabhji, 2020).

Whilst these changes are small, they would predict a significant attenuation of the progress from prediabetes to type 2 diabetes.