Section 1 – Marie

Marie is a 47-year-old lady with type 2 diabetes of 3 years’ duration and has no specific complications from her diabetes. She suffers from depression but has no other significant comorbidities.

Her latest blood results showed HbA_1c 67 mmol/mol; eGFR 82 mL/min/1.73 m²; cholesterol 4.4 mmol/L; non-HDL 2.7 mmol/L. Her blood pressure was 146/93 mmHg and her BMI was 31.7 kg/m².

Marie’s repeat medication consists of metformin 1000 mg twice daily, atorvastatin 20 mg once daily and sertraline 50 mg once daily.

What areas of Marie’s diabetes care should we be aiming to improve?

Section 2

Poor glycaemic control, raised BMI and mild hypertension are issues we need to address with Marie. A reasonable target for Marie’s HbA_1c would be 48 mmol/mol (NICE, 2022a). Weight loss could improve insulin sensitivity and glycaemic control, have a positive effect on blood pressure and reduce the likelihood of the many longer-term consequences of obesity.

How would you classify Marie’s BMI?

Section 3

BMI, defined as weight [kg] ÷ (height [m])², is most commonly used to identify overweight individuals (NICE, 2022b).

• Healthy weight: BMI 18.5–24.9 kg/m².
• Overweight: BMI 25.0–29.9 kg/m².
• Obesity class I: BMI 30.0–34.9 kg/m².
• Obesity class II: BMI 35.5–39.9 kg/m².
• Obesity class III: BMI 40 kg/m² or more.

In people with a Southeast Asian, Black African, African–Caribbean or Chinese family background, lower thresholds should be considered when factoring in BMI as a risk factor, since they are at increased risk of type 2 diabetes and its complications at a lower BMI. Thus, in these ethnic groups, NICE (2022a) advises that the overweight range is 23.0–27.4 kg/m² and obesity is 27.5 kg/m² or above. However, there is good evidence of variation in risk between these ethnic groups, and it has been suggested that ethnicity-specific cut-offs are required to ensure that minority ethnic populations receive appropriate preventative advice, diabetes screening and management of type 2 diabetes (Caleyachetty et al, 2021).

Marie’s BMI of 31.7 kg/m² and her White British ethnicity puts her in the category of obesity class I.

What are the limitations of BMI and do you know another method of assessing adiposity?

Section 4

It is important to remember that BMI does not specifically measure the degree of adiposity. Thus, for example, in highly muscular adults, a raised BMI may be misleading whilst, in the elderly, interpretation of BMI should take account of comorbidities. Waist circumference in combination with BMI may give a better indication of adiposity.

Measurement of waist-to-height ratio (WHR) is recommended by NICE for those with a BMI below 35 kg/m² to more accurately gauge the degree of central adiposity and associated cardiometabolic risk (NICE, 2022b):

• Healthy central adiposity: WHR 0.4–0.49.
• Increased central adiposity: WHR 0.5–0.59.
• High central adiposity: WHR 0.6 or more.

Encourage people to aim for a waist-to-height ratio of under 0.5.

What is the link between obesity and type 2 diabetes?

Section 5

The risk of type 2 diabetes increases significantly in people who are overweight and even more dramatically in those with obesity. The relative risk of an obese person developing type 2 diabetes compared to a person with normal BMI is around 10-fold. Central obesity, whereby excess fat is deposited intra-abdominally (visceral fat), including in the liver and pancreas, and also in the skeletal muscle, is considered to be the principal risk factor for development of type 2 diabetes. This fat deposition gradually increases insulin resistance until the point is reached where insulin secretion (which is initially upregulated) can no longer compensate and type 2 diabetes develops (Golay and Ybarra, 2005).

Not all people with type 2 diabetes are obese, and other features, such as family history and ethnicity, are at play. As described previously, in South Asian, Black African, African–Caribbean and Chinese people, the risk of type 2 diabetes is higher at lower BMI than in Caucasians.

What other medical problems are associated with overweight and obesity?

Section 6

People with overweight or obesity are at increased risk of developing or exacerbating a wide range of medical problems (NICE, 2022b), including:

• Type 2 diabetes.
• Hypertension.
• Dyslipidaemia.
• Stroke.
• Coronary heart disease.
• Breathlessness.
• Gastro-oesophageal reflux disease.
• Gallbladder disease.
• Obstructive sleep apnoea.
• Various cancers.
• Psychological distress, depression.
• Osteoarthritis.
• Reproductive problems.
• Reduced life expectancy.

It has also become clear that both obesity and diabetes are important risk factors for more severe COVID-19 infection (Cao et al, 2021).

How does weight loss benefit the person with type 2 diabetes?

Section 7

Losing weight can reduce the risk of most of the complications listed previously. Weight loss improves insulin sensitivity, enabling improved glycaemic control and reduced need for glucose-lowering medications (ElSayed et al, 2023), and potentially leading to remission of diabetes in someone like Marie, who has a diabetes duration of less than 6 years (Lean et al, 2018; Lean et al, 2019). Weight loss benefits hypertension and dyslipidaemia, improving cardiovascular outcomes in people with type 2 diabetes. There is also good evidence that weight loss can attenuate the progression of prediabetes to type 2 diabetes (Knowler et al, 2002).

What would be your starting point in addressing Marie’s hyperglycaemia and obesity?

Section 8

Starting conversations about weight can feel challenging. Advice and tips on starting weight conversations are available in the Talking about obesity: Obesity UK Language Matters Guide (Obesity UK, 2023).

Lifestyle measures would be worth pursuing first. The subject of weight loss needs to be approached in a sensitive manner. You could ask Marie whether she has thought about losing weight, if she thinks this is possible and what she might need to change for this to happen. Advice should not take the form of personal criticism, as this is likely to be counterproductive. An individualised approach is essential.

Check with Marie if she wishes to discuss diet and eating patterns further. Signposting Marie to resources for healthy eating is useful but also bear in mind that Marie may use eating as a coping mechanism for her depression; in other words, eating for comfort rather than to satisfy hunger (Nash, 2015). Switching to an alternative activity other than eating that is potentially rewarding may help; this could be discussed with Marie and she should be encouraged to come up with some suggestions of her own.

The Mediterranean-style diet probably has the strongest evidence supporting improvement in glycaemic control, weight loss and reduction in cardiovascular disease in people with type 2 diabetes and is widely recommended, although other diets also have merit (Dyson et al, 2018; Evert et al, 2019). Perhaps the most important point is that the diet chosen is achievable and sustainable for the individual concerned, rather than one named diet being right for all those with type 2 diabetes.

Marie should be encouraged to choose carbohydrates with a low glycaemic index and to reduce her total intake of digestible carbohydrate (avoid simple sugars, limit starchy carbohydrates, increase high-fibre carbohydrates). More detail on the recommended diet for people with type 2 diabetes is provided in the NICE NG28 guideline (NICE, 2022a) and from Diabetes UK (Dyson et al, 2018).

For advice on exercise, try and see what interests Marie has that could be built into her lifestyle and are achievable and sustainable. NICE and Diabetes UK recommend at least 150 minutes of moderate to vigorous physical activity per week, spread over at least 3 days (Dyson et al, 2018; NICE, 2022a). Whilst physical activity may have limited effect on weight loss, it can reduce insulin resistance, improving HbA_1c, and benefit cardiovascular and mental health.

Marie should be offered referral to the local structured education programme for type 2 diabetes (along with family members as appropriate) if this has not previously been arranged (NICE, 2022a).

How much weight loss should you advise Marie to aim for?

Section 9

NICE advises setting an initial target body weight loss of 5–10% for adults with type 2 diabetes who are overweight, although lesser degrees of weight loss are still likely to be beneficial (NICE, 2022a). Diabetes UK advises to aim for a weight loss of at least 5%, if overweight, by reducing calorie intake and increasing energy expenditure (Dyson et al, 2018). However, if a target weight is not achieved, this should not simply be declared as “failure”, but rather an opportunity to learn, change and then move forward (Nash, 2017).

What diabetes medications might be useful additions in managing Marie’s obesity?

Section 10

The two therapies in frequent usage in the UK that simultaneously improve glycaemic control and induce weight loss (other than metformin, which may induce a small degree of weight loss) are the SGLT2 inhibitors and the GLP-1 receptor agonists (GLP-1 RAs); both of these could reasonably be considered as an add-on treatment to metformin (Davies et al, 2022).

The SGLT2 inhibitors achieve reductions in HbA_1c and weight by facilitating glycosuria (Marshall, 2018). Weight loss is variable but often around 3 kg (SIGN, 2017; Davies et al, 2022).

Weight loss with the GLP-1 RAs in people with type 2 diabetes is associated with reduced appetite (Sun et al, 2015). This reaches a plateau after around 6 months of treatment and can vary between agents within the class, typically from around 1.5 kg to 6 kg, the highest reductions being found with semaglutide (both subcutaneous and oral formulations) > liraglutide > dulaglutide > exenatide > lixisenatide (Nauck and Meier, 2019; Husain et al, 2019; Davies et al, 2022). At the time of writing, however, the supply of GLP-1 RAs in the UK is very limited.

The weight loss observed with SGLT2 inhibitors and GLP-1 RAs contrasts with the weight gain seen with insulin, sulfonylureas (e.g. gliclazide), meglitinides (e.g. repaglinide) and thiazolidinediones (e.g. pioglitazone). DPP-4 inhibitors (e.g. sitagliptin) are weight-neutral.

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Lifestyle issues are discussed with Marie and she is directed towards the Diabetes UK website for advice on diet. Alternative coping mechanisms to comfort eating are suggested. After considering the options, Marie chooses to try an SGLT2 inhibitor and is commenced on empagliflozin 10 mg once daily.

Section 11 – Anya

Anya is 59 years old with a 12-year history of type 2 diabetes. She is maintained on triple oral therapy for her diabetes: metformin 1000 mg twice daily, gliclazide 160 mg twice daily and linagliptin 5 mg once daily. Glycaemic control remains suboptimal with an HbA_1c of 73 mmol/mol. An SGLT2 inhibitor has been tried but was poorly tolerated because of recurrent thrush.

A major issue for Anya is her weight, and she has a BMI of 35.8 kg/m². Attempts to lose weight have proved difficult, although she is now eating a healthier diet and has been provided with supportive information.

Anya’s renal, liver and thyroid blood tests are normal and her lipid profile is favourable on atorvastatin 20 mg once daily. Anya has background retinopathy but there is no evidence of diabetic nephropathy or neuropathy.

What might you choose as the next treatment option for Anya to address glycaemic control and obesity?

Section 12

An attractive option here would be a GLP-1 RA (noting Anya’s intolerance of SGLT2 inhibitors), which could offer both improvement in glycaemic control and weight loss. Whilst pioglitazone and insulin will benefit hyperglycaemia, both therapies are likely to result in weight gain.

After considering treatment options, Anya is keen to try GLP-1 RA therapy. The possibility of gastrointestinal side-effects, particularly nausea, is explained to her. After discussion of different modes of administration, Anya expresses a preference for oral therapy over injectable therapy. There is no past history of pancreatitis, and Anya had no more than background retinopathy on recent retinal screening.

Anya is commenced on oral semaglutide 3 mg once daily, with a view to uptitrating the dose to 7 mg once daily after one month (Pearson et al, 2019). The linagliptin is discontinued on commencing the semaglutide, and the dose of gliclazide is cut to 80 mg twice daily to reduce the risk of hypoglycaemia.

What instructions would you offer Anya with regard to the dosing schedule of oral semaglutide?

Section 13

Oral semaglutide should be taken on waking with a small quantity of water, and avoiding food, drink and other medications for at least 30 minutes afterwards (see Rybelsus SmPC). The dosing schedule is to ensure sufficient absorption of semaglutide. Even then, bioavailability is very low (given that semaglutide is a peptide) and only made feasible by use of an absorption enhancer to facilitate transcellular passage.

Section 14 – Jason

Jason is 42 years old and was diagnosed with type 2 diabetes 7 years ago. Despite treatment with metformin 1000 mg twice daily, gliclazide 160 mg twice daily, dapagliflozin 10 mg once daily and liraglutide 1.8 mg once daily, his HbA_1c is well above target, at 85 mmol/mol. His BMI is 41 kg/m². Renal function tests are satisfactory and thus far there has been no evidence of microalbuminuria, diabetic retinopathy or neuropathy.

What options are available to improve Jason’s glycaemic control and obesity?

Section 15

Semaglutide is a more powerful GLP-1 RA than liraglutide both in terms of glucose-lowering and weight loss, so you might consider switching the daily liraglutide injections to once-weekly semaglutide injections (assuming availability of semaglutide, which currently, along with other GLP-1 RAs, is not readily available). Beyond this, the introduction of insulin should be considered but, while this would be beneficial for glycaemic control, it will inevitably lead to weight gain. Jason is likely to be strongly insulin-resistant and may well require large doses of insulin to achieve satisfactory control of his hyperglycaemia.

For this degree of obesity, and because Jason is still at a relatively early stage of his diabetes, bariatric surgery should be considered as an option.

How effective and safe is bariatric surgery?

Section 16

Randomised controlled trials in obese people with type 2 diabetes have demonstrated the superiority of various forms of bariatric surgery in improving glycaemic control compared with intensive medical treatment (Mingrone et al, 2012; Shauer et al, 2012), including remission of diabetes, although this effect tends to be eroded over time (ElSayed et al, 2023). For individuals undergoing Roux-en-Y gastric bypass, remission rates of 30–63% have been reported after 1–5 years (Isman et al, 2016). Decreasing insulin resistance and increasing pancreatic insulin production appear to be the main mechanisms at work.  Bariatric surgery reduces the risk of cardiovascular events and the incidence of microvascular complications, decreases cancer risk and improves quality of life compared to non-surgical intervention (ElSayed et al, 2023).

The safety and efficacy of bariatric procedures has improved in conjunction with the utilisation of laparoscopic surgery. There are risks and complications associated with surgery, and patient selection is crucial to maximise the possibility of good outcomes.

When should you consider bariatric surgery for obesity in the context of type 2 diabetes?

Section 17

For people with type 2 diabetes, NICE CG189 recommends bariatric surgery as a treatment option if BMI is 35 kg/m² or more after all appropriate non-surgical measures have been tried and clinically beneficial weight loss has not been achieved (NICE, 2022b). It is a requirement that the person receives an intensive weight management programme in a tier 3 service (a multidisciplinary team comprising a physician [consultant or GP with a special interest], specialist nurse, specialist dietitian, psychologist and physiotherapist/physical activity specialist). The individual will need to be fit enough for anaesthesia and surgery, and to understand the need for long-term follow-up; nutritional and metabolic status monitoring, lifestyle and mental health support are important (ElSayed et al, 2023).

In the case of recent-onset type 2 diabetes (<10 years since diagnosis), an expedited assessment for bariatric surgery should be offered and referral can also be considered for those with a BMI of 30–34.9 kg/m². An assessment for bariatric surgery may be requested for people with Asian family origin at a lower BMI than other populations (NICE, 2022b).

What should you include in a referral letter for bariatric surgery?

Section 18

A checklist you may find useful is outlined below (Wardle et al, 2017).

• Patient height, weight, BMI.
• Problems associated with obesity.
• Weight loss strategies attempted (lifestyle, pharmacological).
• Patient motivation, expectation.
• Past medical history, smoking/alcohol, relevant social history.
• Current medication.
• Recent investigations (HbA_1c, lipids, renal/thyroid/liver function, blood pressure).

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Jason is referred to the bariatric surgery team and the tier 3 service within that.

What complications should you look out for in primary care following bariatric surgery?

Section 19

Acute post-surgery problems include vomiting, acid reflux, abdominal pain, wound infection, haemorrhage and deep vein thrombosis and pulmonary embolus (Birkmeyer et al, 2010). In the longer term, nutritional deficiencies may arise, particularly so in gastric bypass procedures. Vitamin B12, folate and iron deficiencies are all possibilities that may require use of supplements. Calcium deficiency may trigger secondary hyperparathyroidism necessitating the use of calcium/vitamin D supplements to counter the risk of osteoporosis (ElSayed et al, 2023).

Incisional hernias are relatively common (an estimated 10–20% of patients) and there is an increased risk of gallstones post-bariatric surgery. Dumping syndrome is a well-recognised post-prandial event subsequent to consumption of food with a high glycaemic index. High quantities of sugars entering the small intestine trigger release of large amounts of insulin and this leads to hypoglycaemia; clinically, this manifests as fatigue, dizziness, facial flushing, sweating, palpitations and passage of loose stool (Thondam et al, 2012).

The psychological sequelae of bariatric surgery may be significant (risk of anxiety, depression and suicidal ideation), and the importance of continued support following surgery is emphasised (ElSayed et al, 2023).

Can you think of any other medical treatments for obesity that might be of use in type 2 diabetes?

Section 20

In the NICE CG189 guideline, orlistat, an intestinal lipase inhibitor, is recommended as an option in the overall management plan of obesity at a BMI of 28 kg/m² or more in the situation of type 2 diabetes (in comparison to a BMI of 30 kg/m² or more in the absence of associated risk factors). The stipulation for a ≥5% loss in body weight after 12 weeks’ treatment with orlistat is lifted in the case of type 2 diabetes (NICE, 2022b).

Aside from specific use to treat type 2 diabetes, the injectable GLP-1 RAs liraglutide and semaglutide have both gained a licence for weight loss alongside lifestyle management, with steady dose escalation to higher doses than indicated for glycaemic control, if:

• BMI is at least 30 kg/m².

or

• BMI is 27 to < 30 kg/m² and there is at least one weight-related comorbidity (including prediabetes, type 2 diabetes, hypertension, hyperlipidaemia or obstructive sleep apnoea).

Liraglutide 3 mg once daily (Saxenda®) has been recommended by NICE (2020), alongside a reduced-calorie diet and increased physical activity, for individuals who have all of the following:

• Non-diabetic hyperglycaemia (impaired glucose regulation, or “prediabetes”, defined as an HbA_1c of 42–47 mmol/mol or a fasting glucose of 5.5–6.9 mmol/L).
• A BMI of 35 kg/m² or more (or 32.5 kg/m² in a higher-risk ethnic group).
• High risk of cardiovascular disease (hypertension, hyperlipidaemia).

Treatment should be initiated from a tier 3 weight management service. In comparative trials, liraglutide induced greater weight reduction than orlistat (Das, 2021).

Semaglutide 2.4 mg once weekly (Wegovy®) has been recently recommended in NICE TA875 to treat overweight and obesity in people with at least one weight-related comorbidity up to a maximum duration of 2 years, again within the context of a specialist weight management service (NICE, 2023).

Unimolecular co-agonists are being developed that act simultaneously on GLP-1 and other receptors to facilitate greater improvements in glycaemic control and weight loss. Tirzepatide is a dual GIP/GLP-1 receptor agonist that has gained a licence for glycaemic control in type 2 diabetes and has demonstrated impressive reductions in weight both for people with and without type 2 diabetes (Garvey et al, 2023).