If the HbA1c remains above 53 mmol/mol despite metformin or first-treatment, a second-line agent may be considered. In hospital, decisions regarding this are typically guided by the Endocrine or Diabetes team. Broadly, these are some of the considerations we have:

• Established cardiovascular disease: consider SGLT2 inhibitors or DPP-4 inhibitors (or GLP-1 analogues*)
• Established heart failure or CKD: consider SGLT2 inhibitors
• For weight loss: SGLT2 inhibitors (or GLP-1 analogues*)
• For those with contraindications to the above drugs: sulphonylureas or insulin therapy

*Do note that GLP-1 analogues are typically used as a third agent although as they are becoming cheaper & have excellent positive macrovascular outcomes they are being introduced earlier for those who are overweight/have metabolic syndrome.

If the HbA1c still remains high, we will aim to commence a third non-Insulin agent. This will follow the same principles as above, but note that GLP-1 analogues & DPP-4 inhibitors are not given together as they have the same underlying mechanism so have no additive effect.

After this (or if no other agents are suitable), if the HbA1c remains above 58 mmol/mol, we will typically start insulin which is discussed in more detail below.

This drug works by making your pancreas release insulin (regardless of the blood sugar). As it causes the release of insulin, it usually causes weight gain & can cause significant hypoglycaemia.

It was frequently used as a second-line therapy because it is cost-effective & has a significant evidence-base supporting its use. These days, the alternative drugs have much better macrovascular outcomes so we’re using sulphonylureas less & less.

Gliclazide is the most commonly used drug in this class as older sulphonylureas increased macrovascular complications. It is typically used in patients who are lean. In patients who are overweight or have established cardiovascular/cerebrovascular or renal disease – you should strongly consider alternative agents.

Starting sulphonylureas:

If the HbA1c remains above 53 mmol/mol, depending on when the patient is hyperglycaemic 40 mg once or twice daily of Gliclazide will be started and titrated based on response. For example, if the patient’s morning/fasting CBG was elevated above the target, we would add in or increase the dose with dinner. For gliclazide, the dose can go up to 160 mg twice daily.

Be particularly careful when using sulphonylureas in:

• Elderly patients (as they can get potent hypoglycaemia increasing risks of falls & injuries)
• Impaired renal function as they can accumulate and cause profound hypoglycaemia that is sometimes prolonged up to 72 hours
• Patients on insulin. In most circumstances, the sulphonylurea should be stopped due to poorly predictable hypoglycaemia & insulin is much easier to titrate

Sick day rules: Sulphonylureas should be held if the patient is not eating & drinking

These work by stopping the breakdown of GLP-1. They are less potent than GLP-1 analogues causing increased insulin secretion with meals but typically not weight loss. They should not be used alongside GLP-1 analogues as they have no additive benefit. They are useful in the elderly and in obese patients.

Commonly used agents include linagliptin, sitagliptin & alogliptin. Of these, linagliptin can be used without dose adjustment in even severe renal failure.

Sick day rules: Usually can be continued without concern

The class includes canagliflozin, dapagliflozin & empagliflozin. These work by blocking glucose reabsorption in the kidneys, therefore, causing a loss of glucose & fluid. They are not expected to cause hypoglycaemia. They can be used on their own or in conjunction with other therapies.

They seem to be very effective at not only diabetic control but the progression of cardiovascular & cerebrovascular disease as well as exacerbations of heart failure. Furthermore, they cause weight loss. Even without diabetes, they reduce the risk of cardiovascular outcomes & exacerbations of heart failure.

Key points to consider:

• Due to glycosuria can cause increased risk of UTIs
• There is a risk of euglycaemic ketoacidosis which is dangerous as with the normal glucose, it could be easily missed! Therefore this drug is contraindicated in anyone who develops ketoacidosis.
• There is a possibility of an increased risk of diabetic foot ulcers & complications. If a patient develops this, you should discuss whether the treatment should continue with the diabetes team

Sick day rules: These drugs should be stopped if a patient is unwell due to the risk of severe dehydration & hypotension

This is typically started as a third-line therapy that works by promoting insulin secretion with meals & increasing satiety thereby reducing caloric intake & weight. As it increases insulin secretion associated with meals, it is not expected to cause hypoglycaemia. The aim is to achieve a reduction of HbA1c of 11 mmol/mol and/or 3% weight loss within 6 months.

As it has such favourable outcomes & is more frequently being used privately to help weight loss, we tend to start it earlier in patients to reduce the risk of long term complications.

Key things to consider:

• It should not be used in conjunction with DPP4 inhibitors
• Warn the patient about transient nausea & GI side effects
• Contraindicated in severe renal impairment
• Rare risk of pancreatitis (therefore shouldn’t be initiated in patients who have had or otherwise are at high risk of pancreatitis)

Sick day rules: GLP-1 analogues should be held if the patient is unwell/at risk of dehydration

Insulin is usually started when the HbA1c remains above 58 mmol/mol despite maximum tolerated oral agents. Starting insulin is no easy task for a patient or a medical professional. The patient or carer is required to inject the medication, self-monitor, have support in titrating the dose, learn how to manage hypoglycaemia & inform the DVLA if they drive.

If insulin is started, sulphonylureas like gliclazide are usually stopped due to the risk of profound hypoglycaemia or because the treatment is clearly failing – the pancreas is simply unable to release any more insulin.

There are multiple potential regimes:

• Basal only (once or twice daily injection) given at a set time to give a long-acting insulin lasting at least 12-16 hours
• Biphasic (or pre-mixed) insulin given twice daily with meals which contains short-acting & long-acting insulin mixed into one vial
• Basal-bolus insulin where there is a long-acting basal agent with short-acting bolus doses with each meal

Patients will be usually started on a basal-only regime with insulin types such as NPH insulin (Humulin I), Insulin Glargine (Lantus/Abasaglar), or Insulin Detemir (Levemir) typically with a dose that is about 10-20 units per day depending on insulin resistance. If they have high CBGs post-meals then the other two regimes may be considered or if their HbA1c is very elevated (above 75 mmol/mol) as per NICE.

In T1DM, most patients will be on a basal-bolus regime as this allows greater flexibility of meal times & doses can be adjusted for each meal.

We usually start around 0.3 units/kg/day to begin with and titrate this up based on a patient’s blood sugars. Usually, patients will need around 0.7-1 unit/kg/day but it is important to avoid hypoglycaemia as this will often scare patients into running their blood sugars high.

Sick day rules: Never stop insulin as illness often results in increased insulin requirement. If in hospital & not eating/drinking, the patient may need to switch to variable rate insulin infusion usually alongside their basal insulin. You should check your local guidelines.

Here is a list of rarely used drugs & an explanation of why that’s the case. If you meet a patient on these drugs, you should review whether they are appropriate.

• Meglitinides like repaglinide can cause weight gain & can worsen cardiovascular outcomes
• Thiazolidinediones like pioglitazone increase the exacerbations of heart failure & causes weight gain
• Alpha-glucosidase inhibitors like acarbose work by inducing malabsorption of carbohydrates causing poorly tolerated GI side effects