Finally, what comes after metformin – the latest ADA/EASD guidelines made easy

11th October 2018, Dr Chee L Khoo

Over the last 20 years, 5 classes of anti-diabetic agents are now available to choose from. This is great but which do you use after metformin? Guidelines after guidelines in Australia and internationally leave that decision up to us to make the choice on behalf of our patients. They all have different mechanisms of action but pretty much all of them have similar efficacy, reducing HbA1c by about 1.0%. They all have different mechanisms of actions, different additional benefits and different adverse effects. We are meant to individualise and balance up the pros and cons of tight vs less tight glucose control.

This is all well and good but all too confusing for GPs. All we wanted to know is what comes after metformin. Telling us to “individualise” doesn’t help, does it? We are meant to consider, their age, their life expectancy, their co-morbidities and their social environments. We are meant to balanced up the risks and benefits of tight versus less tight control. All sounds very wishy washy, doesn’t it?

The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) came together and issue a joint consensus statement on the management of hyperglycaemia on the 5th October 2018. I was there when it was announced in Berlin. Finally, there is a clear and rational algorithm to guide us to the next agent or agents after metformin.

Let me take you through the 31 page document (without you having to read the 31 pages). It is not just a document about medical treatment for hyperglycaemic control. Comprehensive lifestyle management including weight management and physical activity featured prominently in the recommendations. At every level of intensification of medical treatment, we are reminded to go back and reinforce lifestyle measures. It’s not just the next agent. In a very nice and gentle way, the recommendatons highlighted the issue of clinical inertia. To avoid clinical inertia, “reassess and modify treatment regularly (3-6 months)”.

Specific mention was made on “diet” management. They called it medical nutrition therapy. An individualised programme of medical nutrition therapy should be considered in and offered to all patients with diabetes. Concentrate on food with known health benefits and de-emphasize those associated with harm (saturated fats etc). Overweight and obese patients are encouraged to be in a programme of intensive lifestyle management including food substitution. This may mean VLCD or shakes. Metabolic surgery (Bariatric) is recommended for those with BMI >40 or BMI >35 with poor glycaemic control.

In general, it is recommended that glucose lowering medication be commenced in a stepwise manner if additional agents are required. However, since most agents’ efficacy rarely exceeds 1% of reduction in HbA1c, there are occasions where combination medications may be used at the outset to rapidly achieve glycaemic targets.

Step 1

If HbA1c target is still not met after metformin and lifestyles measures, assess for the presence of cardiovascular disease. If CVD is present, is it atherosclerotic cardiovascular disease (ASCVD) or is it heart failure and/or chronic kidney disease? In other words, is it macrovascular or microvascular disease?

If ASCVD predominates, then choose a SGLT2 inhibitor or a GLP1 injectable that has proven cardiovascular benefit. That means either empagliflozin (Jardiance) or liraglutide (Victoza) or Semaglutide. The problem in Australia is that liraglutide is not on the PBS and Semaglutide is not available yet. Exenatide LAR (Bydureon) do have data that shows a tendency towards cardiovascular benefit although it is not statistically significant.

Please also note that empagliflozin has only been shown to have cardiovascular benefits in patients with diabetes who have established CV disease (not just have the CV risk factors). We don’t have data in patients who do not have established CV disease.

If the patient has heart failure or CKD is present, then choose an agent with proven renal benefits or cardiovascular benefits in cardiac failure if the eGFR is adequate. Once again this leaves us with either empagliflozin, liraglutide or exenatide LAR in Australia.

Step 2

If the patient do not have established ASCVD or CKD, the next question to pose is “is hypoglycaemia a major issue in this patient?” Here, things are simple. You can choose from either an SGLT2 inhibitor, a DPP4 inhibitor, a GLP1 or a TZD. These agents have very low incidence of hypoglycaemia on their own.

Step 3

Does this patient need to lose weight or at least minimise further weight gain? Sulfonylureas are commonly known to cause weight gain. Insulin therapy does the same. The consensus statement specifically recommends that if a patient requires an injectable medication to further lower their glucose levels, GLP1 injectables are preferred the preferred choice to insulin. In other words, use a GLP1 injectable first before using insulin. Initiate and gradually titrate GLP1 injections to HbA1c target.

Insulin is recommended in severe and symptomatic hyperglycaemia.

If, despite maximal dose of the GLP1 injectable, the HbA1c target is not met, add a basal insulin. Initiate at 10U a day (usually before bed) and titrate every 3-5 days to reach fasting glucose target. If despite adequate basal insulin achieving fasting glucose target, the HbA1c target is not reached, add a prandial insulin. Initiate and titrate either a basal plus prandial insulin or a mixed insulin (premix or co-formulation). Further intensification of insulin to a twice or three times a day insulin may be necessary.

In patients on insulin therapy who requires further intensification of therapy, combination of insulin with an SGLT2 inhibitor, GLP1 injectable or prandial insulin can be considered. Evidence of the efficacy and benefit of adding a DPP4 inhibitor to insulin is lacking.

Remember lifestyle measures need to be regularly reinforced and glycaemic control reassessed regularly (every 3-6 months) to avoid clinical inertia.

Access the full guideline here.