8.3 Glucose-lowering agents
Multiple hypoglycaemic pharmacotherapies are available (see Appendix G).
Algorithms have been designed to help navigate choice. However, applying the principles of patient-centred care may mean that choices made by algorithm are not always appropriate.
In Australia, the existing PBS hypoglycaemic pharmacotherapies algorithm was under review by the Pharmaceutical Benefits Advisory Committee at the time of publication. The review is considering how to incorporate the newer agents available on the market.55 The Australian Diabetes Society is also currently developing an evidence-based algorithm which will be made available in the online version of this handbook.
Taking a more holistic approach (e.g. addressing major cardiovascular risks), other evidence-based guidelines such as SIGN suggest ‘standard’ and ‘alternative’ approaches to glycaemic management (see Figure 4).
High-quality, prospective analyses of clinical outcomes with respect to microvascular and macrovascular complications reduction from the use of OHAs are still variable across the different classes.
Additionally, when analysing combination therapies used in current suggested algorithms for management of hyperglycaemia, high-quality trials in positive outcome benefit are lacking. The most studied agents include metformin and sulphonylureas. Newer classes of medications and individual agents such as the incretins and sodium glucose co-transporter 2 (SGLT2) inhibitors have no current randomised placebo controlled prospective trial data to demonstrate positive cardiovascular outcome benefit.
Many different algorithms suggest multiple ways of combining agents. It would be wise to consult the PBS for any combination therapy as the restrictions and reimbursement may change.
Figure 4. Algorithm for lowering glucose in type 2 diabetes
Adapted from the Scottish Intercollegiate Guidelines Network. Management of diabetes. A national clinical guideline: 2010.64 Additional advice and agents added; some advice removed.
Beginning glucose-lowering therapy
Healthy eating, exercise and education remain the foundation of any type 2 diabetes treatment program.
If lifestyle modification is not effective in controlling hyperglycaemia, metformin is the first choice unless contraindicated or not tolerated.
Second-line agents (added to existing metformin) may be necessary and should be chosen using an individualised approach, noting that agents work in different ways and are chosen to work synergistically.
While these guidelines recommend a stepwise approach to the management of type 2 diabetes, glycaemic management has become more complex with an increasing range of medications now available. There are uncertainties about the effects of various therapies on macrovascular events, a lack of data regarding long-term outcomes with newer agents and potentially serious adverse outcomes associated with some medications. Unfortunately a simple stepwise algorithm does not neatly match individualised patient needs. The European/American position statement76 gives patient options depending on choices such as efficacy, risk of hypoglycaemia, major side effects, weight gain and costs but unfortunately does not address the lack of outcome data on individual choices of glycaemic agents.
Start with the correct dose of each medication and review at least every 3 months with the patient’s individual HbA1c target.79
What if medication is not working?
This is where the ‘stop rule’ applies (see Figure 4).
Ask at each visit about hypoglycaemia or other side effects of medication. This is especially relevant for patients who achieve lifestyle changes and are on sulphonylureas or insulin.
As monotherapy agents, metformin, acarbose, glitazones, glucagon-like peptide-1 (GLP-1) mimetics and dipeptidyl peptidase-4 (DPP4) inhibitors will not cause hypoglycaemia.
Some long-acting sulphonylureas are more likely to cause hypoglycaemia than shorter-acting sulphonylureas (e.g. gliclazide).80,81 Special care needs to be taken with those at increased risk of hypoglycaemia, especially in the elderly. People taking sulphonylureas or insulin may need to notify motor vehicle licensing authorities and their insurance company as these medications can affect driving performance (see Section 14).
- International Diabetes Federation. Guideline for management of postmeal glucose in diabetes. Brussels: IDF, 2011.
- Scottish Intercollegiate Guidelines Network (SIGN). Management of diabetes. A national clinical guideline. Edinburgh: SIGN; 2010. (SIGN publication no. 116) Available at: www.sign.ac.uk [Accessed 29 Nov 2013].
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–79.
- Cheung NW, Conn JJ, d’Emden MC, et al. Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Med J Aust 2009;191:339–44.
- Stahl M, Berger W. Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. Diabet Med 1999;16:586–90.
- Ahren B. Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes. Vasc Health Risk Manag 2013;9:155–63.