Medicines for type 2 diabetes: 2022 update

For patients who do not achieve treatment targets with lifestyle changes, blood glucose lowering medicines should be introduced.^1,2 Consider starting medicines earlier in patients who are experiencing symptoms or have a consistently high blood glucose level. ^2,4

Pharmacotherapy typically involves starting with an oral glucose-lowering medicine (metformin unless contraindicated or not tolerated) and is progressively intensified by adding medicines if targets are not met despite adequate adherence and titration.^1,2,4

Healthcare professionals may find targeted counselling can address aspects of treatment such as adherence and ensure that care is aligned with an individual persons values and preferences:^1,5

• Ensure the patient understands why the medicine(s) have been prescribed and the benefits of achieving HbA1c targets.
• Highlight long-term benefits of good glycaemic control, including microvascular outcomes (ie, retinopathy, nephropathy and neuropathy) and possibly macrovascular outcomes (ie, ischaemic heart disease, peripheral vascular disease and cerebrovascular disease) depending on patient risk factors and the medicine(s) prescribed.

Access the Australian Diabetic Society (ADS) type 2 diabetes glycaemic management algorithm here.

Metformin is the usual first-choice medicine for people with type 2 diabetes. It is started either at diagnosis or after 2–3 months of lifestyle modifications depending on each patient’s clinical circumstances.^{1, 2, 4, 6} Metformin has been shown to reduce diabetes- related complications and all-cause mortality in overweight patients with type 2 diabetes.⁷ Starting doses should be low and up-titrated gradually.^{1, 2, 6} Modified- release formulations are available.⁴ If metformin is contraindicated or not tolerated, a sulfonylurea (SU) is an alternate approach.^{1, 2, 6}

This decision aid can support conversations with patients with type 2 diabetes who have tried lifestyle changes and are deciding whether to continue with lifestyle changes alone or start metformin. 

Before adding a second or third blood glucose-lowering medicine, other comorbidities or concurrent medicines affecting blood glucose control should be reviewed, as well as lifestyle factors and adherence to treatment.^{1, 2} If the addition of another medicine is appropriate, an individualised approach should be considered, noting that agents work in different ways and should be chosen to work synergistically.

Sodium–glucose co-transporter-2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are newer classes of medicines available for the treatment of type 2 diabetes.⁴ Adding any of these classes to metformin is common and PBS-subsidised for use with either metformin or a SU or both (for some - see Table 1).⁸

Addition of a SU or insulin to metformin monotherapy is an alternative approach.^{1, 6} Insulin is not usually considered until third-line, although some patients may need to add or change to it sooner.²

Acarbose and thiazolidinedione (pioglitazone), while PBS approved, are less common add on treatment options.²

Choice of additional agent(s) should be guided by clinical consideration (such as presence of or high risk of cardiovascular disease, heart failure, chronic kidney disease, hypoglycaemic risk, obesity), side effect profile, contraindications, and cost.

Prescribers may also consider the additional clinical benefits beyond a glucose-lowering effect for SGLT2 inhibitors and GLP-1receptor agonists.

For example, clinical studies comparing SGLT2 inhibitors with placebo and usual care for treatment of type 2 diabetes have shown:

• improved cardiovascular outcomes for patients who are at high risk or have established cardiovascular disease (CVD).⁹
• improved outcomes for patients who are at high risk or have established heart failure.^{10, 11}
• reductions in important major renal end points for patients with chronic kidney disease (CKD), as defined by albuminuria and/or eGFR >30 ml/ min/1.73m2 when used with usual care.¹²

In clinical studies comparing GLP-1 receptor agonists with placebo and usual care for treatment of type 2 diabetes results have reported:

• a loss in weight (mean of 2-5kg over about 30 weeks) if a person is overweight or obese ⁴
• improved cardiovascular outcomes for patients who are at high risk or have established CVD.¹³
• improved cardiovascular outcomes for patients who are at high risk or have established heart failure.¹³

There is also emerging evidence to suggest there may be a reno-protective benefit for people with type 2 diabetes taking GLP-1 receptor agonists, although this has not been consistently seen.^{13, 14}

See the Royal Australian College of General Practitioners Management of type 2 diabetes: A handbook for general practice, Table 1 for further information on clinical considerations when choosing diabetes medicines.

SGLT2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, a SU or insulin (if not included in current dual therapy) can be considered as additional third-line treatment options.

Avoid use of DPP-4 inhibitors with GLP-1 receptor agonists.^{1, 2, 6} They both work through enhancing GLP-1 activity and combining the two classes is not ideal.¹⁵

To intensify treatment to meet glycaemic targets the following options may be appropriate:²

• If on metformin + SU + DPP-4 inhibitor, consider adding SGLT2 inhibitor, or switching DPP-4 inhibitor to a GLP-1 receptor agonist or an SGLT2 inhibitor.
• If on metformin + DPP-4 inhibitor + SGLT2 inhibitor consider adding SU or adding insulin.
• If on GLP-1 receptor agonist consider adding basal or premixed/c0formulated insulin.
• If on basal insulin, consider adding SGLT2 inhibitor or GLP-1 receptor agonist, or bolus insulin with meals, or change to premixed/coformulated insulin.

In addition to replacing or intensifying therapies, consideration should be given to deprescribing where appropriate. Consider stopping any second or third-line medicine that has not reduced HbA1c by >0.5% after 3 months, unless indicated for non-glycaemic benefits.²

Consider consultation with specialist endocrinologist for patients with clinical complexity.

Several metformin fixed-dose combinations (FDCs) are PBS-listed for the treatment of type 2 diabetes (see Table 1).⁸ These FDC products are PBS-subsidised for the same combinations as the individual non-metformin medicine component.

FDC products may improve adherence by simplifying the treatment regimen, but they are not suitable for all patients because of limited combination and dosing options.

As with all FDC products, stabilise patients on the individual components taken separately, before switching to the combination product.

Insulin can be started at any stage in the treatment of type 2 diabetes.^{1, 2, 6} Although it is often reserved until treatment targets cannot be met with other non-insulin medicines, the ADS recommends it be considered early if blood glucose levels are very high.⁶

Insulin is commonly started as a basal once-a-day add-on to oral glucose-lowering medicines, usually metformin. Combinations with DPP-4 inhibitors, SGLT2 inhibitors and GLP-1 receptor agonists are effective but not all PBS-subsidised.

Currently, in addition to glucose-lowering medicines with Unrestricted Benefits listings, the following medicines are PBS-subsidised for use in combination with insulin (Table 2). ⁸