Care should be taken to address the potential harmful effects of optimising blood glucose control when setting individual glycaemic targets
Interventions to achieve target glycated haemoglobin (HbA1c) should begin with lifestyle modification followed by pharmacological options selected on the basis of individual clinical circumstances, side effects and contraindications
Blood glucose control should be optimised because of its beneficial effects on the development and progression of microvascular complications
*Refer to Summary, explanation and source of recommendations for an explanation of the level of evidence and grade of evidence
In addition to lifestyle modification, people with type 2 diabetes may require pharmacotherapy to achieve long-term glycaemic control and to prevent complications of diabetes. There may be a need to commence medication without delay in patients who are symptomatic of hyperglycaemia or having accompanying metabolic dysfunction (eg ketosis), while providing ongoing lifestyle support.
The benefits of management of hyperglycaemia for the prevention of microvascular complications have been demonstrated in randomised clinical trials. BP and lipidlowering therapy have also been demonstrated in clinical trials to show clear benefits in preventing cardiovascular events and reducing premature mortality.
The choice, order and combination of medications used are based on evidence of improved clinical outcomes, risk of side effects and patient choice/capacity.
Use of these therapies is associated with risks and other negative effects. These should be taken into consideration when deciding the appropriateness of implementing the treatment recommendations contained in these guidelines. These therapies may be contraindicated in some situations and their use may result in troublesome side effects.
Multiple glucose-lowering pharmacotherapies are available (Appendix E. Available glucose-lowering agents).
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.
The Australian blood glucose treatment algorithm for type 2 diabetes (Figure 4) is an evidence-based algorithm developed by the Australian Diabetes Society (ADS) in consultation with all key stakeholders including the RACGP.
Additionally, when analysing combination therapies used in current suggested algorithms for the management of hyperglycaemia, high-quality trials of clinical outcomes may be lacking. The most studied agents include metformin and sulphonylureas. However, randomised controlled trials (RCTs) investigating the safety of newer agents such as the incretins and sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with high CVD risk are now being reported.106–108
Prescribing algorithms suggest multiple ways of combining agents. Always consult the PBS when combining therapy as restrictions and reimbursement may change. Table 6 provides a guide for clinical considerations when choosing diabetes medications.
Appendix F. Table of evidence and properties of glucose-lowering agents provides the evidence and properties of glucose-lowering agents for this algorithm.
What if medication is not working – The ‘Stop rule’
At each visit, ask about the patient’s understanding of their diabetes and the role of medication in management. Specific enquiry may help decisions on medication efficacy and choices.
Symptoms suggestive of hypoglycaemia or other side effects of medication should trigger a clinical examination and review. Symptoms of hyperglycaemia (eg polyuria, polydipsia), fatigue and visual changes may warn of poor adherence to medication by the patient, or indicate that the medication(s) is/are not effective in glycaemic management.
Confirmation with an assessment of HbA1c (usually every three months) in relation to the individual’s goals may be appropriate. Consideration of the effect of comorbidities (refer Chapter 12.
Diabetes multimorbidity and medication complications) or other medication affecting glycaemic control may need to be assessed and managed. Consideration of a home medicines review by the treating pharmacist may also assist assessment of clinical reasons for problems of persistence, side effects with medication or patient concerns.
The ‘Stop rule’ emphasises that before advancing through additional glycaemiclowering combinations, after evaluating each patient’s HbA1c response after three to six months, support the patient to engage in healthy lifestyle choices, assess for comorbidities and complications (eg CVD risk or distress) and then evaluate the need for additional or altered medication/combination therapy.
Table 6. Clinical considerations when choosing diabetes medications
||Dipeptidyl peptidase-4 inhibitor (DPP-4i)
||Sodium glucose co-transporter 2 inhibitor (SGLT2i)
||Glucagon-like peptide-1 receptor agonist (GLP-1 RA)
|Patients with established or high isk cardiovascular disease (CVD)
||Increase risk when SU compared to metformin monotherapy (excluding gliclazide), but neutral when used in combination with etformin110
||Neutral107,111–114 Refer to Note A
||Not yet known115
||Contraindication if symptomatic heart failure*116
||Selective benefit/not yet known117 Refer to Note B
||Selective benefit/118,119 not yet known Refer to Note C
|Patients with risk from hypoglycaemia
||Lower rates compared to SU110
||Higher clinical risks as monotherapy and combination with other agents110 Gliclazide – 50% fewer hypoglycaemia episodes versus glimepiride122
||Lower rates compared to SU110
||Lower rates compared to SU110
||Lower rates compared to SU110
||Lower rates compared to SU110
||Lower hypoglycaemia when metformin is added to basal versus premixed insulin (consider risks greater with prandial insulin)123
|Patients at risk of gastrointestinal conditions (eg irritable bowel syndrome [IBS], inflammatory bowel disease [IBD] and gastroparesis)
||Known intolerance as monotherapy or combination therapy – diarrhoea110,124
||Known Intolerance – bloating and flatulence†
||Known intolerance – nausea and vomiting, and diarrhoea ‡ 110
|Patients in whom stabilisation of body mass index [BMI] or weight loss is desired
||Neutral effect (gliclazide)125 Modest gain (other SUs) compared to metformin monotherapy110
||Less weight gain (when added to metformin versus metformin and SU)110
||Modest gain compared with other dual combination therapies110
||Modest weight loss (in monotherapy, plus in combination with metformin versus metformin with alternate dual oral drug combinations)§ 110
||Weight loss (in monotherapy, plus in combination with metformin versus metformin with alternate dual oral drug combinations)||
||Modest gain – risk greater with prandial insulin110,123
|Patients with renal dysfunction (eg lowered estimated glomerular filtration rate [eGFR])
||Reduce dose eGFR 30–60
Contraindication with eGFR <30124
|Hypoglycaemia risk increases
||Safe with dose reduction# Refer to Note D
||Contraindication in severe renal impairment**
||Efficacy decreases, thus contraindication with moderate renal impairment††
||Hypoglycaemia risk increases
|Unique/class-specific pharmacological effects
||Monotherapy or combination with other agents (DPP- 4i or SGLT2i) is available to reduce ‘pill burden’
||The Australian algorithm (refer to Figure 4) suggests they may be used as monotherapy or combined with other agents
||Contraindication – do not use with a GLP–1 RA
||Increased atypical fractures relative risk (RR) 1.57127 in women* Rare – Pioglitazone has been associated with an overall 63% increased risk of bladder cancer, with the risk increasing with increasing duration of use and dose128
||Modest lowering of blood pressure (BP)110 Increased genitourinary (especially females) Refer to Note E Rare – euglycaemic ketoacidosis‡‡
||Once weekly formulations are available‡ Contraindication – do not combine with a DPP-4i
||Dose required to be titrated to glycaemic goals
DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon like peptide-1 receptor agonist; IBD, Inflammatory bowel disease; IBS, Irritable bowel syndrome; insulin, basal, basal analogue, NPH and rapid-acting or prandial insulins including mixed insulins; PI, product information; SGLT2i, sodium glucose co-transporter 2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione
Important to note
Clinical considerations have been derived from the attached main references: Bennet W et al,127 Qaseem A et al 129 and Bolen T et al110
Careful interpretation of results is recommended due to medication in combination studies having variance from Australian prescribing algorithms Due consideration to each individual patient, diabetes and metabolic goals, disease and complication burden, medication side effects, and costs and psychosocial factors need to be incorporated in decision making, not just the medication factors (Table 6)
SU: Statements of evidence (SOEs) strengths110 are related to the common forms available in the US – but are not inclusive of gliclazide, the most commonly used SU agent in Australia
Note A. DPP-4i and heart failure: In the SAVOR-TIMI 53 trial107 – hospitalisations for heart failure (a secondary outcome) increased with saxagliptin. Despite this, a recent meta-analysis found difficulty in drawing firm negative conclusions on the comparative safety of this class of drugs in heart failure
Note B. SGLT2i: The EMPA-REG outcome trial117 found that patients with diabetes with existing CVD risk had reduced all-cause mortality and death from cardiovascular causes with empagliflozin. There have been no reported clinical trials for other drugs in this class
Note C. GLP-1 RA – The LEADER trial, a prospective cardiovascular safety outcomes trial for liraglutide, found a 13% reduction in major adverse cardiac events and a 22% reduction in cardiovascular death in high-risk cardiovascular patients.130 This effect has not been replicated in similar trials for lixisenatide and no trials on exenatide have yet been reported
Note D. DPP-4i: All except linagliptin (no dose reduction) as this is hepatically metablised
Note E. All classes: The recent Agency for Healthcare Research and Quality (AHRQ) US review110 determined no moderate to high levels of evidence for the following adverse events (this does not mean no risk):
- Lactic acidosis (metformin)
- Urinary tract infections/fractures/volume depletion (SGLT2i)
- pancreatitis (DPP-4i and GLP-1 RA)
- bladder cancer risks (pioglitazones)
- thyroid cancer (GLP-1 RA)
*Pioglitazone product information
†Acarbose product information
‡Exenatide product information
§Dapagliflozin product information (–2.14 kg) as an add-on to metformin versus placebo at 104 weeks; empagliflozin (–1.63 kg) and (–2.03 kg) at doses 10 mg and 25 mg respectively as an add-on to metformin at 24 weeks\
||Exenatide –1 kg to 3.9 kg in comparative trials with combinations including metformin and SU and TZD
#All except linigliptin (no dose reduction)
**Exenatide (Bydureon) product information
††Dapagliflozin contraindicated of eGFR <60; empagliflozin/canagliflozin contraindicated of eGFR <45
‡‡Safety advisory – risk of diabetic ketoacidosis
Beginning glucose-lowering therapy
Healthy eating, physical activity and education remain the foundation of all type 2 diabetes treatment programs.
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 a number of trials exploring the effects of various therapies on major cardiovascular events such as myocardial infarction (MI) and stroke.These trials include short-term trials of dipeptidyl peptidase-4 inhibitors (DPP-4i; oral: saxagliptin, alogliptin and sitagliptin) and glucagon like peptide-1 receptor agonists (GLP-1 RA; injectables: lixisenatide and liraglutide) and a sodium glucose co-transporter 2 inhibitor (SGLT2i; empagliflozin). However, there is a lack of data regarding long-term outcomes as well as potentially serious adverse outcomes associated with some of the newer agents. Unfortunately, a simple stepwise algorithm cannot match all individual patient’s needs.
The Australian Diabetes Society position statement131 provides patient options based on consideration of efficacy, side effects, and costs.
Start with the correct dose of each medication and review on an individual basis at least every three to six months, keeping in mind the patient’s individual HbA1c target.132
Each different class of glycaemic medications may have common and uncommon side effects that impact quality of life and require careful clinical re-assessment. Examples include some weight gain with sulphonylureas,110 or mycotic infections and the rare euglycaemic diabetic ketoacidosis with SGLT2i.
Some patient groups (eg elderly and those with multiple comorbidities) may not be represented in the published clinical outcome trials of newer diabetes agents, so caution should be exercised when considering choice of agents for these patients.
When used as monotherapy, metformin, acarbose, glitazones, GLP-1 RA, DPP-4i and SGLT2i should not cause hypoglycaemia.
Long-acting sulphonylureas (eg glimepiride) or sulphonylureas with renally excreted active metabolites (eg glibenclamide) are more likely to cause hypoglycaemia than shorter-acting sulphonylureas (eg gliclazide).133,134
Special care needs to be taken with those at increased risk of hypoglycaemia, especially the elderly. People taking sulphonylureas or insulin may need to notify motor vehicle licensing authorities as these medications can affect driving performance, as well as increase the patient’s burden by requiring glucose self monitoring, especially on initiation or dose titrations. It is important that patients inform their insurance agents or companies (also refer to Chapter 14. Management of other impacts of diabetes).