- Medicine selection for treatment of type 2 diabetes has become increasingly complex – especially selecting medicines available on the PBS for use when metformin monotherapy is no longer sufficient.
- Finding the most suitable ‘add-on’ treatment option(s) for an individual patient requires assessing the patient’s characteristics and preferences, and understanding key characteristics of different glucose-lowering medicines, including their efficacy and safety profiles.1,2
- Sulfonylureas are the usual initial add-on treatment to metformin – they have similar efficacy for HbA1c reduction, the most extensive long-term safety and outcome data, and lower cost1,3 compared with other oral glucose-lowering medicines.
- Other oral medicines are suitable alternative add-on options to metformin in some clinical situations, based on medicine and patient characteristics.1,4
An individualised approach
The current approach to management of type 2 diabetes involves individualisation of treatment and is centred on achieving glycaemic control while minimising the risk of hypoglycaemia. When choosing between oral blood glucose-lowering medicines for people who have not achieved adequate glycaemic control from first-line treatments, consider: 1,5
- efficacy in reducing HbA1c
- adverse effect profile
- impacts on microvascular and macrovascular outcomes
- long-term safety data
- individual patient characteristics, preferences and clinical situation, including body weight and comorbidities.1
Glucose-lowering medicines: beyond metformin
Current Australian guidelines recommend sulfonylureas as the usual initial second-line option, if treatment with metformin has failed to adequately control blood glucose levels.1,5,6
For most patients with type 2 diabetes, sulfonylureas:
- achieve similar reductions in HbA1c compared to other second-line oral agents (Table 1)1
- have long-term safety data which are supported by decades of clinical experience1, 3 and beneficial microvascular outcome data7, 8
- are cost-effective3 for the healthcare system and for some patients.1
|Medicine class||Expected decrease in HbA1c|
a HbA1c reduction is presented as percentage change from levels reported at baseline. Reported HbA1c reduction may be impacted by medicine class, dose, duration of diabetes and baseline glycaemia. Created using data from updated ADS guidelines.
b injectable agents
Not all sulfonylureas are the same
While comparable HbA1c-lowering effects are seen across the class,12-14 short-acting sulfonylureas (gliclazide and glipizide) have significant advantages and are generally preferred over long-acting sulfonylureas (glibenclamide and glimepiride), particularly because they are less likely to cause hypoglycaemia.1, 5, 15 In addition, it has been shown that people taking gliclazide can avoid escalation to insulin treatment for longer (14.5 years) than those taking the long-acting sulfonylurea glibenclamide (mean of 8 years).16
The lower risk of hypoglycaemia in patients taking gliclazide compared to glimepiride has been demonstrated across multiple studies. A 2015 systematic review and meta-analysis has also demonstrated a significantly lower risk of hypoglycaemia for gliclazide in comparison to other sulfonylureas (risk ratio 0.47, 95% CI 0.27–0.79, p = 0.004).13
There are currently limited data available comparing incidence of hypoglycaemia with gliclazide to other classes of oral blood glucose-lowering medicines. A recent systematic review and meta-analysis reported the risk of mild hypoglycaemia with gliclazide was not significantly different from other oral blood glucose-lowering medicines, including DPP-4 inhibitors (risk ratio 0.85, 95% CI 0.66–1.09, p = 0.20).13
Another study has reported incidence of non-severe hypoglycaemic events to be 2.2% for gliclazide users, compared to 1.8% for those using other oral blood glucose-lowering medicines (risk ratio 1.09, 95% CI 0.20–5.78).14 However, it was noted that there was a high heterogeneity across studies, and the definition and recording of hypoglycaemic events differed substantially between studies.14
Long-acting sulfonylureas have metabolites that are excreted renally,17 and should be avoided in older people, particularly those with deteriorating kidney function.15 Gliclazide and glipizide are metabolised by the liver, and are the sulfonylureas of choice for these patients.15
Short-acting sulfonylureas are comparable to long-acting sulfonylureas in their effects on weight. There are limited data on weight comparisons between gliclazide and other glucose-lowering medicines.
Which patients require additional monitoring on sulfonylureas?
- Those at increased risk of hypoglycaemia require additional blood glucose monitoring, including4 the elderly, and people on concurrent medicines which can impact glycaemic control.d,4
- Those with mild or moderate hepatic impairment may require dose adjustment and monitoring of impact on liver and risk of hypoglycaemia.1
- Those with mild (CrCl 30–60 mL/min) or moderate renal impairment (CrCl 15–30 mL/min) may require dose adjustment and monitoring of risk of hypoglycaemia.1
d Medicines which are more likely to have a clinically significant effect on glycaemic control include glucocorticoids, antipsychotics, calcineurin inhibitors such as cyclosporin or tacrolimus, somatotropin and thiazide diuretics (high doses), and possibly beta blockers (data are conflicting), and alcohol (counsel patients to limit alcohol intake or take food with alcohol).4
When to consider other add-on oral glucose lowering medicines
Patient-centred factors such as comorbidities, risk of hypoglycaemia, tolerability and glycaemic control also influence treatment choices.3 So, while sulfonylureas are the preferred choice, DPP-4 inhibitors and SGLT2 inhibitors can also be considered second-line options and have been PBS-listed for this use in recent years.
These medicines show similar efficacy to sulfonylureas for HbA1c reduction, and can be suitable for addition to metformin in some clinical situations (Table 2).1,3, 5 In addition, the side effect profiles of oral blood glucose-lowering medicines vary greatly, which can impact individual decisions to prescribe (Table 3).
For some patients, injectable blood glucose-lowering medicines may also be an appropriate second-line option (Table 4).
|Clinical situation||Consider an alternative second-line medicine?||Alternative medicine|
|If adverse effects are unacceptable or intolerable||Yes, if adverse effects cannot be controlled through dose adjustment or diet/lifestyle,15 or using short-acting sulfonylureas15||If weight gain is problematic: a DPP-4 inhibitor, SGLT2 inhibitor, or GLP-1 analogue may be appropriate1,15 If hypoglycaemia is problematic: a DPP-4 inhibitor or SGLT2 inhibitor may be appropriate1|
|During pregnancy and while breastfeeding||Yes. Sulfonylureas are contraindicated4||Insulin is safe to use, but seek specialist advice4|
|Children under 18 years of age||Yes. Sulfonylureas are not recommended, limited data on the safety and efficacy of sulfonylureas in children18-20||Seek specialist advice4|
|Severe hepatic impairment||Yes. Sulfonylureas are contraindicated4||Limited experience,1 but options include sitagliptin,21 saxagliptin22and linagliptin,23 exenatide24 or insulin18|
|Severe renal impairment||Yes or reduce sulfonylurea dosage due to increased risk of hypoglycaemia. Short-acting agents are preferred||Options include sitagliptin, alogliptin, saxagliptin and vildagliptin with dose adjustment, and linagliptin without dose adjustment|
|Class of oral glucose-lowering medicine||Tolerability and side effect profile|
Fixed-dose combination products
NPS Radar (December 2015) examined the active ingredients in the wide range of fixed-dose combination medicines now available for lowering blood glucose.
|Place in therapy||
Third-line option: Particularly if patient has BMI > 30 kg/m2 or wishes to lose weight.5
Consider if blood glucose levels are very high or there are signs of metabolic decompensation, and other situations including perioperatively, or when high-dose corticosteroids are used.1
Slightly superior to oral agents.1
Benefits: Low risk of hypoglycaemia,5 improves satiety and may be associated with weight loss,25 beneficial effect on blood pressure (appears to be independent of weight loss) but with a mild increase in resting heart rate.1
The most potent glucose-lowering medicine available.
Benefits: With adequate dose and dietary adherence, will almost always achieve target glucose levels.1
Limited long-term safety and efficacy data available.4
Side effects: Hypoglycaemia and weight gain.1,4,5
More long-term safety data are required
Long-term trials assessing DPP-4 inhibitors on clinical endpoints, such as macrovascular and microvascular outcomes, are lacking,25 as are long-term data assessing any potential impact on immune responses and the pancreas.4
In addition, the recent EMPA-REG OUTCOME trial demonstrated some positive short-term cardiovascular outcomes of empagliflozin in patients with type 2 diabetes who were at high risk of cardiovascular events.27 These benefits included lower risk of death from cardiovascular causes (hazard ratio 0.62, 95% CI 0.49–0.77), death from any cause (hazard ratio 0.68, 95% CI 0.57–0.82) and hospitalisation for heart failure (hazard ratio 0.65, 95% CI 0.5–0.85) when compared to placebo.27 Although these results showed benefits in the short term (median observation time was 3.1 years),27 the longer-term efficacy and safety of SGLT2 inhibitors is not yet known.25,4
The impact of canagliflozin* on bone strength also requires further investigation, after a slightly increased incidence of fractures was observed in women during the first 26 weeks of treatment.4
* Canagliflozin (Invokana) has been delisted from the PBS, effective 1 August 2015.
Improve patient safety through adverse event reporting
Remember to follow up with patients about any adverse effects they experience, particularly with newer agents whose full adverse effect profile is still emerging.
- Dr Roy Rasalam, Head of Clinical Skills and Medical Director, James Cook University, Townsville, Qld.
- Dr Joey Kaye, Director of Diabetes Services, Sir Charles Gairdner Hospital, Nedlands, WA.
- Australian Diabetes Society. A new blood glucose management algorithm for type 2 diabetes. A position statement of the Australian Diabetes Society. Australia: Australian Diabetes Society, 2014. [Online] (accessed 23 March 2015).
- Davoren P. Glucose-lowering medicines for type 2 diabetes. Aust Fam Physician 2015;44:176-9. Online].
- Australian Therapeutic Guidelines (etg). Choice of antihyperglycaemic drug and combination therapies in type 2 diabetes. 2015. [eTG online] (accessed 23 March 2016).
- Australian Medicines Handbook [online]. Drugs for diabetes, type 2 diabetes. ed. Australian Medicines Handbook, 2015, Online] (accessed 9 March 2015).
- Royal Australian College of General Practitioners. General practice management of type 2 diabetes 2014-2015. 2014. [Online] (accessed 23 March 2016).
- Australian Diabetes Society. Australian Blood Glucose Treatment Algorithm for Type 2 Diabetes. Sydney, 2016.
- Simpson SH, Lee J, Choi S, et al. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol 2015;3:43-51. [PubMed].
- Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72. PubMed].
- Zhang Y, Hong J, Chi J, et al. Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas – a meta-analysis from randomized clinical trials. Diabetes Metab Res and Rev 2014;30:241-56. [PubMed].
- Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015-22. [PubMed].
- Australian Diabetes Society. Australian Blood Glucose Treatment Algorithm for Type 2 Diabetes. Table of evidence and properties of glucose-lowering agents. Sydney, 2016.
- Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest 2004;34:535-42. [PubMed].
- Chan SP and Colagiuri S. Systematic review and meta-analysis of the efficacy and hypoglycemic safety of gliclazide versus other insulinotropic agents. Diabetes Res Clin Pract 2015;110:75-81. [PubMed].
- Landman GWD, de Bock GH, van Hateren KJJ, et al. Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials. PLoS One 2014;9:e82880. [PubMed].
- Australian Therapeutic Guidelines (etg). Sulfonylureas in type 2 diabetes. 2015. [eTG online] (accessed 23 March 2016).
- Satoh J, Takahashi K, Takizawa Y, et al. Secondary sulfonylurea failure: comparison of period until insulin treatment between diabetic patients treated with gliclazide and glibenclamide. Diabetes Res Clin Pract 2005;70:291-7. [PubMed].
- Veitch PC and Clifton-Bligh RJ. Long-acting sulfonylureas - long-acting hypoglycaemia. Med J Aust 2004;180:84-5. [Online].
- Actavis Pty Ltd. Glimepiride product information. 2011. [Online] (accessed 7 March 2016).
- Alphapharm Pty Ltd. Melizide (glipizide) product information. 1993. [Online] (accessed 7 March 2016).
- Sanofi-Aventis Australia Pty Ltd. Glibenclamide product information. 2000. [Online] (accessed 7 March 2016).
- Merck Sharp & Dohme (Australia) Pty Ltd. Januvia (sitagliptin phosphate monohydrate) product information. 2008. [Online] (accessed 7 March 2016).
- AstraZeneca Pty Ltd. Onglyza (saxagliptin) product information. 2011. [Online] (accessed 7 March 2016).
- Boehringer Ingelheim Pty Ltd. Trajenta (linagliptin) product information. 2011. [Online] (accessed 7 March 2016).
- AstraZeneca Pty Ltd. Bydureon (exenatide) product information,. 2012. [Online] (accessed 7 March 2016).
- Australian Therapeutic Guidelines (etg). Antihyperglycaemic therapy. 2015. [eTG online] (accessed 7 March 2016).
- Australian Government Pharmaceutic Benefits Scheme. Exenatide. 2016. [Online] (accessed 8 March 2016).
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New Engl J Med 2015;373:2117-28. [PubMed].