Type 2 diabetes: when metformin is not enough

Key points

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 HbA_1c reduction, the most extensive long-term safety and outcome data, and lower cost^1,3 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 HbA_1c
adverse effect profile
impacts on microvascular and macrovascular outcomes
long-term safety data
cost-effectiveness
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 HbA_1ccompared to other second-line oral agents (Table 1)¹
have long-term safety data which are supported by decades of clinical experience^{1, 3} and beneficial microvascular outcome data^{7, 8}
are cost-effective³ for the healthcare system and for some patients.¹

Table 1: Expected decrease in HbA_1c using different glucose-lowering medicines^a
Medicine class	Expected decrease in HbA_1c
Metformin	0.5%–1.5%
Sulfonylureas	1.0%–2.0%
Acarbose	~0.5%–1%
Thiazolidinediones	0.5%–1.4%
GLP-1 analogues^b	0.75%–1.03%
DPP-4 inhibitors	0.6%–0.8%
SGLT2 inhibitors	0.9%
Insulin^b	1.5%–3.5%

^a HbA_1c reduction is presented as percentage change from levels reported at baseline. Reported HbA_1c 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 HbA_1c-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, including⁴the 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 HbA_1c 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).

Table 2: When sulfonylureas are not appropriate to add on to metformin for blood glucose lowering
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 appropriate1,¹⁵If 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 children^18-20	Seek specialist advice⁴
Severe hepatic impairment	Yes. Sulfonylureas are contraindicated⁴	Limited experience,¹ but options include sitagliptin,²¹ saxagliptin²²and linagliptin,²³exenatide²⁴ 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

Table 3: Common side effects and tolerability concerns associated with non-sulfonylurea oral glucose-lowering medicines
Class of oral glucose-lowering medicine	Tolerability and side effect profile
DPP-4 inhibitors	Common adverse effects include headache, musculoskeletal pain, mild gastrointestinal disturbance and nasopharyngitis.^1,4 Pancreatitis and joint pain have been reported in post-marketing experience.^21-23 Well-tolerated and not associated with weight gain or hypoglycaemia.²⁵
SGLT2 inhibitors	Common adverse effects include genital and urinary tract infections.^1,4 Associated with modest weight loss, generally do not cause hypoglycaemia unless used with a sulfonylurea or insulin.^1,4
Acarbose	Common adverse effects include bloating and flatulence that can be difficult to tolerate.¹ Limited role in therapy.⁴
Thiazolidinediones	Associated with more serious and severe adverse effects.¹ These include heart failure, bladder cancer, increased risk of non-axial fractures in women.¹ Also associated with weight gain and fluid retention.¹ Not generally recommended as initial choice for dual or triple therapy.¹

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.

See 'Pharmacological therapies in Australia for type 2 diabetes'.

Table 4: Injectable glucose-lowering medicines: safety and efficacy
	GLP-1 analogue	Insulin
Place in therapy	Second-line option: In combination with metformin or a sulfonylurea, if patient is willing to inject.^1,5 Only exenatide is PBS-listed, liraglutide is not.²⁶ Third-line option: Particularly if patient has BMI > 30 kg/m² or wishes to lose weight.⁵	Can be used at any stage in the treatment cascade, but often reserved for when oral therapies fail to achieve glycaemic targets^1,25 or cannot be used (pregnancy, breastfeeding, surgery).⁴ 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
Efficacy	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
Safety	Side effects: Weight loss, gastrointestinal effects such as nausea and vomiting.^1,5 Associated with increased risk of pancreatitis.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.

Expert reviewers

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.

Type 2 diabetes: when metformin is not enough

Key points

An individualised approach

Glucose-lowering medicines: beyond metformin

Not all sulfonylureas are the same

Which patients require additional monitoring on sulfonylureas?

When to consider other add-on oral glucose lowering medicines

Fixed-dose combination products

More long-term safety data are required

Improve patient safety through adverse event reporting

Expert reviewers

References

Date published: 01 June 2016

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Type 2 diabetes: when metformin is not enough

Key points

An individualised approach

Glucose-lowering medicines: beyond metformin

Not all sulfonylureas are the same

Which patients require additional monitoring on sulfonylureas?

When to consider other add-on oral glucose lowering medicines

Fixed-dose combination products

More long-term safety data are required

Improve patient safety through adverse event reporting

Expert reviewers

References

Date published: 01 June 2016

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