Optimising pharmacological management of HbA_1c levels in patients with type 2 diabetes: from metformin to insulin

Choosing a target: the first step

A HbA_1c target should be individualised and determined by factors such as the patient’s co-morbidities, history of hypoglycaemia and overall health status (Table 1).^{1, 5, 6}

Reaching and maintaining target HbA_1c levels can reduce a patient’s risk of microvascular complications.^1,7 Reducing HbA_1c in patients with particularly high levels, e.g. > 80 mmol/mol, to a more moderate level, e.g. < 65 mmol/mol, is thought to offer the greatest reductions in risk of microvascular complications.¹

Aiming for a very low target is not always best if the risks associated with reducing HbA_1c levels outweigh the benefits.^1,5 Three major clinical trials, the ACCORD, ADVANCE and VADT studies, assessed the effects of treating patients with type 2 diabetes with intensive reduction and maintenance of HbA_1c levels to 46–52 mmol/mol, compared with reducing HbA_1c levels to 58–68 mmol/mol.⁶ Patients in these trials were prescribed a range of medicines to reduce HbA_1c levels, including many of the medicines currently subsidised in New Zealand. These studies found that intensive reduction of HbA_1c levels was associated with a 20% reduction in renal outcomes, such as new or worsening nephropathy, and a 13% reduction in ocular outcomes, such as new or worsening retinopathy; absolute risk reductions were 1–3%.^{6, 8} However, rates of hypoglycaemia were two or more times higher in patients treated to intensive HbA_1c targets and one of the studies, the ACCORD trial, was stopped early due to a higher rate of mortality in patients treated intensively.¹

Table 1: Patient characteristics to consider when selecting an example HbA_1c target^{1, 3}

Regular review is needed to optimise treatment

Measuring HbA_1c levels at three to six month intervals is recommended to determine the effect of lifestyle and pharmacological approaches (Figure 1).⁹ Treatment can then be optimised by checking and reinforcing lifestyle approaches, adjusting doses, adding or withdrawing medicines, or adjusting HbA_1c targets, as appropriate.

Discuss diet and physical activity. For all patients, sustaining lifestyle changes and maintaining weight loss is required for long term improvements in HbA_1c levels and cardiovascular risk factors. Achieving this can be difficult; offer regular encouragement and assessment of any barriers the patient is experiencing.

Discuss medicine use and adverse effects. Ask patients about adverse effects or any difficulties they are having with their prescribed medicines which could contribute to reduced adherence.

Consider the simplicity of the patient’s medicine regimen, including medicines prescribed for co-morbidities, and whether any changes are possible to improve adherence.³

Ask about hypoglycaemia. If patients have symptoms of hypoglycaemia, discuss when they occurred, and the circumstances involved, e.g. a missed meal, acute illness. Ensure the patient is aware of symptoms of nocturnal hypoglycaemia, such as nightmares or disturbed sleep, being particularly hungry in the morning or waking with wet sheets due to sweating.^10,11 Problems with hypoglycaemia should prompt consideration of reducing doses of medicines, changing medicines or adjusting HbA_1c targets.

Patient information on hypoglycaemia is available from: www.healthnavigator.org.nz/health-a-z/l/low-blood-glucose

Hypoglycaemia most often occurs in patients prescribed insulin or a sulphonylurea; the use of metformin, vildagliptin, pioglitazone or acarbose is associated with low rates of hypoglycaemia, with little to no differences in rates compared to treatment with diet alone.¹² Self-monitoring of blood glucose levels is recommended in patients with type 2 diabetes injecting insulin, and may be useful for some patients prescribed sulphonylureas to help identify episodes of hypoglycaemia.

Review management of cardiovascular and renal risk factors: Annual review of cardiovascular and renal risk factors including blood pressure and lipid levels, albumin:creatinine ratio and eGFR are recommended.¹³ In addition, an annual foot check and recall for retinopathy screening every two to three years is recommended.^13,14

Metformin is the initial choice of oral medicine for most patients

Metformin is recommended as the initial pharmacological approach for patients with type 2 diabetes, as it reduces HbA_1c levels and may assist with weight loss (Figure 1 and Table 2).^{3, 5, 6} Metformin should be initiated in all patients at, or soon after, diagnosis unless they have contraindications, such as creatinine clearance (CrCl) < 15 mL/min^*.¹⁵ People who have contraindications to using metformin, or cannot tolerate it, can initiate an alternative oral hypoglycaemic medicine.

Initiate metformin treatment at a low dose, e.g. 500 mg once daily, and gradually increase the dose over the following weeks to a maximum of 1.5–2 g daily, in divided doses, as tolerated.^9,15 A higher maximum dose of 3 g, daily may be prescribed for patients with creatinine clearance > 120 mL/min.¹⁵

Metformin use is associated with gastrointestinal adverse effects in up to 20% of patients. Slow titration may help to avoid this.¹⁶ These adverse effects may improve with continued use, or a temporary decrease in dose could be trialled.¹⁶ Vitamin B12 deficiency occurs in a minority of patients taking metformin; a meta-analysis found that metformin treatment reduces vitamin B12 levels by an average of approximately 60 pmol/L, which may lead to deficiency in some patients.¹⁷

^* The NZF recommends that the Cockcroft-Gault equation should be used to estimate renal function in patients using metformin.¹⁵ A calculator is available here: www.nzf.org.nz/nzf/resource/Creatinine%20Clearance%20Calculator.htm

Consider initiating insulin with metformin in patients with high HbA_1c levels at diagnosis. For patients with particularly high levels of HbA_1c at diagnosis, e.g. > 75 mmol/mol, initiating treatment with metformin in combination with insulin is recommended.³ Alternatively, a second oral glucose-lowering medicine could be added to metformin. Once HbA_1c levels have reduced sufficiently, it may be possible to simplify treatment by withdrawing insulin or reducing doses of oral medicines.

^* Acarbose is another oral glucose lowering medicine available subsidised. It may be useful for some patients, however, when added to metformin treatment it is less effective at lowering HbA_1c levels than other oral medicines.^{12, 18}

^† A vildagliptin + metformin combination formulation is available subsidised

Figure 1: Optimising the management of HbA_1c levels in patients with type 2 diabetes^{3, 5, 6}

Prescribing combination treatment with two oral medicines

If patients require intensification of pharmacological management, the recommended second-line treatment is to combine metformin with another oral glucose-lowering medicine (or use two of these medicines if metformin is contraindicated or not tolerated). Subsidised options include:^{3, 5}

• Vildagliptin^*
• A sulphonylurea: either gliclazide or glipizide^†
• Pioglitazone

^* Subsidised in a single formulation and in combination with metformin

^† Glibenclamide is another subsidised sulphonylurea, however, prescribing glibenclamide is generally not recommended as it is associated with a higher risk of hypoglycaemia than other sulphonylureas¹⁹

When prescribed in combination with metformin there are no clinically meaningful differences in the extent of HbA_1c lowering between vildagliptin, a sulphonylurea or pioglitazone; adding one of these medicines to metformin treatment generally reduces HbA_1c by approximately 8–11 mmol/mol.^{1, 20}

Acarbose is another subsidised glucose-lowering medicine which could be added to metformin treatment, however, available data suggest it is less effective at lowering HbA_1c levels when added to metformin than the medicines above.^{12, 18}

Unsubsidised medicines which could be added to metformin, recommended in international guidelines, include oral sodium glucose cotransporter-2 (SGLT-2) inhibitors and injectable glucagon-like peptide-1 (GLP-1) agonists.⁵

Which medicine to choose?

Clinicians and patients can jointly decide which of the above options to add to treatment after considering any contraindications, medicines interactions or adverse effects (Table 1). Some guidelines favour the addition of vildagliptin or a sulphonylurea instead of pioglitazone due to potential adverse effects associated with pioglitazone.²¹ A combination formulation of metformin + vildagliptin is available subsidised, which may be the simplest second-line approach to help patients achieve their HbA_1c target with less pill burden.²² Vildagliptin or pioglitazone may be preferred over a sulphonylurea if patients have problems with hypoglycaemia or wish to avoid weight gain.

N.B. Prior to initiating vildagliptin, assess liver health by requesting liver function tests (Table 2).²³

For further information on prescribing vildagliptin, see: www.bpac.org.nz/2018/vildagliptin.aspx

Escalating beyond single or dual oral treatment

Discuss insulin initiation with patients who have HbA_1c levels above the desired target despite optimal use of two oral medicines and lifestyle approaches, or where a rapid escalation of pharmacological treatment is required because of high HbA_1c levels.

When discussing the possibility of initiating insulin with a patient, reassurance and advice is often required to ensure that any anxieties about insulin are addressed, e.g. feeling that it signifies an escalation in the seriousness of their condition, being worried or embarrassed about self-injection, needles or calculating doses, and fear of weight gain or hypoglycaemia.

After discussing options some patients may wish to trial more intensive changes to their dietary or physical activity approaches instead of initiating insulin. If this is the case, agree to a time limit for review to ensure that insulin treatment is not unduly delayed.

The use of three oral hypoglycaemic medicines is an alternative to initiating insulin. However, there is little evidence available from clinical trials to guide this practice; in general, the incremental effect of adding a third oral medicine is likely to be less than when these medicines are used alone or in dual treatment combinations^.5 Take into account the patient’s other prescribed medicines, which will often include an angiotensin-converting enzyme (ACE) inhibitor, statin, antihypertensives and aspirin, and consider whether triple oral therapy is likely to create difficulties with adherence.

Table 2: Subsidised oral glucose-lowering medicines and factors to consider when prescribing.^{1, 6, 15}

^* The combination vildagliptin + metformin formulation is not recommended in patients with eGFR< 60 mL/min/1.73m²; prescribing metformin and vildagliptin in separate tablets may be preferable to allow for an appropriate reduced dose of metformin.

Basal insulin is typically the first insulin regimen used

There is no universally preferred insulin regimen: all regimens reduce HbA_1c and clinicians should recommend an approach that will optimise adherence and persistence.

A reasonable initial approach is to prescribe a once daily basal insulin. Basal insulin reduces HbA_1c by controlling hepatic glucose production. Either an intermediate or long-acting insulin formulation can be prescribed as a basal insulin regimen. In contrast short-acting insulin formulations reduce HbA_1c by decreasing glucose levels after a meal (post-prandial).⁵

Once daily injections of a basal insulin are usually administered in the evening and help reduce high blood glucose levels in the morning. However, administering the injection in the morning may be appropriate for some patients who have increases in blood glucose levels throughout the day (Table 3). For example, older people with type 2 diabetes can have greater increases in glucose levels after a meal and lower fasting glucose levels compared to younger people.⁴

For some patients self-monitoring of blood glucose levels (see below) may be useful before initiating insulin to determine their daily pattern of glycaemia. For example, a patient may measure levels before and after main meals for three days prior to initiation.

Table 3: Patient characteristics to guide once daily dosing of basal insulin ³⁰

Most patients can be prescribed isophane insulin

Two types of basal insulin are available fully subsidised in New Zealand:

• Isophane insulin, also known as neutral protamine Hagedorn (NPH) insulin, is an intermediate-acting insulin
• Insulin glargine, an insulin analogue, is a long-acting insulin

Patients can typically be initiated on isophane insulin. Although isophane insulin has a shorter duration of action, both of these insulin formulations result in the same extent of HbA_1c reduction and are associated with similar rates of severe hypoglycaemia.^6,9

Clinicians could consider switching a patient to insulin glargine if they experience problems with hypoglycaemia, as the use of insulin glargine is associated with lower rates of symptomatic and nocturnal hypoglycaemia.⁹ However, switching is not necessary unless there are clinical reasons for doing so.

Patients using insulin should begin self-monitoring of blood glucose

Self-monitoring of blood glucose is recommended to help guide insulin dosing and meal planning.³ For patients with type 2 diabetes initiating basal insulin, a once daily measurement is sufficient, taken either:

• Before breakfast (fasting) if initiating insulin injections in the evening; OR
• Prior to evening dinner if initiating insulin injections in the morning

The aim of treatment is to achieve blood glucose levels between 6–8 mmol/L at these times.³

Start low and increase slowly

Start patients on a basal insulin dose of 10 IU per day.⁵ Patients will need to titrate the insulin dose upwards from this starting point. Having patients adjust their own doses, rather than waiting for instructions from a clinician, is usually a more successful approach for achieving HbA_1c targets.³¹

There are different methods for titration; one example is for patients to start taking 10 IU per day, and then increase the dose by 2 IU every third day until blood glucose levels before breakfast or before dinner are between 6–8 mmol/L.³

If fasting blood glucose levels < 6 mmol/L are recorded, insulin doses should be reduced:³

• Between 4–6 mmol/L: decrease insulin dose by 2 IU
• < 4 mmol/L: decrease insulin dose by 4 IU

If high doses of basal insulin are being used, e.g. approaching or over 1.0 IU/kg, consider switching patients to an alternative regimen which includes short-acting insulin formulations.⁵

Weight gain and hypoglycaemia are the most common adverse effects

Rates of weight gain and hypoglycaemia are dose-dependent. Data from randomised controlled trials of long-acting insulin regimens report that patients have an average weight gain of 2–3 kgs within the first six months of treatment and 2.5% of patients have an episode of severe hypoglycaemia.³² Continuing the use of metformin can help reduce the amount of weight gain when insulin is initiated.

Ask patients to check their blood glucose levels if they experience symptoms consistent with hypoglycaemia. If episodes of hypoglycaemia occur, consider possible causes, e.g. missed meals, changes in usual carbohydrate intake, sudden changes in exercise. If an obvious cause is not apparent, patients should reduce their insulin dose by 10–20%.⁵ If patients have fasting blood glucose results < 4.0 mmol/L without experiencing symptoms of hypoglycaemia, insulin should be reduced by 10%.²⁹

Patient information on recognising and responding to hypoglycaemia is available at: www.healthnavigator.org.nz/health-a-z/l/low-blood-glucose

Intensifying insulin treatment

Patients who continue to have elevated HbA_1c levels while using a basal insulin regimen may require intensification of insulin treatment. This could include switching to a biphasic insulin formulation, which includes long-acting and short-acting insulins in a premixed solution, or continuing with a basal insulin and adding a short-acting insulin at mealtimes. When intensifying insulin regimens, additional self-monitoring of blood glucose before and after meals is likely to be necessary to check levels and calculate insulin doses.³⁰

In general, insulin regimens used to manage blood glucose levels in patients with type 1 diabetes can be used in patients with type 2 diabetes. Various regimens and injection devices are available; treatment should be tailored to each patient’s need for glucose lowering and their ability to manage administering insulin and calculating dose requirements. Insulin intensification can be managed in primary care, however referring patients to or discussing options with an endocrinologist or diabetes nurse specialist may be appropriate in some situations.⁶

Further information on biphasic and short-acting insulin regimens will be available in a future bpac^nz article on the management of type 1 diabetes.