NPS Prescribing Practice Review 40: Early use of insulin and oral antidiabetic drugs
Published in MedicineWise News
Date published: About this date
- Early and continuing lifestyle interventions decrease disease progression
- Initiate insulin early by adding night-time basal insulin to oral antidiabetic agents
- Ensure metformin is part of ongoing therapy and use of thiazolidinediones does not delay progression to insulin
- Review use of thiazolidinediones in heart failure and ischaemic heart disease
Reinforce the importance of lifestyle change at every opportunity
Encourage people to eat healthily, quit smoking and be more active whenever an opportunity arises. Lifestyle changes improve outcomes among people with type 2 diabetes1 but can be difficult to make and sustain. The SNAP or Lifescripts programs can be used to help people achieve and sustain lifestyle changes.
Prescribe 30 minutes of moderate intensity exercise at least 5 times a week
Encourage moderate intensity exercise (e.g. brisk walking) for at least 30 minutesA ≥ 5 times a week.2,3 This should cause a slight, but noticeable, increase in breathing and heart rate and can be accumulated in bouts of 10–15 minutes.2 Unless contraindicated, encourage 3 or more 30 minute sessions of vigorous exercise (causing 'huffing and puffing') a week as well as the minimum amount to provide further health benefits.2
Assess before prescribing a more vigorous exercise program
Assess people with type 2 diabetes before prescribing exercise more strenuous than brisk walking.4,5 Check for symptoms and risk factors of cardiovascular disease or conditions that might rule out more strenuous exercise or increase the risk of injury (e.g. severe neuropathy, retinopathy, nephropathy, microalbumnuria, osteoporosis or arthritis).4,5 Vigorous exercise is contraindicated in people with proliferative and pre-proliferative retinopathy. Prescribe nonweight bearing exercise (e.g. stationary cycling or swimming) for those at greater risk of falls, injuries or foot damage.4,5
Encourage resistance training in addition to aerobic exercise
Encourage people to undertake resistance or strength training (e.g. resistance bands, weights) on 2–3 non-consecutive days per week, in conjunction with aerobic exercise.6,7 This should include 3 sets of 8–10 repetitions, targeting all major muscle groups using weights that cannot be lifted more than 8–10 times each set.5,6
Improvements in HbA1c subside a few days after exercise
The beneficial effects of regular exercise on blood glucose control subside within a few days. Inform people that they should not allow more than 2 days to pass without undertaking some form of exercise.4,6A. At least 60 minutes per day may be required for people who sit for ≥ 4–5 hours a day, or who wish to lose weight.3
Initiate insulin early by adding night-time basal insulin to oral antidiabetic agents
Aim for a target HbA1c ≤ 7% in most patients
The recommended target for glycaemic control is HbA1c ≤ 7%.8 This is suitable for most people but higher targets may be more appropriate for the elderly and those with a history of severe hypoglycaemia or comorbidities.
Consider insulin if HbA1c > 7% after 3 months
Despite intensive therapy, blood glucose control will progressively deteriorate due to the destruction of beta cells.9 Initiation of insulin early in the disease process can reduce hyperglycaemia, reduce microvascular and macrovascular risk, and potentially improve or preserve beta-cell function.10
Consider insulin for people with inadequate glycaemic control (HbA1c > 7%) for a period of 3 months — despite making lifestyle changes and taking maximally tolerated doses of metformin and a sulfonylurea — even if they do not have any symptoms.11
Initiating insulin safely and simply – add bed-time isophane insulin to oral antidiabetic agents
Table 1: Stepwise guide for initiating and adjusting insulin 8,9,12,13
ADD 10 units isophane insulin at bedtime.
CONTINUE metformin, a sulfonylurea or both (at the same dosage, but no greater than the maximum recommended dose)
ADJUST Insulin therapy gradually every 3–4 days according to fasting blood glucose (FBG) level until target FBG is reached (usually 4.0–6.0 mmol/L)B
Mean FBG (mmol/L)
Adjustment to insulin doseB
Increase by 8 units
Increase by 6 units
Increase by 2 units
Decrease by 2–4 units
CHECK overall blood glucose control by measuring HbA1c
If FBG and evening blood glucose are on target but HbA1c is not, look for hidden 'hypers' – blood glucose peaks that occur during the day, often before lunch or after dinner.
Options to correct hidden 'hypers' include:
These are general guidelines for initiating insulin; targets and treatment regimens may differ for some people. Long-acting insulin analogues (insulin glargine or insulin detemir) may be an alternative to isophane insulin for some people.
The above guide to initiating insulin suggests adjusting insulin by 6 to 8 units for patients with mean FBG levels ≥ 8 mmol/L. We have received feedback that this varies from other local guidelines. This guidance is just one way to initiate and titrate insulin. Prescribers concerned about the risk of hypoglycaemia can adjust insulin in increments up to 4 units (every 3–4 days, according to mean FBG), rather than 6 or 8 units. Alternatively, they can follow RACGP (adjust by increments of 10% to 20%) or local guidelines.
Continuing oral antidiabetic agents minimises the risk of weight gain and hypoglycaemia
Add a single, daily injection of basal insulin to metformin and a sulfonylurea. This leads to less weight gain than using insulin alone.15 It also allows insulin to be used at a smaller dose that can be titrated gradually, minimising the risk of hypoglycaemia.13,16 Continue using metformin with insulin. Sulfonylureas should be discontinued if hypoglycaemia develops or once a rapid-acting insulin is added.16 If a thiazolidinedione (or 'glitazone') is being used, consider stopping it once insulin is begun (see final page).
Long-acting insulin analogues are an alternative
All three basal insulins (isophane, glargine and detemir) improve HbA1c levels to a similar extent in people with type 2 diabetes.17,18 The risk of severe hypoglycaemia is similar with insulin glargine and insulin detemir compared with isophane insulin, while the risk of nocturnal hypoglycaemia is lower.17,18 However, data on the long-term safety of insulin glargine and insulin detemir is limited, and their use should be approached cautiously.18,19
Both long-acting insulin analogues reduce, but do not eliminate, the risk of hypoglycaemia. Severe hypoglycaemia has been reported in 0.4% to 2.6%, and nocturnal hypoglycaemia in 17% to 31%, of participants enrolled in trials of insulin detemir or insulin glargine.18
Insulin glargine and insulin detemir are more expensive than isophane insulin.20 Insulin detemir is not currently PBS-listed for use in type 2 diabetes.D Insulin glargine was PBS-listed despite its higher cost as the PBAC accepted that the reduced rate of hypoglycaemic events was cost effective at the price proposed.21,22 Refer to the December 2006 edition of NPS RADAR for more information about insulin glargine.D. Insulin detemir is PBS-listed for use in type 1 diabetes.
Ensure metformin is part of ongoing therapy and use of thiazolidinediones does not delay progression to insulin
Use metformin as a monotherapy and combine with a sulfonylurea if glycaemic control
If lifestyle interventions do not adequately control blood glucose (HbA1c > 7%), start metformin. If metformin is contraindicatedE use a sulfonylurea. If metformin alone (≤ 3 g/day) does not adequately control blood glucose add a sulfonylurea (glibenclamide ≤ 20 mg/day; glicazide ≤ 320 mg/day; glimepiride ≤ 4 mg/day; or glipizide ≤ 40 mg/day).23
A thiazolidinedione may be combined with either metformin or a sulfonylurea if one of these drugs is contraindicated or not tolerated. Be aware that thiazolidinediones increase the risk of oedema and heart failure.
Triple oral therapy using a thiazolidinedione should only be prescribed in limited circumstances
Initiating insulin when metformin and a sulfonylurea no longer provide adequate glycaemic control is preferred to adding a glitazone as a third oral agent (i.e. triple oral therapy).4 Insulin has a better defined long-term safety profile than the thiazolidinediones and is known to reduce microvascular complications.9
While initiating insulin is preferred, triple oral therapy using a thiazolidinedione has a place among people with a severe needle phobia, who are very reluctant to use insulin, who require assistance to administer insulin, or whose job security may be threatened if they use insulin. Be aware that thiazolidinediones increase the risk of oedema and heart failure.
Do not delay initiating insulin if HbA1c > 7% after 3 months despite triple oral therapy
Triple oral therapy (including a thiazolidinedione) should not delay the initiation of insulin if it is required. Around 25% to 30% of people in clinical trials did not respond to thiazolidinediones with an adequate reduction in HbA1c or fasting plasma glucose concentration.24 Consider insulin if triple oral therapy does not adequately control blood glucose (HbA1c > 7%) after 3 months.11E. Impaired renal function (creatinine clearance < 30 mL/min) or history of lactic acidosis. Use with caution in those with heart failure or ischaemic heart disease; the elderly; heavy drinkers and people with impaired liver function.
Review use of thiazolidinediones in heart failure and ischaemic heart disease
Avoid thiazolidinediones in people with heart failure
Thiazolidinediones double the risk of heart failure.25,26 Do not prescribe them for someone with moderate or severe heart failure (New York Heart Association Class III or IV).
Prescribe a thiazolidinedione with caution in people who are asymptomatic or have only mild cardiac insufficiency. Start at the lowest dose and monitor closely for signs of oedema or rapid weight gain.27
Do not prescribe rosiglitazone to those with ischaemic heart disease
Rosiglitazone may increase the risk of myocardial infarction.28 Do not prescribe rosiglitazone for people with known ischaemic heart disease.28 Use with caution in people at high risk of cardiovascular events.28 Pioglitazone does not appear to carry the same risk of myocardial infarction as rosiglitazone.29
Be particularly cautious if adding insulin to a regimen that includes a thiazolidinedione
Rosiglitazone should not be prescribed to people already using insulin as this increases the risk of heart failure and ischaemia.30 It should only be combined with insulin in exceptional circumstances under close supervision due to an increased risk of fluid retention and ischaemia.31,32 Monitor closely for signs of oedema, rapid weight gain or other indicators of potential cardiovascular risk.
Pioglitazone in combination with insulin is also associated with increased fluid retention.33 If combining pioglitazone and insulin, start on a low dose and monitor closely for signs of oedema, rapid weight gain or other indicators of potential cardiovascular risk.
More information on the thiazolidinediones is available in NPS RADAR or in NPS News 56: Managing hyperglycaemia in type 2 diabetes.
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- American Diabetes Association. Diabetes Care 2007;30 Suppl 1:S4–S41.
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- Sigal RJ, et al. Diabetes Care 2006;29:1433–8.
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- Diabetes Australia, RACGP. Diabetes management in general practice 2007/8, 13th edn. Diabetes Australia, 2007.
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- Blonde L. Diabetes Educ 2007;33 Suppl 7:232S–40S.
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- Twigg S, Phillips P. Starting insulin in type 2 diabetes. Medical Observer 4 May 2007.
- Cheng AY, Fantus IG. CMAJ 2005;172:213–26.
- Goudswaard AN, et al. Cochrane Database Syst Rev 2004;(4):CD003418.
- Wong J, Yue D. Aust Prescriber 2004;27:93–6.
- Tran K, et al. Long-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost-effectiveness. Ottawa: Canadian Agency for Drugs and Technologies in Health, 2007
- Horvath K, et al. Cochrane Database Syst Rev 2007;(2):CD005613.
- National Prescribing Centre. MeReC Bulletin 2007;17(4).
- Australian Government Department of Health and Ageing, Canberra.
- Australian Government Department of Health and Ageing. March 2006 Extraordinary Meeting PBAC outcomes - positive recommendations. Canberra: Australian Government Department of Health and Ageing, 2006.
- Australian Government Department of Health and Ageing. Public Summary Document for Insulin glargine, injection, 100 units per mL, 10 mL vials and 3 mL x 5 cartridges, Lantus, March 2006. Canberra: Australian Government Department of Health and Ageing, 2006.
- Australian Medicines Handbook, 2007.
- Diamant M, Heine RJ. Drugs 2003;63:1373–405.
- Singh S, et al. Diabetes Care 2007;30:2148–53.
- Lago RM, et al. Lancet 2007;370:1129–36.
- Nesto RW, et al. Circulation 2003;108:2941–8.
- ADRAC. Australian Adverse Drug Reactions Bulletin 2007;26:22.
- Lincoff AM, et al. JAMA 2007;298:1180–8.
- GlaxoSmithKline Australia Pty Ltd. Avandia product information 8 November 2007. Australia.
- FDA Medwatch. Information for Healthcare Professionals - Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl). Rockville, Maryland: Food and Drug Administration, 2007
- European Medicines Agency. Questions and answers on the benefits and risks of rosiglitazone and pioglitazone. 18 October 2007.
- Rosiglitazone and pioglitazone: cardiovascular safety. Drug Safety Update 2007;1:5–6.