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30 November 2009
This open label randomised trial suggests that using insulin detemir in people with type 2 diabetes leads to similar median HbA1c levels as twice daily biphasic insulin aspart or prandial insulin, but with fewer episodes of mild hypoglycaemia. However, NICE guidance recommends that, when insulin therapy is necessary, human NPH insulin (which was not compared in this study) is the first choice preparation, with alternatives only in specific circumstances. Moreover, the evidence that tight control of blood glucose brings important benefits to patients with type 2 diabetes is limited.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
Health professionals should continue to follow NICE guidance on the management of type 2 diabetes. If insulin therapy is considered appropriate, it should be initiated with human NPH insulin (isophane insulin) injected at bed-time or twice daily according to need. Alternative insulins should be considered only in specific circumstances. As we have previously blogged, it may well be prudent for prescribers and prescribing managers to review the use of these drugs to see if this is indeed in line with NICE guidance, given that the costs per QALY for these insulins are so large (between 3 and 20 times the usual threshold of £20,000 to £30,000),
What is the background to this?
We have consistently pointed out in other blogs and NPC materials on type 2 diabetes the need to consider glycaemic control in the context of other important interventions (both lifestyle and drug interventions) to reduce cardiovascular (CV) risk. Priority should be given to lifestyle interventions (stopping smoking, losing weight, and taking more exercise as appropriate), controlling blood pressure, taking a statin, and taking metformin.
In some patients, additional hypoglycaemic drugs may be considered to control blood glucose. It is important that practitioners follow NICE guidance on the management of type 2 diabetes and agree individual targets for HbA1c with each patient. These could be greater than the 6.5% (48mmol/mol) target set for people with type 2 diabetes in general and should take into account patient preferences and the balance of likely benefits and harms (such as hypoglycaemia) as well as the medicines management issues.
NICE recommends that if insulin therapy is considered appropriate, it should be initiated with human NPH. Alternative insulins should be considered only in specific circumstances. Long acting analogues such as insulin detemir (marketed by the sponsors of this paper) and insulin glargine are particularly expensive and are of limited cost-effectiveness, according to both NICE and the Canadian Agency for Drugs and Technologies in Health (CADTH).
What does this study claim?
This open label trial recruited 708 people with type 2 diabetes (median duration 9 years) and HbA1c levels of 7.0 to 10.0% (53 to 86mmol/mol) on maximally tolerated doses of metformin and sulfonylurea for at least 4 months. They were randomised to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once-daily (twice if required).
The median HbA1c levels (primary outcome) converged after 1 year and remained stable in all groups, with an overall value at 3 years of 6.9% [52mmol/mol] (95% confidence interval [CI], 6.8 to 7.1% [51 to 54mmol/mol]); these values did not differ significantly in the three groups (P=0.28 for the overall comparison).
Fewer patients in the biphasic group (31.9%) achieved HbA1c levels ≤6.5% (48mmol/mol) than in either the prandial group (44.7%, P=0.006) or the basal group (43.2%, P=0.03). The median number of hypoglycemic events per patient per year was 3.0 in the biphasic group, 5.7 in the prandial group, and 1.7 in the basal group (P<0.001 for the overall comparison). However, this appears to have been due mainly to differences in rates of grade 1 hypoglycemia (symptoms plus a self-measured capillary glucose level of ≥3.1mmol/L): rates of hypoglycemia of grade 2 (symptoms with a self-measured capillary glucose level of <3.1mmol/L) or grade 3 (third-party assistance required) converged among the groups during the second and third years of the study and did not differ significantly in the third year (P=0.44). Given that the primary outcome (median HbA1c levels) did not differ significantly between groups, these differences in secondary outcomes must be viewed with some circumspection.
No significant differences were seen in blood pressure, lipids or renal function, nor were there significant differences in mean changes from baseline on the EuroQol quality of life questionnaire.
So what?
As we have previously blogged, the evidence that tight control of blood glucose (to the target in this trial, HbA1c ≤6.5% [48mmol/mol]) brings important benefits to patients with type 2 diabetes is limited. However, if insulins are included in a patient’s care, the results of this study should not persuade health professionals to depart from NICE guidance. The long-acting insulin analogues have a role in some patients, but their benefits over standard insulin preparations are not as convincing as may be perceived, as discussed in this NPC blog. This study suggests that the advantages of insulin detemir over some other insulin analogues are not large.
Even the apparent simplicity of a regimen of basal insulin detemir may be illusory. During the first year of the study, sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable (an HbA1c of >10.0% [86mmol/mol] or two consecutive values of 8.0% [64mmol/mol] at or after 24 weeks of therapy) or subsequently if HbA1c levels were more than 6.5% (48mmol/L). Notwithstanding the question over the appropriateness of this target for all patients, more patients randomised to insulin detemir required an additional insulin than patients in other groups: 81.6% compared with 67.7% in the biphasic group and 73.6% in the prandial group (P=0.002) for the overall comparison.
Analyses by NICE and CADTH suggest that the relative cost-effectiveness of these drugs is very low. A CADTH meta-analysis from February 2009 concluded that long-acting insulin analogues offer little benefit relative to conventional insulins in terms of glycaemic control or reduced hypoglycemia. In an accompanying health economic analysis, it concluded that use of long-acting analogues, particularly in type 2 diabetes, was unlikely to represent an efficient use of finite health care resources. In type 2 diabetes, insulin glargine was associated with an incremental cost of 642,994 Canadian dollars per QALY compared to NPH insulin and insulin detemir was less effective and more costly.
NICE updated its clinical guideline on management of type 2 diabetes in May 2009. The Assessment Group undertook a de novo cost-effectiveness analysis of the various regimens. The base-case results of the comparison of insulin glargine and insulin detemir against NPH insulin found the insulin analogues to be more effective but more costly ( p 62 of the document). In a male population with starting BMI 30kg/m2, the incremental cost effectiveness ratios (ICERs) for insulin detemir were £187,726 per QALY with no complications at baseline and £417,625 per QALY with complications. Importantly, this analysis incorporated the anticipated health-related quality of life gain associated with the reduced fear of severe hypoglycaemic episodes. ICERs were more than £100,000 per QALY in all scenarios (women and men, greater starting BMIs, etc) and ICERs for insulin glargine were of a similar magnitude.
NICE guidance recommends that, if insulin therapy is considered appropriate, it should be initiated with human NPH. Alternative insulins should be considered only in specific circumstances. Its effect ought to be that the insulin analogues are not used routinely. However, as we have previously blogged, the prescribing data for England show that the uptake of insulin glargine and insulin detemir is now extensive: approximately 40% of all intermediate/long acting insulin items are for these products. Given the financial constraints likely to be placed on the NHS and the very high costs/QALY associated with these drugs, it may be prudent for prescribers and prescribing managers to now review their use to see if this is indeed in line with NICE guidance.
Design: open-label, multicentre randomised controlled trial
Patients: 708 people with type 2 diabetes (median duration 9 years) and HbA1c levels of 7.0 to 10.0% (53 to 86mmol/mol) on maximally tolerated doses of metformin and sulfonylurea for at least 4 months (or monotherapy if either sulfonylurea or metformin was not tolerated).
Intervention and comparison: Twice-daily biphasic insulin aspart (NovoMix 30), three-times-daily prandial insulin aspart (NovoRapid), or once-daily (twice if required) basal insulin detemir (Levemir). During the first year of the study, sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable (an HbA1c of >10.0% [86mmol/mol] or two consecutive values of 8.0% [64mmol/mol] at or after 24 weeks of therapy) or subsequently if HbA1c levels were more than 6.5%
Outcomes and results: Primary outcome: median HbA1c levels converged after 1 year and remained stable in all groups, with an overall value at 3 years of 6.9% [52mmol/mol] (95%CI, 6.8 to 7.1% [51 to 54mmol/mol]); these values did not differ significantly in the three groups (P=0.28 for the overall comparison).
Secondary outcomes: fewer patients in the biphasic group (31.9%) achieved HbA1c levels of ≤6.5% (48mmol/mol) than in either the prandial group (44.7%, P=0.006) or the basal group (43.2%, P=0.03) The corresponding proportions of patients with an HbA1c level of ≤7.0% (53mmol/mol) also differed significantly between the biphasic group (49.4%) and each of the two other groups, with 67.4% in the prandial group (P<0.001) and 63.2% in the basal group (P=0.02). Overall hypoglycemia rates were highest in the prandial group and lowest in the basal group. The median number of hypoglycemic events per patient per year during the trial was 3.0 in the biphasic group, 5.7 in the prandial group, and 1.7 in the basal group (P<0.001 for the overall comparison). However, rates of hypoglycemia of grade 2 (symptoms with a self-measured capillary glucose level of <3.1mmol/L) or 3 (third-party assistance required) converged among the groups during the second and third years of the study and did not differ significantly in the third year (P=0.44).
At 3 years, no clinically relevant between-group differences were seen in changes from baseline in either systolic or diastolic blood pressure, high-density lipoprotein or low-density lipoprotein cholesterol, triglycerides, or the ratio of urinary albumin to creatinine, although the differences in high-density lipoprotein cholesterol were significant (P=0.03). In addition, no significant differences were seen in changes from baseline with respect to Winsorized mean scores on the EuroQol Group 5-Dimension Self-Report Questionnaire
Sponsorship: Supported by Novo Nordisk and Diabetes UK.
More information on type 2 diabetes can be found on the relevant section of NPC
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