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Waugh N, Cummins E, Royle P, et al. Newer Agents for Blood Glucose Control in Type 2 Diabetes (Supplement) [Internet]. London: National Institute for Health and Clinical Excellence (UK); 2009 May. (NICE Clinical Guidelines, No. 87S.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Summary

Background

NICE issued an updated guideline (Clinical Guideline 66) for the management of all aspects of type 2 diabetes in May 2008. However new drug developments means that this guideline itself already requires an update. This technology assessment report aims to provide information to support the Short Guideline Development Group (GDG) which will produce a “new drugs update” to the 2008 guideline.

The four classes of drugs which the GDG have been asked to consider are;

  • The glucagon-like peptide 1 analogue, exenatide, in its currently available form, given by injection twice daily. The second drug in that class, liraglutide, was not licensed in time to be included in the guideline update, and nor was the long-acting form of exenatide.
  • The dipeptidyl peptidase 4 inhibitors, sitagliptin and vildagliptin
  • The long-acting insulin analogues, glargine and detemir. Glargine had been the subject of a previous technology appraisal (TA 43) but it was felt that this needed updated. Detemir had not previously been appraised by NICE.
  • The thiazolidinediones (hereafter referred to as the glitazones), more from the safety aspects than for glycaemic control.

Methods

Systematic review of clinical effectiveness studies (systematic reviews and new trials) and economic evaluations.

The bibliographic databases searched were MEDLINE 1990- April 2008, Embase 1990 – April 2008, the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000 – April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Agency (EMEA) and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers’ websites. References cited by retrieved studies were checked for other trials. Auto-Alerts were set up so that new studies were identified as they appeared. For the review of the DPP-4 inhibitors, we searched only for studies published since the time of the searches for the very recent Cochrane review, and used data from that review.

Abstracts of retrieved studies were checked for relevant studies by two reviewers, and in cases where there was doubt, copies of full papers were obtained. Only English language studies were obtained.

Data extraction was carried out by one person, and checked by a second, using pre-defined tables. Studies were assessed for quality using standard methods for reviews of trials as appropriate.

Meta-analyses were done using the Cochrane Review Manager software.

Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE Clinical Guideline 66. This meant that only studies of the new drugs versus an appropriate comparator, and in an appropriate situation, were used. It was assumed that treatment of type 2 diabetes would start with lifestyle measures, principally diet, followed by metformin monotherapy, then by the addition of a sulphonylurea. So the new drugs would be used in addition to metformin and sulphonylurea combination treatment, or as second-line therapy, particularly in those unable to tolerate adequate doses of those drugs. The main implication of this was that trials of the new drugs versus placebo, or as first-line monotherapy, or comparators not relevant to standard practice as laid down in CG 66, were excluded.

The outcomes of most interest for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were;

  • Glycaemic control, as reflected by HbA1c, and taken to be an indicator of the risk of long-term complications of diabetes
  • Hypoglycaemic episodes
  • Changes in weight
  • Adverse events
  • Quality of life
  • Costs

We did not expect to find any trials long enough to have microvascular or macrovascular events as endpoints.

For the glitazones, the main interest was safety, especially the risk of cardiovascular events.

Cost-effectiveness analysis

Modelling of the cost effectiveness of the various regimes has used the UKPDS Outcomes Model, which models the first occurrence of a variety of downstream complications of diabetes and estimates the cost and quality of life impact of these. This was undertaken first for a representative male patient of BMI 30kg/m2 who was assumed to be reaching the 7.5% HbA1c intensification threshold, but was repeated for males with BMI 35, and for females with BMIs 30 and 35.

The absolute HbA1c impacts, weight impacts, cholesterol impacts and SBP impacts for the head to head comparisons as identified within the clinical effectiveness section were applied as 1st line treatment and the UKPDS Outcomes Model given an initial run to predict the evolution of HbA1c. Since treatment would be intensified again once the 7.5% HbA1c intensification threshold was reached; e.g. intensification from 1st line oral treatment to 2nd line basal insulin at the point the UKPDS Outcomes Model predicted the HbA1c would rise above 7.5%, the effectiveness of the 2nd line treatment was applied. The UKPDS Outcomes Model was run a second time to predict the sawtooth evolution of HbA1c for this 1st line, 2nd line combination treatments. In a like manner, where a 3rd line intensification was possible; i.e. switching from 2nd line basal insulin to 3rd line basal bolus insulin, the procedure was undertaken once more with the assumption of a 0.5% improvement in HbA1c on the switch to 3rd line basal bolus insulin.

Costs took into account the need for education and support on starting insulin, and the need for home blood glucose testing. This contrasts with exenatide which has a fixed dose. The UKPDS Outcomes Model predicted the total cost and QALYs arising from routine care and the microvascular and macrovascular complications of diabetes for each treatment sequence.

However, while the UKPDS Outcomes Model is well validated, it does not directly address aspects of the treatments under consideration: e.g. the direct utility effects from weight loss or weight gain, severe hypoglycaemic events, and the fear of severe hypoglycaemic events. As a consequence, the survival curves of the UKPDS Outcomes Model were used to append these effects to the cost and QALY estimates of the UKPDS Outcomes Model.

Results – clinical effectiveness

The GLP-1 analogue - exenatide

We looked first for trials in which exenatide was added to dual therapy with metformin and sulphonylurea, when that combination failed to achieve adequate glycaemia control. Comparators could be placebo, or a glitazone, or insulin.

There were five randomised controlled trials of reasonable quality which addressed our main questions. The main quality problems were insufficient reporting of methods (such as how randomisation was done) and lack of optimisation of other treatments (such as insulin dose). One trial was of exenatide versus insulin in people who were already on insulin. We added two other trials which did not meet our original criteria. One was added in order to provide more data on the insulin versus exenatide comparison; it was in patients who had failed only monotherapy with metformin. The other compared metformin monotherapy with metformin plus exenatide, and was added at the request of the NICE Guideline Development Group to address the question of how to treat patients whose weight was of considerable concern, and in whom adding a sulphonylurea or a glitazone would cause undesirable further weight gain. All trials were sponsored by, and/or had co-authors from, the manufacturer.

HbA1c

In patients with inadequate control on two oral glucose lowering agents, the addition of exenatide led to a fall in HbA1c of about 1%.

In trials against insulins, results on HbA1c were comparable. In one trial in which insulin glargine or exenatide were added to the metformin and sulphonylurea combination, HbA1c was reduced by 1.1% in both groups. In the trial in which exenatide or glargine were added when metformin monotherapy failed, both groups had a reduction of almost 1.4% in HbA1c.

Hypoglycaemia

Severe hypoglycaemic events were few in the trials. With oral combinations, most hypoglycaemic events seen with exenatide were when it was used in combination with a sulphonylurea.

Compared to insulin, there was less nocturnal hypoglycaemia with exenatide, but differences were not marked.

Weight

When exenatide is added to dual therapy, patients tend to lose weight – on average about 2 kg. In comparisons with insulin, patients on exenatide lost weight whereas those on insulin tended to gain it, giving a difference which can be of the order of 5 kg.

Adverse effects

About half the patients on exenatide suffer from nausea. This is usually more at the start of treatment, and is usually moderate or mild. Vomiting is quite common. In the trials, only a small proportion had to stop exenatide because of nausea. In some observational studies, there were higher cessation rates. It is worth noting that the weight loss is not due only to nausea.

Issues

At present, exenatide has to be given by injection, twice daily. A long-acting form is under development which can be given once-weekly. It has been suggested, based on animal experiments, that the GLP-1 agonists may preserve beta cell function. This is unproven in humans. Some studies show that the effect of exenatide wears off after it has been stopped, suggesting that there is no significant effect on beta cell capacity.

Cases of pancreatitis have been reported in people taking exenatide. Most of the early reports were in people with other possible causes of pancreatitis, but with more cases being reported, it looks as if pancreatitis may be a real but rare side-effect of exenatide treatment. The FDA and the MHRA have asked for heightened vigilance and reporting, but have not suggested that exenatide should not be used. If the link is confirmed, the balance of risks between occasional pancreatitis and poorly controlled diabetes will need to be considered.

Summary on exenatide

Exenatide is effective in improving glycaemic control by 1% or a little more, and has the added benefit of modest but useful weight loss. The downside is that it causes frequent nausea (although usually not major and tending to wear off with time), that it has to be given by (at present) twice daily injections, and that there may be a small risk of pancreatitis.

The DPP-4 inhibitors (gliptins)

The licences for these drugs at the time of the review were only for dual therapy with metformin, a glitazone, or (vildagliptin only) a sulphonylurea. However we thought that triple therapy with a metformin, sulphonylurea and a gliptin would be a logical use of the drugs, and looked for trials of that as well. We also looked for trials in which a gliptin was used in combination therapy as an alternative to adding insulin to (usually) metformin.

Only four published trials met our inclusion criteria. All were sponsored by, and had coauthors from, the manufacturers. Two compared a gliptin plus metformin with a glitazone plus metformin. One examined the effect of adding sitagliptin to dual therapy with metformin and sulphonylurea (glimepiride or glipizide). The fourth took patients failing on metformin and added a gliptin or glipizide.

HbA1c

In combination with metformin, the gliptins reduced HbA1c by similar amounts (about 0 .8%) to a glitazone. When added to dual therapy with metformin and glimepiride, sitagliptin reduced HbA1c by about 0.8% compared to the placebo group. When compared to glipizide in dual therapy with metformin, both reduced HbA1c by 0.7%. Reductions are higher in those whose baseline HbA1c is higher, for example a drop of 1.3% in those with baseline HbA1c over 9%.

Hypoglycaemia

No severe hypoglycaemic episodes were reported in patients in the trials. In the wider Cochrane review, severe hypoglycaemia was not reported in any patient on sitagliptin or vildagliptin. Hypoglycaemia was rare in the dual therapy combinations.

Weight

The DPP-4 inhibitors did not seem to have the same weight loss effect as exenatide. In the trials against glitazones, there was less weight gain in the DPP-4 groups, but that reflected weight gain on glitazones rather than loss on a DPP-4 inhibitor. However, absence of significant weight gain is a useful benefit, compared to sulphonylureas and glitazones.

Adverse events

In the short term, the gliptins were very well tolerated. Nausea was not increased. Longer-term data are needed to ensure that there are no adverse effects mediated by the immune system. Data from the Cochrane review show a statistically significant increase in infections with sitagliptin (relative risk 1.29; 95% CI 1.1 – 1.5, p = 0.003) but not with vildagliptin (RR 1.04; 95% CI 0.87 – 1.24).

Other studies

The Cochrane review found 29 comparisons from 25 trials, most of which did not meet our inclusion criteria, usually because they were of gliptin monotherapy versus placebo, or against metformin monotherapy. However these trials suggest that compared to placebo, the gliptins reduce Hba1c by 0.6–0.7%. When compared to monotherapy with other agents, neither drug showed any advantage in HbA1c.

Summary

The gliptins are effective in glycaemia control, reducing HbA1c by about 0.8% in the included trials. Hypoglycaemia was not a problem, and nor was weight gain. Data are required on long-term safety.

Exenatide versus the gliptins

There are no published head to head trials comparing exenatide with either of the gliptins. The main differences are that the DPP-4 inhibitors are given orally, are less expensive, cause fewer side-effects in the short-term, and are weight –neutral rather than having the weight loss seen with exenatide. They may be a little less potent in lowering HbA1c, but that impression is based on indirect comparison, and should be treated with caution.

Long-acting insulin analogues

Given the number of previous reviews, we started by identifying good quality systematic reviews, and then looked for new trials published since the reviews. We drew on three good quality reviews, which included 14 trials of glargine and two of detemir. Three new trials were found, one of glargine and two of detemir. We combined the new trials with the relevant older ones in updated meta-analyses. We also noted one trial of glargine versus detemir.

HbA1c

There was no difference in HbA1c between glargine and NPH, and only a small but non-significant difference in trials of detemir versus NPH (HbA1c was higher with detemir by 0.08%; 95% CI − 0.03 to + 0.19).

Hypoglycaemia

There were no differences in the frequency of severe hypoglycaemia between the analogues and NPH, but overall hypoglycaemia was less frequent with both glargine (OR 0.74; [95% CI: 0.63 to 0.89]) and detemir (OR 0.51 [95% CI 0.35 to 0.76]). Many of the hypoglycaemic episodes were nocturnal, and the odds ratios for those were 0.47 (95% CI: 0.37, 0.59) for glargine and 0.48 (95% CI: 0.37, 0.63) for detemir.

Weight

The meta-analyses showed that those on glargine gained slightly less weight than those on NPH (0.28kg; 95% CI −0.72 to + 0.15) but this was neither clinically nor statistically significant. On detemir, the difference was a little greater (1.2kg; 95% CI −1.6 to − 0.8kg). In the head to head trial of glargine versus detemir, those on glargine gained 3.5kg on average, compared to a gain of 2.7kg on detemir, but the difference of 0.8kg is of doubtful clinical significance. The difference applied only to those on once daily detemir; those on two injections daily gained 3.7 kg.

Insulin dose

In the head to head trial, the mean daily dose was higher for detemir (0.52 units/kg with once daily injections; 1.0 units/kg with twice daily) than for glargine (0.44units /kg with once daily).

Summary

Glargine and detemir are equivalent to NPH (and to each other) in terms of glycaemic control as reflected in HbA1c, but have modest advantages in terms of hypoglycaemia, especially nocturnal. There is little to choose between the two analogues. Detemir when used once daily only, appears to have slightly less weight gain than glargine, but the difference in the head to head trial was under 1 kg and is probably not clinically significant and detemir requires a slightly larger daily dose, at higher cost with present prices.

The glitazones

Little new has emerged since the last guideline was produced. Pioglitazone and rosiglitazone appear to have similar effectiveness in controlling hyperglycaemia, and similar toxicity in terms of oedema, heart failure and fractures (in women only). However the current evidence suggests that rosiglitazone increases the risk of heart attacks and cardiovascular mortality but that pioglitazone reduces it. The statistical significance of the increased risk for rosiglitazone is still debated. Most analyses show an increase in relative risk but some find that this is not statistically significant. This is partly because in most of the trials, the absolute risk of cardiovascular events was low. Most trials were short-term with HbA1c as the main outcome.

Most of the regulatory and prescribing advisory bodies have asked for warnings on rosiglitazone but have allowed its continued use. Some have suggested that in future, pioglitazone be used in preference. Recent prescribing data from the USA shows a marked drop in the use of rosiglitazone, but suggest a shift to gliptins rather than a straight switch to pioglitazone.

Pioglitazone added to insulin

Pioglitazone is licensed for use with insulin when metformin is contraindicated or not tolerated. We included eight trials that examined the benefits of adding pioglitazone to an insulin regimen. In our meta-analysis, the mean reduction in HbA1c was 0.5% (95% CI: −0.73 to − 0.28). Hypoglycaemia was more frequent in the pioglitazone arms (relative risk 1.30; [95% CI: 1.04 to 1.63]). In most studies, those on pioglitazone gained more weight than those who were not, with an average difference of almost 3kg.

Results - costs and cost-effectiveness

The comparisons below are based on evidence from trials of direct comparisons, and so we are limited in what can be done. Costs were changing during the review. The analysis was bedevilled by very small differences in QALYs amongst the drugs, leading to fluctuations in ICERs even with 250,000 iterations.

All costs given here will almost certainly be out of date by publication time.

In terms of annual acquisition costs, among the non-insulin regimes for a representative patient with a BMI of around 30kg/m2 the gliptins are the cheapest of the new drugs with costs of between £386 and £460. The glitazone costs are similar with a total annual cost for pioglitazone of around £437 and for rosiglitazone of around £482 (though this is expected to fall shortly), though this situation may change as they come off patent and generic varieties become available. Exenatide is somewhat more expensive, with an annual cost of around £830. Regimens containing insulin fall between the gliptins and exenatide in terms of their direct costs (including all costs), with NPH-based regimen having an annual cost of around £468 for the representative patient while the glargine and detemir ones are considerably more expensive at around £634 and £716 respectively. Also, insulin dose increases with patient weight and for a BMI of 35 the annual cost of the NPH regime rises to £576, while the cost of glargine rises to £806.

But it should be noted that this is for an insulin regime containing only basal insulin. As beta cell function declines and control worsens, mealtime insulin will be required, increasing annual costs, for example, to around £617 for NPH and £783 for glargine for the representative patient with BMI of 30kg/m2.

For the comparison of exenatide with glargine it is anticipated that the net lifetime cost difference will be between a little over £1,000 more costly with exenatide. (NB it is assumed that patients will only stay on exenatide for a few years before insulin is required because of disease progression.) Given an anticipated QALY gain of around 0.057, this results in an estimated cost effectiveness of around £20,000 per QALY. This improves to a cost effectiveness estimate of around £1,600 per QALY for a patient with a BMI of 35kg/m2 due mainly to the increased cost of the glargine regime. The dose of glargine increases with weight, whereas that of exenatide is fixed. However, these cost effectiveness estimates are sensitive to the direct utility gain assumed for weight loss and weight gain, and if this effect is excluded the anticipated cost effectiveness of exenatide relative to glargine increases to between £9,000 per QALY and £21,000 per QALY, for the no-complications and with complications scenarios respectively. The term “direct utility gain” refers to the fact that people feel happier if they lose weight, and is in contrast to the indirect gain achieved when weight loss favourably affects variables such as cholesterol or blood pressure. The UKPDS model already allows for indirect gains from weight loss.

So what this analysis is telling us is that over a lifetime, there is little difference in costs of using exenatide for a few years instead of going straight to insulin; there is a slight benefit in QALY terms mostly due to the weight loss with exenatide. If patients did not lose sufficient weight, exenatide would not be cost-effective.

In summary, taking into account effects, side-effects, costs and expected time to progression, and assuming sufficient weight is lost, exenatide when compared to glargine appears to give ICERs within the range usually regarded as cost-effective. Provided that the effect of exenatide on BMI is reasonably consistent across the weight range, the cost-effectiveness of exenatide relative to glargine improves as BMI worsens, due in large part to the increasing cost of the required total glargine dose.

Comparing sitagliptin and rosiglitazone, the anticipated net QALY gain from sitagliptin is only 0.02 to 0.03 which is marginal and well within the bounds of error. However, sitagliptin is anticipated to be less expensive. If the direct utility effects of weight changes are excluded from this sitagliptin is associated with a very small utility loss of −0.006 QALYs though this does not affect the anticipated cost saving. Hence, the two drugs could be regarded as clinically equivalent but with sitagliptin marginally less costly at current prices.

For vildagliptin compared with pioglitazone the differences are again slight, with vildagliptin being associated with an insignificant QALY difference of between −0.011 and −0.007 QALYs. Hence the two drugs could be regarded as clinically equivalent, but vildagliptin is anticipated to be around £600 less expensive than pioglitazone (at current prices – a fall of 22% in the cost of pioglitazone would equalise costs).

In summary, the gliptins and the glitazones appear roughly equivalent in glycaemic effect, but the former have an advantage in avoidance of weight gain, which together with their lower (at present) costs gives them an edge. However, given the uncertainties around the ICER estimate, it would be inappropriate to say that the glitazones were definitely less cost-effective than the gliptins. The cost-effectiveness hangs heavily on the benefits of weight differentials.

This does not take into account the side-effects of the glitazones. Both have problems with fractures (in women only) and heart failure, but rosiglitazone also appears to increase the risk of cardiovascular disease. However, until we have longer follow-up we will not know whether the gliptins have as yet unreported side-effects.

For the comparison of glargine with NPH, the additional anticipated cost of around £1,800 is associated with an insignificant QALY gain: yielding cost effectiveness estimates of between £280,000 per QALY and £320,000 per QALY.

Within the comparison of detemir and NPH, the overall treatment costs from detemir are slightly higher being between £2,700 and £2,600. QALY gains are again slight – about 0.015 to 0.006. Cost per QALY range from £188,000 to £412,000.

Hence on cost-effectiveness grounds, NPH should be the first choice insulin in type 2 diabetes. However, some patients will have more trouble with hypoglycaemia than others, and will potentially have more to gain.

In summary, as in Clinical Guideline 66, NPH should be preferred as first line insulin, rather than a long-acting analogue. The analogues have modest advantages but at present much higher cost.

In some patients, the benefits of the analogues relative to NPH may be greater, and cost-effectiveness correspondingly better.

Discussion

The main weaknesses in the evidence base at present are;

  • long-term data on the safety of exenatide and the gliptins
  • a lack of trials directly comparing exenatide and the gliptins
  • lack of data on the effects of exenatide and the gliptins on cardiovascular outcomes
  • a lack of head to head trials of exenatide and NPH.

Research needs

We need long-term follow-up studies of exenatide and the gliptins, although it is likely that exenatide will in future be used as the long-acting form, once weekly or even less often, and trials should use that form. Preliminary data from trials suggests that it will be more effective than the twice daily form.

Data on combined insulin and exenatide treatment would be useful. The combination appears logical, but practice appears to be running ahead of evidence.

In routine care, how much does compliance fall off as complexity of regimens increases?

More economic analysis is required, done independently of the manufacturers, including;

  • When does it become cost-effective to switch from NPH to a long-acting analogue?
  • The evidence for the direct utility of weight gain, or of avoiding weight loss, needs strengthened.

Conclusion

The new drugs, exenatide, the gliptins and (the not so new) detemir are all clinically effective.

The long-acting insulin analogues, glargine and detemir, have only slight clinical advantages over NPH, but have much higher costs, and hence very high ICERs. They are not cost-effective as first line insulin compared to NPH insulin in type 2 diabetes.

Exenatide, when used as third drug instead of progressing immediately to insulin therapy after failure of dual oral combination therapy, appears cost-effective relative to glargine, the current market leader, with most ICERs around £20,000, acceptable by current NICE standards. However exenatide would not be cost-effective compared to NPH.

The gliptins are comparable to the glitazones in glycaemic control and costs, but at present appear to have fewer long-term side-effects.

Copyright © 2009, National Institute for Health and Clinical Excellence.

All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the express written permission of NICE.

Cover of Newer Agents for Blood Glucose Control in Type 2 Diabetes (Supplement)
Newer Agents for Blood Glucose Control in Type 2 Diabetes (Supplement) [Internet].
NICE Clinical Guidelines, No. 87S.
Waugh N, Cummins E, Royle P, et al.

NICE (National Institute for Health and Care Excellence)

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