Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation.
BACKGROUND
In May 2008, the National Institute for Health and Clinical Excellence (NICE) issued an updated guideline [clinical guideline (CG) 66] for the management of all aspects of type 2 diabetes. This report aims to provide information on new drug developments to support a 'new drugs update' to the 2008 guideline.


OBJECTIVE
To review the newer agents available for blood glucose control in type 2 diabetes from four classes: the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones.


METHODS
The following databases were searched: 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 Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers' websites.


METHODS
Data extraction was carried out by one person, and checked by a second. Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (RevMan) software. Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE CG 66. The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycaemic control, reflected by glycated haemoglobin (HbA1c) level, hypoglycaemic episodes, changes in weight, adverse events, quality of life and costs. Modelling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model.


RESULTS
Exenatide improved glycaemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycaemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycaemic control but had modest advantages in terms of hypoglycaemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycaemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in our meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) -0.70 to -0.38] and hypoglycaemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between 386 pounds and 460 pounds. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around 437 pounds and 482 pounds, respectively. Exenatide was more expensive, with an annual cost of around 830 pounds. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with a NPH-based regimen having an annual cost of around 468 pounds for the representative patient, whereas the glargine and detemir regimens were more expensive, at around 634 pounds and 716 pounds, respectively. Comparisons of sitagliptin and rosiglitazone, and of vidagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around 1800 pounds. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between 2700 pounds and 2600 pounds.


CONCLUSIONS
The UKPDS Outcomes Model does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycaemic events and the fear of severe hypoglycaemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios.


CONCLUSIONS
Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.
Waugh
N
N
University of Aberdeen, UK.
Cummins
E
E
Royle
P
P
Clar
C
C
Marien
M
M
Richter
B
B
Philip
S
S
D000218:Adamantane / Q000031:analogs & derivatives / Q000191:economics / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D003362:Cost-Benefit Analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000191:economics / Q000627:therapeutic use; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000191:economics* / Q000627:therapeutic use*; D007328:Insulin / Q000031:analogs & derivatives / Q000191:economics / Q000627:therapeutic use; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D009570:Nitriles / Q000191:economics / Q000627:therapeutic use; D010455:Peptides / Q000191:economics / Q000627:therapeutic use; D011719:Pyrazines / Q000191:economics / Q000627:therapeutic use; D011759:Pyrrolidines / Q000191:economics / Q000627:therapeutic use; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D000068900:Sitagliptin Phosphate; D013222:State Medicine; D045162:Thiazolidinediones / Q000191:economics / Q000627:therapeutic use; D014230:Triazoles / Q000191:economics / Q000627:therapeutic use; D006113:United Kingdom; D014688:Venoms / Q000191:economics / Q000627:therapeutic use; D000077597:Vildagliptin
D000218:Adamantane; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D009570:Nitriles; D010455:Peptides; D011719:Pyrazines; D011759:Pyrrolidines; D000068900:Sitagliptin Phosphate; D045162:Thiazolidinediones; D014230:Triazoles; D014688:Venoms; D000077597:Vildagliptin