Effects of Early Use of Pioglitazone in Combination With Metformin in Patients With Newly Diagnosed Type 2 Diabetes

By Chalmers, J Hunter, J E; Robertson, S J; Baird, J; Et al

Key words: Combination therapy – Glycaemic control – Metformin – Pioglitazone- Type 2 diabetes ABSTRACT

Background: Type 2 diabetes is characterised by a progressive decline in HbA^sub 1c^ control over time. Early combination therapy, rather than sequential introduction of individual oral glucose- lowering agents, has been proposed to prevent this gradual rise in HbA^sub 1c^. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naive patients with type 2 diabetes.

Patients and methods: This was an observational, open-label, non- randomised study in newly diagnosed patients with type 2 diabetes, aged 35-70 years, with HbA^sub 1c^ levels >8.0% at diagnosis or >7.0% at the 3-6-month follow-up. Patients were allocated to dietary management alone if the HbA^sub 1c^ level was 7.0-8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA^sub 1c^ was >8.0%. Similar treatments were introduced at 3-6 months if the HbA^sub 1c^ was >7.0%. Over a 3- year period, HbA^sub 1c^ was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA^sub 1c^ was

Results: 416 patients were considered eligible for inclusion, with a mean (+-SD) age of 54.1 +- 9.2 years, BMI of 33.5 +- 6.1 kg/ m^sup 2^, and baseline HbA^sub 1c^ of 8.6 +- 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3-6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA^sub 1c^ values. Amongst those patients treated with the metformin/ pioglitazone combination there was an estimated 0.1% increase in HbA^sub 1c^/year. This was much less pronounced than the rises seen in HbA^sub 1c^/year of 0.5% with the metformin/gliclazide and metformin/repaglinide combinations.

Conclusions: This preliminary analysis of an obervational, non- randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3-6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the beta-cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology.

Introduction

Type 2 diabetes mellitus is a metabolic disorder characterised by chronic hyperglycaemia, and defects in insulin secretion and action (insulin resistance). Patients with type 2 diabetes typically experience a progressive rise in glycated haemoglobin A^sub 1c^ (HbA^sub 1c^) over time. A key aim of therapy is to maintain glycaemic control as well as to normalise the other associated metabolic abnormalities, including diabetic dyslipidaemia and hypertension to minimise the risk of micro- and macrovascular disease. However, for many patients, glycaemic control is often inadequate and deteriorates after an initial response to treatment1- 3.

The traditional approach to the management of patients with newly diagnosed type 2 diabetes has been to start with diet and lifestyle advice, then, when glycaemic control is lost, to progress to monotherapy with either metformin or a sulphonylurea and subsequently (after some years) to combination therapy on loss of control with monotherapy. This ‘failure-orientated’ strategy means that treatment is altered only when symptoms become apparent or when the HbA^sub 1c^ continues to rise. An alternative strategy is an ‘intensive goal-orientated’ strategy to treat early for success rather than to await failure4. However, to date, there have been no data regarding the early use of combination therapy with glucose- lowering agents, introduced at the time of diagnosis, to see which combination gives the better glycaemic control over a prolonged period of some years.

Table 1. Glycaemic data from previously reported long-term (>/= 1- year) studies of the effects of metformin and thiazolidinedione combination therapy in patients with type 2 diabetes6-13

The thiazolidinediones, pioglitazone and rosiglitazone, offer the potential for novel combination therapy regimens. The thiazolidinediones are PPARgamma receptor-stimulating insulin sensitizers that reduce insulin resistance. The inability of the beta-cell to overcome insulin resistance is primarily responsible for the progressive decline in glycaemic control in type 2 diabetes. As such, a beneficial effect on beta-cell function is an important characteristic if long-term glycaemic control is to be achieved. Animal studies and data from clinical trials using indirect measures of beta-cell function (e.g., homeostasis model assessment of beta- cell function (HOMA-%B)) suggest that the thiazolidinediones may preserve and perhaps even improve beta-cell function5. As metformin and thiazolidinediones have distinct molecular mechanisms of action and differing effects on metabolic dysfunction, their combination provides an opportunity for complementary beneficial effects in the treatment of type 2 diabetes and on the potential consequences of insulin resistance, such as dyslipidaemia and atherosclerosis. Indeed, the combination of metformin with a thiazolidinedione has been shown to give sustained reductions in HbA^sub 1c^ (Table 1(6- 13)). These studies were not performed in newly diagnosed patients with type 2 diabetes followed up for 3 years to establish the possible sustained benefits of combination treatment of metformin plus a thiazolidinedione in the early years of treatment.

Here, we report data from an ongoing observational study that was modelled on the United Kingdom Prospective Diabetes Study 49 (UKPDS 49)3 to reflect the ‘real world’ management of patients with type 2 diabetes. The study is being conducted in a secondary care setting to which newly-diagnosed patients with type 2 diabetes are referred by their general practitioner. Patients are allocated to metformin plus gliclazide, metformin plus repaglinide, or metformin plus pioglitazone. The glycaemic results after 3 years of treatment with these different therapies are reported.

Patients and methods

Study design

This is an ongoing, single-centre, clinical observation, open- label, non-randomised study. The first patient was admitted to the study in October 1999. At the time of this initial analysis, 669 patients have been enrolled.

Patients

Study participants were previously untreated, newly diagnosed, drug-naive patients with type 2 diabetes, aged 35-70 years of age, all of whom had to have an HbA^sub 1c^ >7.0% at diagnosis.

Study treatments

Patients were allocated to diet alone at diagnosis if the Hb^sub 1c^, was 7.0-8.0% and continued at the 3-6 month Ic follow-up if the HbA^sub 1c^ was <7.0%. If the HbA^sub 1c^ was >8.0%, treatment was started with metformin plus gliclazide (1999-2001), metformin plus repaglinide (2000-2002), or metformin plus pioglitazone (from March 2002). The first regimen of metformin and gliclazide was chosen in 1999 as this was the commonest combination of glucose-lowering medication in use in the UK. The next combination of metformin and repaglinide was then selected as the short-acting insulin secretagogue was proposed to give longer beta-cell protection and, in 2002, the metformin combination with pioglitazone was chosen for similar reasons. These different oral glucose-lowering agent regimens were introduced immediately at diagnosis if the HbA^sub 1c^ was >8.0% at that stage. At each 3-month visit, the patient was weighed, BMI calculated, and glycaemic control assessed with HbA^sub 1c^ measurements. During the follow-up period, the target HbA^sub 1c^ was

Based on efficacy, metformin was titrated according to clinical response from an initial dose of 0.5 g b.d. to a maximum of 1 g b.d., gliclazide from 80 mg to 160 mg b.d., repaglinide from 0.5 mg to 4 mg t.i.d., and pioglitazone from 30 mg to 45 mg o.d.

Efficacy analyses

The primary efficacy outcome was the change in HbA^sub 1c^ control over time. If the target HbA^sub 1c^ level was not achieved on combination therapy, the patient was withdrawn from the study and insulin therapy was initiated (as emphasised by the recent ADA/EASD guidelines14).

Statistical analysis

This analysis deals with the 178 patients who started on combination therapy, either immediately, or following a period of dietary therapy for 3-6 months. The change in HbA^sub 1c^ levels during the course of the study was investigated using a mixed models analysis of variance. A random coefficients model was used to compare the pattern or response over time between the different treatment regimens from the first visit on combination therapy (3-6 months) until such time as they switched treatment, were withdrawn from the study, or their last assessment (whichever was the earlier). The data were analysed from 3 to 6 months after starting therapy to account for the expected initial decrease in Hb^sub A1c^ levels following initiation of treatment. Initial combination treatment and time from the start of initial combination treatment (in years) were included as fixed effects. The actual times were used in the model since the assessment times were not always exactly at 3-month intervals and some visits were missed. The slope and intercepts for each patient were considered as random. A linear pattern of response was fitted. In addition, significance of a quadratic effect was also investigated. The effects of prognostic factors, including HbA^sub 1c^, age, and BMI at first assessment, were also investigated and, if significant (p < 0.05), they were retained in the model. The patterns of response for the various treatments were compared by including a term for the interaction between treatment and time in the model. Estimates of the slopes (i.e., the rate of change of HbA^sub 1c^ for each treatment) were derived and estimated mean values for each treatment at 1, 2, and 3 years were calculated and are presented with 95% confidence intervals (CIs). Results

Of the 669 patients screened, 416 patients newly diagnosed with type 2 diabetes (mean +- SD age 54.1 +- 9.2 years, BMI 33.5 +- 6.1 kg/m^sup 2^, and baseline HbA^sub 1c^ 8.6 +- 1.7%) were enrolled in the study. Of these 416, 178 received combination therapy immediately or after 3-6 months of diet. The demographic characteristics of this group were similar to the overall group, with mean +- SD age of 53.7 +- 8.9 years and BMI of 33.2 +- 6.7kg/ m^sup 2^. Their mean baseline HbA^sub 1c^ was slightly higher at 9.3 +- 1.7%, as would be expected.

The baseline demographic data by the initial treatment allocation are summarised in Table 2. Note that, of the 164 patients initially allocated to diet, 42 patients subsequently switched at 3-6 months to combination therapy with metformin and either gliclazide, repaglinide, or pioglitazone. Patients initially allocated to dietary management alone had slightly lower HbA^sub 1c^ levels at baseline than those patients allocated to oral glucose-lowering therapy. Of those initially allocated to metformin plus other oral glucose-lowering therapy, patients allocated to pioglitazone combination therapy had the highest baseline HbA^sub 1c^ levels. Mean age and BMI were comparable across the treatment groups. The median follow-up was 2 years and the longest duration of follow-up was 6.2 years.

HbA^sub 1c^ levels

Investigations using a mixed models analysis of variance showed a gradual increase in HbA^sub 1c^ levels in all three combination treatment groups (metformin plus gliclazide, repaglinide, or pioglitazone) (Figure 1) after the first 3 months. The rate of increase in HbA^sub 1c^ levels among patients treated with metformin plus pioglitazone (0.1%/year) was less pronounced than for patients receiving either of the other combination therapies (0.5%/year for each treatment arm) (Table 3). The estimated rates of change for both gliclazide and repaglinide were statistically significant (95% CI: 0.13-0.96 and 0.36-0.68, respectively), whereas the rate of change for pioglitazone was not (95% CI: -0.32-0.47).

The estimated mean HbA^sub 1c^ levels at 3 years were 9.1% for metformin plus gliclazide, 8.7% for metformin plus repaglinide, and 7.6% for metformin plus pioglitazone.

Of the other prognostic factors investigated, only baseline HbA^sub 1c^ had a statistically significant effect on subsequent HbA^sub 1c^ levels. However, the estimates of the rate of change obtained from rerunning the analysis taking into account the baseline HbA^sub 1c^ were very similar to the original estimates and are not shown here. The estimated means from the original, unadjusted analysis are plotted in Figure 1. Mean data and 95% CIs are given in Table 4.

Table 2. Baseline demographics from an ongoing observational study of patients newly diagnosed drug-naive with type 2 diabetes allocated to dietary management alone or early dual combination with metformin plus gliclazide, repaglinide, or pioglitazone within 6 months of diagnosis

Discussion

We have shown in this ‘real world’ study that the rate of decline in the control of HbA^sub 1c^ over a 3-year observation period varied depending upon the combination therapy allocation. Early oral glucose-lowering combination treatment was used, rather than a sequential introduction of agents to try to prevent the gradual increase in HbA^sub 1c^ rise that was observed in the UKPDS3. For patients allocated to the combination of metformin plus pioglitazone, the rate of decline was 0.1%/year compared with the more rapid decline of 0.5%/year for patients allocated to the combination of metformin plus gliclazide or repaglinide.

Figure 1. Estimated mean HbA^sub 1c^ over time in the first 3 years of an ongoing observational study of early combination oral glucose-lowering therapy with metformin plus gliclazide (n = 39), repaglinide (n = 76), or pioglitazone (n = 21) in drug-naive patients newly diagnosed with type 2 diabetes

Table 3. Estimated rate of change per year in HbA^sub 1c^ levels in the first 3 years of an ongoing observational study of early combination oral glucose-lowering therapy with metformin plus gliclazide, repaglinide, or pioglitazone in drug-naive patients newly diagnosed with type 2 diabetes

Table 4. Estimated mean HbA^sub 1c^ levels at 1, 2, and 3 years of an ongoing observational study of early combination oral glucose- bwering therapy with metformin plus gliclazide, repaglinide, or pioglitazone in drug-naive patients newly diagnosed with type 2 diabetes

The UKPDS 49 has shown that the therapeutic effectiveness of oral glucose-lowering monotherapy, diet, and insulin all declined over the 9 years of follow-up (at 3 years only approximately half of the patients achieved targets of HbA^sub 1c^ <7.0% or fasting plasma glucose <7.8mmol/L and this declined to approximately one-quarter at 9 years). The majority of patients required combination therapy to achieve target HbA^sub 1c^ levels during long-term treatment3. Several other studies have also highlighted the decline in glycaemic control over the long term and the high likelihood of patients progressing to combination therapy within a relatively short time after their initial diagnosis1-3. There is an increasing use of combination therapy, with a US study showing an 8% use in 1990 rising to 22% in 1996 and 39% in 2001; however, this was a cross- sectional analysis and did not reflect early combination treatment at the time of diagnosis of type 2 diabetes15.

Introducing early combination therapy may slow or delay the progressive decline in glycaemic control observed with current treatment regimens. However, if early combination therapy at the time, or within a few months of diagnosis, is to be employed, the question arises as to which combination of drugs would give the greatest benefit in maintaining glycaemic control over the long term. Currently, the most common combination of oral glucose- lowering drugs has been that of metformin combined with a sulphonylurea. This combination takes advantage of complimentary mechanisms of action – metformin is an inhibitor of hepatic glucose overproduction and sulphonylureas are insulin secretagogues. The addition of a sulphonylurea to metformin has been shown in a retrospective analysis to offer maintained control for as little as 6 months before deterioration in control occurs16.

The combination of a thiazolidinedione and metformin offers a novel combination of agents with differing mechanisms of glucose- lowering action and the potential to preserve beta-cell function. As an insulin-sensitizing agent, pioglitazone improves the use of circulating insulin (and thus glucose disposal) and therefore reduces the excess stimulation of beta-cells, which should prolong their functional life. Short-term (<1 year) and recent long-term (>/ =1 year) studies have demonstrated the efficacy of adding pioglitazone to failing monotherapy with metformin or a sulphonylurea in improving and maintaining glycaemic control (Table 1(6-8,10-13)). Similar results have also been reported with rosiglitazone plus metformin in combination (Table 1(7,9,13)). The study design employed here, although observational rather than randomised, was based on the UKPDS 49 protocol3, with the aim of evaluating the effectiveness of combination therapy in newly diagnosed patients with type 2 diabetes who were referred to a secondary care unit and who were drug naive. Our results, and those of a previous study17, suggest that early intervention with a combination of oral glucose-lowering agents with differing modes of action, such as metformin and pioglitazone, may represent a useful strategy to delay the progressive loss of glycaemic control. Other potential advantages include improvements in diabetic dyslipidaemia and other metabolic risk markers and risk factors for cardiovascular disease18.

The recent introduction of short-acting insulin secretagogues (postprandial regulators, such as repaglinide and nateglinide), are thought to protect beta-cell function by a shorter duration of insulin secretion, thereby possibly maintaining longer beta-cell function. No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in HbA^sub 1c^ over a 6- month period in a recent report19. Over a 2-year period, similar changes in HbA^sub 1c^ were also found with the combination of nateglinide or glyburide with metformin20. A number of other compounds with novel mechanisms of actions, such as the incretin hormone glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase IV (DPP-IV) inhibitors, are currently in development and animal/ preclinical studies using these agents suggest protective effects towards beta-cell function and may offer alternatives for future combination therapy regimens.

The conclusions that can be drawn from this initial analysis of data from a study designed to evaluate the utility of combination therapy in newly diagnosed patients with type 2 diabetes are limited by the variability of the duration of follow-up for the combination treatment arms and the fact that treatment allocation was not randomised. Although the study was initiated in 1999, no patients were allocated to the pioglitazone combination arm until 2002, and so patients in the gliclazide and repaglinide combination arms have been followed-up for longer than those allocated to pioglitazone combination therapy. This observational study is ongoing and future analyses will overcome this limitation. In addition, patients on metformin/gliclazide had lower BMIs at baseline compared with the metformin/pioglitazone patients. This is a major confounder, as it is possible that patients with higher BMIs may respond better to the metformin/pioglitazone combination as they are more insulin- resistant. However, inclusion of BMI as a covariate in the analysis of HBA^sub 1c^ was not statistically significant (p = 0.46). Conclusions

The preliminary data presented here represent the first ‘in clinic’ experience of the use of early combination therapy with metformin and either gliclazide, repaglinide, or pioglitazone. We have shown that patients allocated to open-label combination therapy with metformin plus pioglitazone experience a slower deterioration in glycaemic control compared with metformin in combination with either gliclazide or repaglinide for up to 3 years. This could offer an advantage for the early pioglitazone plus metformin combination over other oral agent combinations for successful long-term treatment of diabetes. These data need to be confirmed by further studies with a more robust design and methodology.

Acknowledgements

This study was sponsored at various times by Servier, Novo Nordisk, Takeda, and Pfizer Pharmaceuticals Ltd.

Dr J. Chalmers has received fees/honoraria from GSK, Sanofi- Aventis, Novo Nordisk, and Pfizer. Dr J. E. Hunter has received fees/ honoraria from Takeda. C. Whately-Smith was contracted by Takeda to provide statistical analyses of these data. Dr S. Mariz was an employee of Takeda Global Research and Development at the time of development of this paper. Professor I. W. Campbell has received fees/honoraria from GSK, Takeda, Astra-Zeneca, Pfizer, and Merck Serono.

Editorial support was provided by Absolute Healthcare Communications and funded by Takeda Global Research and Development; however, the views expressed in the manuscript are entirely the authors’ and were not influenced by Takeda.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3846_3, Accepted for publication: 21 May 2007

Published Online: 25 June 2007

doi:10.1185/030079907X210606

J. Chalmers(a), J. E. Hunter(a), S.J. Robertson(a), J. Baird(a), M. Martin(a), C.I. Franks(a), C. R. Whately-Smith(b), S. Mariz(c) and I. W. Campbell(a)

a Diabetes Centre, Victoria Hospital, Kirkcaldy, Fife, UK

b Hunton Bridge, King’s Langley, Hertfordshire, UK

c Takeda Global Research & Development Centre (Europe) Ltd, London, UK

Address for correspondence: Dr J. Chalmers, Diabetes Centre, Victoria Hospital, Hayfield Road, Kirkcaldy, Fife, KY2 5AH, UK. Tel.: +44 1592 643355; Fax: +44 1592 648041; john.chalmers@faht.scot.nhs.uk

Copyright Librapharm Aug 2007

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