By Barnett, Anthony Allsworth, Josie; Jameson, Kevin; Mann, Rachel
Key words: DPP-4 inhibitor – Glitazone – Incretin – Metformin – Type 2 diabetes – Weight gain ABSTRACT
Background: Current American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) treatment guidelines recommend metformin (which does not promote weight gain) as the first-line antihyperglycaemic drug for patients with type 2 diabetes. However, when metformin fails, the recommended add-on treatment options (sulphonylureas, glitazones and basal insulin) can lead to significant weight gain. This article reviews the effect on body weight of current treatments for type 2 diabetes and discusses the potential impact of weight gain in this patient group.
Scope: MEDLINE searches were performed to evaluate the prevalence and impact of changes in body weight in type 2 diabetes (articles published between January 1966 and August 2006) and the effects of sulphonylureas, glitazones, insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors and incretin analogs on body weight in these patients (search between January 2004 and September 2006).
Findings: Weight gain in general affects not only the physiological capability of patients with diabetes to achieve glycaemic control, but also their psychological well-being, quality of life and persistence with antihyperglycaemic treatment. Excess body weight and obesity in patients with diabetes are also associated with increased healthcare resource utilisation. Development of obesity is also associated with increased cardiovascular risk, although a link between drug-induced weight gain per se and increased cardiovascular risk has not been established. Initial clinical trial experience with the new oral DPP- 4 inhibitors such as sitagliptin and vildagliptin suggests that these agents are weight-neutral, while providing improved glycaemic control when added to metformin.
Conclusions: Because currently available add-on treatments can cause weight gain, physicians initiating add-on therapy in patients who can no longer achieve glycaemic control with metformin are faced with the problem of improving glycaemic control while causing weight gain. Initial clinical trial experience with oral DPP-4 inhibitors such as sitagliptin and vildagliptin suggest that these agents may represent an important oral treatment option for weight-neutral, glycaemic control when added to metformin. The new oral DPP-4 inhibitors, therefore, represent a potentially important addition to the oral treatment options currently available for the management of type 2 diabetes mellitus. Long-term clinical trials are now required to evaluate the relative risk/benefit profile of these drugs compared with the established antihyperglycaemic drug classes.
Introduction
There is currently great concern regarding the epidemic of excess body weight (body mass index [BMI] > 25 kg/m^sub 2^) and obesity (BMI > 30kg/m^sub 2^) in many countries, owing to the profound health consequences. These include, but are not limited to, type 2 diabetes and cardiovascular disease1,2. Much less attention is paid, however, to the significance of weight gain and obesity in patients who have already been diagnosed with diabetes. This is likely to be important as an increase in insulin resistance associated with obesity may make glycaemic control harder to achieve. Obesity and weight gain may also affect psychological well-being, and thereby reduce patient quality of life, productivity and adherence to antihyperglycaemic treatment.
Metformin is a highly effective first-line antihyperglycaemic drug treatment for patients with type 2 diabetes who have not achieved glycaemic control with lifestyle intervention alone. The UK Prospective Diabetes Study (UKPDS) showed that metformin is cardioprotective and significantly reduces mortality in overweight patients with type 2 diabetes3. The current American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus algorithm for the management of hyperglycaemia in type 2 diabetes recommends that, when glycaemic control can no longer be maintained with metformin (glycated haemoglobin [HbA^sub 1C^] >/= 7%), add-on treatment should be initiated with a sulphonylurea, a glitazone or basal insulin4. A convincing body of evidence from largescale clinical outcome trials such as the UKPDS has demonstrated the microvascular outcome benefits of glycaemic control with metformin, sulphonylureas and insulin5. Recent outcome studies have also provided evidence that glitazones may improve clinical outcomes in patients with type 2 diabetes6. In contrast to metformin, however, all of these add-on options can lead to weight gain. Physicians are therefore faced with the problem of improving glycaemic control while possibly provoking weight gain in patients for whom metformin monotherapy is no longer adequate.
In this article, we review the effect on body weight of current treatment options for type 2 diabetes, and discuss the impact of weight gain with antihyperglycaemic drugs in this patient group. We also review the emerging clinical evidence on the dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral antihyperglycaemic agents that offer the prospect of improved glycaemic control without weight gain when added to existing antihyperglycaemic drugs.
Search strategy and selection criteria
A comprehensive review of the prevalence, causes and impact of changes in body weight in type 2 diabetes was performed via a MEDLINE search of articles published between January 1966 and August 2006. A broad search strategy was employed according to the following search terms: general disease terms (adult, type 2 diabetes, type 2 diabetes mellitus, type 2 diabetic), weight terms (weight, body weight, weight gain, body weight gain, body weight increase, body mass index, BMI), prevalence and impact terms (prevalence, incidence, frequency, symptoms, cost, cost utility, cost effectiveness, health related quality of life, HRQoL, health related utility, HRU, QoL, utility, satisfaction, patient satisfaction, treatment satisfaction, adherence, medication/ treatment adherence) and therapy terms (sulphonylurea, sulfonylurea, pioglitazone, rosiglitazone, metformin, insulin).
A literature review of the effects of sulphonylureas, glitazones, DPP-4 inhibitors and incretin analogs on body weight in patients with type 2 diabetes was performed via a MEDLINE search of articles published between January 2004 and September 2006. This search did not include the alpha glucosidase inhibitors or prandial glucose regulators, as these drug classes are rarely used in the UK. Search terms were as follows: drug class (sulphonylurea or sulfonylurea or thiazolidinedione or glitazone or PPAR or pioglitazone or rosiglitazone or metformin or insulin), and (body mass index or body weight or weight or weight gain or weight increase) and (type 2 diabetes mellitus or type 2 diabetic) and (adult). Similar searches were constructed for DPP-4 inhibitors by replacing the drug class terms with (DPP-4 inhibitor or vildagliptin or LAF-237 or sitagliptin or MK-0431 or saxagliptin or BMS-477118), and, for incretin analogs, by replacing the drug class terms with (incretin analog or exenatide or AC2993 or liraglutide or NN211). Exclusion criteria for articles were as follows: (1) review article; (2) studies without documented mean weight change with study treatment; (3) studies assessing changes in BMI and not mean weight gain; (4) studies in type 1 diabetes; and (5) studies in adolescents or children.
Although no language limit was placed on the search terms, papers where the abstract had not been translated into English were excluded due to time and translation constraints. References to papers of interest not identified via the electronic search were examined. References from review papers were cross-checked with papers retrieved electronically where necessary. Meeting abstracts were also searched for studies on DPP-4 inhibitors, as much of the data are currently available only in abstract form.
Prevalence and consequences of increased body weight in type 2 diabetes
Excess body weight and obesity are increasingly prevalent in patients with type 2 diabetes. A survey of 74 general practices in England and Wales showed that the proportion of patients with type 2 diabetes who were overweight (BMI > 25kg/m^sup 2^) increased from 73.0% in 1994 to 80.6% in 200G. More recent findings from a study of 3637 patients with diabetes identified from a UK hospital electronic diabetes register showed that 86% of patients with type 2 diabetes were overweight or obese, 52% were obese and 8.1% had morbid obesity (BMI > 40kg/m^sup 2^) (Figure I)8.
It is widely accepted that obesity is a major modifiable risk factor for type 2 diabetes, because excess body weight is associated with insulin resistance2. Increased body weight associated with the natural history of obesity can lead to worsening of other cardiovascular risk factors such as lipid profile and blood pressure910, and is an independent risk factor for coronary disease1. Indeed, a prospective cohort study of outcomes over a 2- year period in 17 195 patients in the United States showed that patients aged 51-61 years with diabetes and obesity had a 6.8-fold greater mortality compared with patients with no medical conditions (p 2 kg after diagnosis of diabetes was associated with a relative risk for coronary heart disease of 1 . 1 6 (95% confidence interval [CI] 0.75-1.78), and weight loss of > 1 1 kg with a relative risk of 0.87 (0.49-1 .55), but there were no significant differences among subgroups. Figure 1. The majority of patients with type 2 diabetes in the UK are overweight or obese8. (Reproduced from Daousi et al.8, with permission from the BMJ PubUshing Group)
Nevertheless, it is well established that weight loss reduces cardiovascular risk in overweight patients with or without type 2 diabetes. Prospective clinical outcome trials such as the Diabetes Prevention Project have demonstrated that weight reduction in overweight patients improves glycaemic status, lipid profile and blood pressure, and significantly reduces the risk of developing type 2 diabetes1314. Moreover, a prospective analysis with a 12- year follow-up of 4970 overweight individuals with diabetes enrolled in the American Cancer Society Cancer Prevention Study I showed that intentional weight loss of 10-15% of initial body weight was associated with a significant 33% reduction in mortality15.
Weight gain as a barrier to glycaemic control in patients with type 2 diabetes
The consequences for glycaemic control of weight gain associated with the natural history of obesity are well understood. As weight increases, the response to insulin at the liver and peripheral tissues such as muscle diminishes (so-called ‘insulin resistance’). To compensate, insulin levels rise (hyperinsulinaemia). In certain individuals, such as those pre-disposed to diabetes, the beta-cell insulin secretion response is inadequate – insulin levels are insufficient to compensate for impaired insulin action – and glucose intolerance or elevated fasting glucose levels result2.
Although the physiological effects of weight gain associated with obesity and medication-induced weight gain are likely to be different, several important consequences of increased body weight are likely to be manifest independent of the stimulus for weight gain. Thus, obesity is associated with reduced physical activity16, and so lifestyle interventions are less likely to be successful in patients with higher body weight. Indeed, overweight and obese patients treated with medications that are associated with weight gain are less likely to lose weight during weight loss programmes17. Moreover weight affects not only physical health, but also psychological well-being18. In a UK survey of 27924 hospital- treated patients, health-related utility, as measured by the EQ- 5D19, was found to decrease as body mass index (BMI) increased (Figure 2)20. The EQ-5D is a questionnaire developed by the EuroQoL group that assesses five aspects or ‘domains’ of health outcome (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression), each of which are rated in one of three categories (no problems, some problems, serious problems)19. In the EQ-5D, an individual with no problems in any domain (i.e., a state of perfect health) has a score of 1 . Health-related utility was significantly lower in patients with type 2 diabetes than those without diabetes in all BMI classes20. Similarly, studies in patients with type 2 diabetes have shown that increasing BMI is associated with poorer physical function21 and an increase in work disability22, as well as a lower subjective health-related quality of life23 and mental health (including lower self-esteem and increased anxiety and depression)24.
Figure 2. Increasing body mass leads to reduced healthrelated utility and quality of life (EQ-5D score) in patients with or without type 2 diabetes20. (Reproduced from Lee et al.20, with permission from Blackwell Publishing)
Negative impact of weight gain on treatment adherence
Although it is widely accepted that increasing body weight is associated with poorer health-related quality of life and an increased incidence of anxiety and depression, these issues are of particular concern in patients with type 2 diabetes. Continued weight gain despite attempts to maintain dietary advice, and the inevitable increase needed in medications, lead to a cycle of despondency and failure that affect the patient’s desire to comply with strict glycaemic goals and adherence to recommended diets25.
In a study of patient beliefs regarding antihyperglycaemic medication in 121 patients with type 2 diabetes, the belief that regular use of diabetes medicine would lead to weight gain was significantly associated with reduced medication adherence26. A study using the World Health Organization Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ) showed that type 2 diabetes patients with higher BMI have lower reported levels of satisfaction with their diabetes treatment27.
The effect of weight gain on patient attitudes to drug treatment must not be underestimated, because nonpersistence with antihyperglycaemic therapy in patients with type 2 diabetes is a key problem. A retrospective study in the United States showed that after the first prescription, 1 0.5% of patients failed to fill a second prescription for the initial or any other antihyperglycaemic medication. At 12 months, 37.0% of patients had discontinued pharmacotherapy completely, and rates of non-persistence were particularly high with insulin therapy (69. 2%)28. Clearly, non- compliant patients are exposed to the risks of uncontrolled hyperglycaemia. While patient compliance with antihyperglycaemic therapy is influenced by a multitude of issues, any factor such as weight gain that may have a negative impact on treatment adherence is of clinical importance.
Healthcare resource implications of weight gain
Weight gain also has important healthcare resource implications. A retrospective cohort study conducted in the United States showed that patients with a weight gain of > 20 lb (9 kg) over 3 years incurred significantly greater total medical care costs compared with patients with less or no weight gain29. Importantly, the highest costs associated with weight gain were incurred in patients with diabetes; the mean increase in costs with a >/= 20 lb weight gain over 3 years was $1379 in this group, compared with a $561 increase in the overall population.
Most of the additional costs due to weight gain were pharmacy costs, in part reflecting the use of drug treatment to promote weight loss. Increases in body weight due to drug treatment may bring a large number of patients with type 2 diabetes above the threshold at which weight loss medications are recommended. For example, approximately one-third of patients with type 2 diabetes in the UK fall within the BMI range 25-29.9 kg/m^sup 2^, and current treatment guidelines from the UK National Institute of Health and Clinical Excellence (NICE) allow for the use of anti-obesity medication in patients with type 2 diabetes who have a BMI > 27 kg/ m^sup 2^ (for sibutramine) or > 28 kg/m^sup 2^ (for orlistat)8,30,31.
The newest weight management agent, the cannabinoid CB^sub j^- receptor antagonist rimonabant, has recently been investigated in overweight or obese patients with type 2 diabetes in the RIO- Diabetes (Rimonabant in Obesity-Diabetes) trial32. This was a 1- year, randomized, double-blind, placebo-controlled trial of 1047 patients with type 2 diabetes and BMI 27-40 kg/m2 who were receiving either metformin or sulphonylurea therapy and were asked to follow a hypocaloric diet (600kcal/day deficit) for the duration of the trial. After 1 year of treatment, once-daily rimonabant 5 mg or 20 mg reduced body weight from baseline by 2.3kg and 5.3 kg compared with a 1.4kg reduction with placebo (p = 0.013 and ?
Antihyperglycaemic drug therapy and weight gain
Treatment algorithms for type 2 diabetes
The current ADA/EASD consensus algoritiim for the management of hyperglycaemia in type 2 diabetes, and other national guidelines such as the Joint British Societies guidelines (JBS 2) for die prevention of cardiovascular disease in the UK, recommend that lifestyle intervention (professional dietary advice and increased physical activity) to reduce body weight should be the first approach to achieve blood glucose control in type 2 diabetes4,34. In clinical practice, however, weight loss is difficult to achieve. Patients with type 2 diabetes consider intensive diet and lifestyle changes to be restrictive35, and clinical studies have shown that lifestyle interventions do not achieve sustained weight loss sufficient to provide normal glycaemic control in most patients36,37. The majority of patients with type 2 diabetes will therefore require antihyperglycaemic drug treatment in order to achieve glycaemic control.
Metformin
Guidelines for drug treatment of type 2 diabetes are based largely on die findings of die UKPDS trial. ADA/ EASD guidelines recommend metformin as the drug of first choice for patients widi diabetes, based on its outcome benefits and lack of effect on body weight4. The clinical benefits of intensive blood glucose control with metformin were established in UKPDS 34. This study showed that, compared witii conventional treatment, intensive treatment with metformin over a median duration of 10.7 years significantly lowered HbAlc levels, and reduced diabetes-related death by 42% (p = 0.017) and all-cause mortality by 36% (p = 0.01 1)3. Moreover, metformin treatment provided significant reductions in any diabetes-related endpoint (p = 0.0034), all-cause mortality (p = 0.021) and stroke (p = 0.032) compared witii intensive treatment based on sulphonylureas or insulin, witiiout the weight gain associated witii these agents. What happens when metformin fails?
In patients who fail to achieve glycaemic control (HbAlc > 7%) with metformin alone, ADA/EASD guidelines recommend combination of metformin with a sulphonylurea (considered to be the least expensive option), basal insulin (the most effective option) or a glitazone (an option without the risk of hypoglycaemia associated with sulphonylureas and insulin)4. National guidance in some countries differs from this algorithm; in the UK, for example, current guidance from NICE is for a glitazone to be used only in patients for whom either metformin or a sulphonylurea is contra-indicated or not tolerated in combination38, with insulin treatment considered when oral agents fail to achieve the audit target HbA]C of 7.5%34. It should be noted, however, that a position statement on the use of glitazones was also published by the Association of British Clinical Diabetologists (ABCD) following the NICE appraisal and subsequent extension to the license of both pioglitazone and rosiglitazone by the European Agency for the Evaluation of Medicinal products (EMEA) in September 2003. The ABCD recommended that glitazones should be considered as monotherapy in patients unable to take metformin or in patients with renal impairment, and that glitazones should be the preferred second-line oral antihyperglycaemic agent (following metformin) in obese patients with type 2 diabetes39. The ABCD also stated that carefully monitored triple therapy comprising metformin, a sulphonylurea and a glitazone, should be considered in patients who are severely obese and/or who are unable to take insulin. The ABCD statement noted that caution is needed to monitor for fluid retention and heart failure during glitazone treatment, particularly in patients with renal disease and/or those on insulin39.
Sulphonylureas
The clinical outcome benefits of intensive blood glucose control with sulphonylureas or insulin were demonstrated in UKPDS 33. Over 10 years, intensive treatment with sulphonylureas or insulin provided significant improvements in glycaemic control compared with conventional therapy (HbAlc 7.0% vs. 7.9%), and significantly reduced the risk of any diabetes-related endpoint by 12% (p = 0.029), largely due to a 25% reduction {p = 0.0099) in the rate of microvascular endpoints5. Intensive treatment with sulphonylureas or insulin, however, was also associated with substantially greater weight gain at 10 years (mean 3.1 kg; 99% CI -0.9 to 7.0, ?
Most clinical studies showing weight gain with sulphonylurea treatment have investigated the effects of first-generation compounds such as chlorpropamide and tolbutamide, or second- generation agents such as glyburide (glibenclamide) and glipizide42. ‘Third-generation’ sulphonylureas such as glimepiride have a number of benefits over older compounds, including once-daily dosing, rapid onset and more effective maintenance of lower insulin levels in conditions of low blood glucose43, and, as a consequence, may also be associated with less weight gain than older drugs in this class. An open-label study of 284 patients with type 2 diabetes showed that treatment with glimepiride at doses of up to 4 mg once daily was associated with a mean reduction in body weight from baseline of 1 .9 kg at 4 months, 2.9kg at 1 year and 3.0kg at 1.5 years41. A retrospective cohort study of 520 patients with type 2 diabetes in routine outpatient practice showed greater mean weight reduction with glimepiride (2.0 kg reduction from baseline) than with glibenclamide (0.6kg reduction; ?
Figure 3. Weight gain with (A) intensive glucose control compared with conventional therapy and (B) insulin and sulphonylureas in patients with type 2 diabetes5. (Reproduced from UKPDS 335, with permission from Elsevier)
Another once-daily sulphonylurea that may be associated with less weight gain than older sulphonylureas is the modified release (MR) formulation of gliclazide. A 2-year study of 800 patients with type 2 diabetes showed that gliclazide MR 30-1 20 mg once daily significantly improved glycaemic control with no notable effect on body weight (mean increase at 2 years 0.36 kg)44. The GUIDE study (Glucose control in type 2 diabetes: Diamicron MR vs. glimepiride), a randomized, double-blind comparator trial in 845 type 2 diabetic patients, showed that treatment with gliclazide MR 30-1 20 mg once daily for 27 weeks was statistically non-inferior to glimepiride 1- 6 mg once daily for glycaemic control, while mean body weight increased by 0.5 kg with gliclazide MR and 0.6 kg with glimepiride45. Moreover, gliclazide MR was associated with a significantly lower incidence of hypoglycaemic episodes than glimepiride (3.7% vs. 8.9% of patients, respectively; ? = 0.003)45. It should be noted, however, that the current ADA/EASD treatment algorithm for type 2 diabetes cites the low cost of generic sulphonylureas as the major advantage of this class4, and the relative increased cost of newer agents that are only available as brand medications must be balanced against their relative benefits.
Insulin
It is well documented that improvement of glycaemic control with insulin treatment is often associated with weight gain. In the UKPDS, patients who received insulin gained most weight of all treatment groups, exhibiting a weight gain of 4.0kg (3.1-4.9, ?
Compared with traditional insulin formulations, insulin replacement with novel insulin analogs (such as the fast-acting insulin aspart and insulin lispro, and the long-acting insulin glargine and insulin detemir) more closely approximates the normal daily insulin profile of healthy individuals. Studies comparing the effects on body weight of novel insulin analogs and traditional insulin formulations have, however, generally provided conflicting results. For example, although one 28-week, open-label study in patients with type 2 diabetes showed significantly less weight gain with once-daily insulin glargine than with once- or twice-daily NPH insulin47, studies of bedtime administration of insulin glargine or NPH insulin showed no notable difference in weight gain between groups48,49. The exception is insulin detemir, which clinical studies have consistently shown to be associated with less weight gain than other basal insulins. Thus, a 22-week, randomized, open- label study in 395 patients with type 2 diabetes showed that treatment with basal insulin detemir (with mealtime insulin aspart) provided similar glycaemic control to basal NPH insulin (with mealtime regular insulin), but was associated with smaller increases in body weight (0.5kg vs. 1.1 kg; ? = 0.038)50. Similarly, a 26- week, randomized, open-label study in 505 patients with type 2 diabetes showed significantly less weight gain from baseline with basal insulin detemir than NPH insulin when insulin aspart was used at mealtimes in both regimens (1.0 vs. 1.8 kg from baseline respectively; p = 0.01 7)51. At present it is unclear why insulin detemir has less effect on body weight than other insulins.
The weight gain associated with antihyperglycaemic treatment with insulin has important consequences; insulin treatment is commonly delayed in type 2 diabetes, in part because of physician and patient concerns regarding increase in body weight5,42, unsuitability of insulin for some patients (due to employment considerations or needle aversion), and consequent high level of non-persistence with insulin treatment28. Indeed, the Diabetes Attitudes, Wishes, and Needs (DAWN) study showed that 50-55% of general practitioners and nurses delay insulin treatment in type 2 diabetes as long as possible52. Glitazones
The glitazones are the most recent class of oral drugs to be approved for the treatment of type 2 diabetes in the UK. Several outcome studies with these agents have been recently reported, and provide long-term data on the changes in body weight associated with these medications. The Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)6 investigated the effect on cardiovascular outcomes of treatment with pioglitazone 15-45 mg or placebo for approximately 3 years in patients with type 2 diabetes and macrovascular disease. The effect of pioglitazone treatment on the primary composite cardiovascular endpoint (including all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries and amputation above the ankle) did not reach statistical significance (hazard ratio [HR] 0.90, 95% CI 0.80-1.02, ? = 0.095). A significant 16% reduction was observed in the principal secondary composite endpoint of all-cause mortality, non- fatal myocardial infarction and stroke (HR 0.84, 95% CI 0.72-0.98, p = 0.027)6. However, 21% of patients in the pioglitazone treatment arm experienced oedema, and there was an increase in reported incidence of new cases of heart failure with pioglitazone compared with placebo (11% vs. 8%; ?
The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, conducted in 5269 adults with impaired fasting glucose and/or impaired glucose tolerance, compared the effect on progression to type 2 diabetes of rosiglitazone 8 mg or placebo over a median 3 years of treatment53. DREAM showed that rosiglitazone treatment reduced the composite primary endpoint of progression to diabetes or death by 60% compared with placebo (HR 0.40, 95% CI 0.35-0.46, ?
ADOPT (A Diabetes Outcome Progression Trial) compared rosiglitazone, metformin and glyburide (glibenclamide) as initial treatment in 4360 patients with recentiy diagnosed diabetes54. The primary outcome of ADOPT was the durability of antihyperglycaemic treatment, defined as the cumulative incidence of monotherapy failure (fasting plasma glucose > 10mmol/L) at 5 years. This trial demonstrated that rosiglitazone therapy provided more durable glycaemic control relative to either metformin or glyburide (incidence of monotherapy failure with rosiglitazone, metformin and glyburide was 15%, 21% and 34% respectively; a significant risk reduction for rosiglitazone relative to both the other agents). A statistically significant difference in HbA]C after 4 years was also observed – although the difference relative to metformin was small. As observed in other glitazone outcome trials, rosiglitazone was associated with an increase in mean weight at 5 years (4.8kg). Notably, the weight gain with rosiglitazone was progressive over time, and did not seem to reach a clear plateau over the treatment period. Glyburide also led to an increase (1.6 kg), while metformin was associated with a mean decrease in weight (2.9kg). Rates of oedema were also significantly (p
The significant weight gain observed with glitazone treatment in the PROactive, DREAM and ADOPT trials has been a consistent observation in glitazone trials, both when used as monotherapy and in combination with odier antihyperglycaemic agents. Similarly, metaanalyses conducted for a Health Technology Appraisal (HTA) showed dose-dependent weight gain with pioglitazone and rosiglitazone administered as monodierapy or in combination with sulphonylureas, metformin or insulin56. A systematic Medline search for glitazone studies published since the 2004 HTA review confirms these results, showing significant mean weight gain widi glitazone treatment in combination with a sulphonylurea, metformin, repaglinide or insulin in studies of at least 24 weeks’ duration (Figure 4). This needs to be balanced against die increasing evidence from outcome studies diat diese agents are an important drug class widi the potential to sustain glycaemic control and reduce cardiovascular events. Moreover, diere is some evidence that weight loss can be achieved despite glitazone therapy. A study of eight patients with type 2 diabetes with a history of weight gain on glitazone therapy showed that a programme of caloric restriction and behaviour modification reduced body weight as effectively as in 16 age- and gender-matched patients with type 2 diabetes who were not receiving glitazone treatment57.
Mechanisms of weight gain with oral diabetic drugs
Altiiough sulphonylureas, insulin and glitazones all cause weight gain, it is important to note diat die mechanisms by which this occurs differ between drug classes. Insulin treatment (and die insulinotropic effects of sulphonylureas) increases body fat and lean mass58 through reductions in glycosuria and anabolic effects on adipose tissue, and due to an effect to enhance appetite42.
By contrast, glitazones have the paradoxical effect of decreasing insulin resistance despite increasing body weight (which would generally be expected to exacerbate insulin resistance). The beneficial effect of glitazones on insulin sensitivity may be explained by the fact that these drugs primarily redistribute fat away from the visceral depot and liver/skeletal muscle (which contributes to insulin resistance)59,60, and toward the subcutaneous fat depot (which may reduce insulin resistance through beneficial effects mediated by adipocytokines). Indeed, die DREAM study showed preferential deposition of fat in die hip rather dian the abdomen, leading to a significant reduction in waist-to-hip ratio53. Moreover, glitazone treatment is generally associated with small reductions in blood pressure; effects on the lipid profile differ between rosiglitazone and pioglitazone, although both tend to increase high-density lipoprotein (HDL)-cholesterol and may reduce small dense, more atherogenic low-density lipoprotein (LDL) particles. Rosiglitazone tends to increase LDL-cholesterol with no effect on triglyceride levels (in a meta-analysis, rosiglitazone treatment was associated with a weighted mean change of +15.3mg/dL in LDL-cholesterol and -1.1 mg/dL in triglycerides) while pioglitazone tends to have a more neutral effect on LDL-cholesterol and reduces triglyceride levels (weighted mean change of -0.4 mg/dL in LDLcholesterol and -39.7 mg/dL in triglycerides)61.
Glitazone treatment may be associated widi a more favourable distribution of fat compared with insulin or sulphonylureas. Glitazone treatment also leads to an increase in fluid retention62,63, however, which is the cause of the increased oedema and possible increased risk of heart failure with these drugs. Moreover, irrespective of the mechanisms involved, weight gain with antihyperglycaemic treatment remains a concern for health professionals, as it is difficult to give clear lifestyle messages to overweight patients with hyperglycaemia – for whom weight loss is a central feature of their management – while prescribing drugs that promote weight gain.
Figure 4. Glitazones cause weight gain ahne or in combination with other oral hypoglycaemic agents or insulin in patients with type 2 diabetes6,63 ,86-89 , MF = metformin; SU = sulphonylurea
Need for new weight-neutral antihyperglycaemic drugs
Evidence from large-scale clinical trials supports the long-term benefits of treatment with metformin, sulphonylureas, glitazones and insulin in providing blood glucose control and improving clinical outcomes in patients with type 2 diabetes. These trials have, however, also shown that, while metformin is weight neutral, other add-on oral antihyperglycaemic drugs and insulin can lead to significant weight gain. These findings have been confirmed by studies in a real-life clinical practice setting. A retrospective study of 9546 patients with type 2 diabetes receiving a single antihyperglycaemic drug for at least 12 months in a managed care setting in the United States showed significant weight loss witii metformin, but significant weight gain following initiation of treatment with a sulphonylurea, glitazone or insulin (Figure 5)64.
Weight reduction is difficult to achieve in patients with type 2 diabetes regardless of the confounding effects of drug treatment. The add-on treatments to metformin recommended by the current ADA/ EASD treatment algorithm (sulphonylureas, glitazones or basal insulin) can all lead to weight gain. Physicians initiating add-on therapy in patients who can no longer achieve glycaemic control with metformin are therefore faced with the choice of weight management or improving glycaemic control. Clearly, there is a place for new oral antihyperglycaemic drugs that offer add-on glycaemic control with no weight gain. Figure 5. Weight changes over 12 months of treatment in patients with type 2 diabetes receiving antihyperglycaemic drug treatment in clinical practice64
Glycaemic control without weight gain: DPP-4 inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycaemic control by preventing die rapid degradation of the incretin hormones, gastric inhibitory polypeptide (GIP) and in particular glucagon-like peptide-1 (GLP-I) by the enzyme DPP-465. Incretin hormones are secreted from the gastrointestinal tract during food intake, and act to amplify the insulin response to glucose delivered orally, but not intravenously (the ‘incretin effect’)66. GLP-I has a wide range of short-term glucoregulatory actions67, and may act to preserve or enhance pancreatic ss-cell function68. The incretin response is impaired in patients with type 2 diabetes69, and so DPP- 4 inhibition is a theoretically attractive approach to restore the incretin effect by increasing levels of biologically active GLP-I. Moreover, because DPP-4 inhibition affects only glucose-dependent insulin secretion and glucagon release, DPP-4 inhibitors should cause smaller insulinotropic effects relative to sulphonylureas and little or no hypoglycaemia (and hence no need for increased energy intake to offset hypoglycaemia). These properties would predict a reduced risk of weight gain with DPP-4 inhibition compared with existing antihyperglycaemic drugs.
The DPP-4 inhibitor sitagliptin (Januvia; MK-0431, Merck & Co., Whitehouse Station, New Jersey, USA) has been approved by the United States Food and Drug Administration (FDA) as monotherapy or add-on treatment to metformin or glitazone for the treatment of type 2 diabetes. Another DPP-4 inhibitor, vildagliptin (Galvus; LAF-237, Novartis, Basel, Switzerland), is currently in late-stage development. Clinical trials in patients widi type 2 diabetes have been performed with sitagliptin and vildagliptin over treatment durations of up to 52 weeks, with administration of these drugs as monotherapy in drug treatment-naive patients, or as add-on therapy in patients failing to achieve glycaemic control with metformin or glitazones70.
Sitagliptin
Placebo-controlled studies in patients with type 2 diabetes who have not achieved blood glucose control with diet and exercise alone showed diat sitagliptin 100 or 200 mg once daily provided significant reductions in HbA10 of 0.6-1 .0% over treatment durations of up to 24 weeks71,72. A study in 741 patients widi type 2 diabetes showed that once-daily treatment for 24 weeks with sitagliptin 1 00 mg or 200 mg provided placebo-subtracted reductions in HbA10 of 0.79% and 0.94% respectively73. Sitagliptin monotherapy was well tolerated, associated with no notable increase in hypoglycaemic events, and had no significant effect on body weight (- 0.2 kg and -0.1 kg compared with baseline with sitagliptin 100 mg and 200 mg respectively).
In a 24-week study in 701 type 2 diabetes patients with mild-to- moderate hyperglycaemia (Hb A]C a 7.0%) despite ongoing metformin (> 1500 mg/day), addition of sitagliptin 1 00 mg once daily for 24 weeks reduced HbA10 by 0.65% compared with placebo (Figure 6)70,74. The addition of sitagliptin also significantly improved fasting plasma glucose, 2-hour post-meal glucose, fasting and post-meal insulin and C-peptide levels, and homeostasis model assessment of beta-cell function, compared with addition of placebo, widi no significant difference in body weight. A 52-week trial comparing add- on treatment with sitagliptin 1 00 mg or glipizide 5-10 mg twice daily in patients with type 2 diabetes receiving metformin showed that sitagliptin reduced HbA10 by 0.67% and was non-inferior to glipizide for reduction in HbA1075. Moreover, addition of sitagliptin to metformin was associated with a lower incidence of hypoglycaemia (4.9% vs. 32% with glipizide), and sitagliptin reduced body weight (by 1.5 kg) whereas glipizide increased weight (by 1.1 kg).
A 24-week study in 353 patients with type 2 diabetes with HbA10 > 7.0% despite treatment widi pioglitazone 30-45 mg showed a 0.7% reduction in HbA10 with addition of sitagliptin 100 mg to pioglitazone compared with addition of placebo, witii no significant difference in the change in body weight between treatment groups76.
Figure 6. DPP-4 inhibition with sitagliptin or vildagliptin provides significant improvements in glycaemic control when added to metformin treatment in patients with type 2 diabetes70,74,80. (Reproduced from Barnett70, with permission)
Vildagliptin
In a 1 2-week, placebo-controlled study in patients witii type 2 diabetes who had not achieved blood glucose control witii diet and exercise alone, vildagliptin 25 mg twice daily reduced HbAlc from baseline by 0.6%, and also significantly reduced fasting glucose and mean prandial glucose levels compared with placebo77. Vildagliptin treatment was not associated with a notable increase in the incidence of hypoglycaemic events, and had no significant effect on body weight. A 52-week study of monotherapy with a higher dose of vildagliptin (50 mg twice daily) in treatment-naive patients with type 2 diabetes showed inferior reductions in HbAlc (-1.0% vs. – 1.4%) to metformin 1000 mg twice daily over 52 weeks78. Vildagliptin treatment did not alter body weight (mean change +0.3 +- 0.2 kg), whereas metformin-treated patients exhibited a modest weight loss (- 1.9 +- 0.3kg). Another study showed noninferior HbA]C reductions with vildagliptin 50 mg twice daily compared with rosiglitazone 8 mg daily over 24 weeks79. Again, vildagliptin had no notable effect on body weight (-0.3 +- 0.2 kg), whereas rosiglitazone significantly increased mean weight by 1 .6 +- 0.3 kg.
Add-on treatment with vildagliptin 50 mg once daily provided significant reductions in HbA1 c when added to ongoing metformin (> 1500mg/day) treatment70,80. The improvement in HbAlc with the vildagliptin/ metformin combination was maintained for up to 52 weeks of treatment (Figure 6), whereas glycaemic control deteriorated with metformin.
Published clinical evidence to date tiierefore indicates tiiat DPP-4 inhibitors provide weight-neutral glycaemic control witii a low risk of hypoglycaemia when administered as monotherapy or when added to other oral antihyperglycaemic agents in patients with type 2 diabetes. Until evidence is available from long-term outcome trials as to the benefits of DPP-4 inhibition on the clinical endpoints in patients with type 2 diabetes, DPP-4 inhibitors are likely to be used as part of combination drug regimens. The possibility that DPP-4 inhibitors may target the underlying cause of type 2 diabetes by reversing the decline in pancreatic ss-cell function is, however, potentially of considerable therapeutic importance, and the results of clinical outcome trials with these drugs are awaited witii interest.
Incretin analogs
An alternative therapeutic approach to harness the glucoregulatory actions of GLP-I is treatment with a GLP-I mimetic that is resistant to degradation by DPP-4. The two drugs most advanced in clinical development are exenatide and liraglutide, both of which must be administered by subcutaneous injection81,82. Exenatide (Byetta; exendin-4/AC2993, Eli-Lilly, Indianapolis, Indiana, USA) was approved by the United States FDA in April 2005 as adjunctive therapy to improve glycaemic control in patients with type 2 diabetes who have not achieved adequate control on metformin and/or a sulphonylurea. Liraglutide (NN211, Novo Nordisk, Bagsvaerd, Denmark) is currentiy being investigated in Phase III clinical trials.
Long-term clinical studies have investigated the effects of exenatide, administered as twice-daily 5 or 10 pg subcutaneous injections, as add-on therapy in patients with type 2 diabetes who have failed to achieve blood glucose control witii either sulphonylureas or metformin83,84. These studies demonstrated that addition of exenatide provided maintained additional glycaemic control (additional HbA^sub 1c^ reduction of > 1 .0%) for up to 82 weeks, although > 30% of patients in these trials experienced nausea and vomiting characteristic of pharmacological GLP-I levels. Exenatide treatment was associated with progressive reductions in body weight that continued throughout the studies; patients who completed 82 weeks of metformin/exenatide combination treatment experienced a mean reduction from baseline in body weight of 5.3 +- 0.8kg84. It is important to note, however, tiiat the number of patients who completed 82 weeks of treatment was relatively low (92 out of a total of 150 patients who started the open-label extension period and 223 randomized to the original placebo-controlled trial), and the impact of drop-outs on the results is unclear. Altiiough there is no published information as to die long-term effects of liraglutide, short-term clinical studies indicate that this GLP-I mimetic exerts similar reductions in body weight and HbA^sub 1c^ when added to metformin, but is also associated widi a similar increased incidence of nausea and vomiting85.
Although the weight loss induced by exenatide is independent of the nausea and vomiting associated with the drug83,84, the gastrointestinal side-effects contrast with the placebo-like tolerability of the DPP-4 inhibitors. There is also evidence that clinically significant weight loss with exenatide treatment may be restricted to a subset of patients83,84. As GLP-I mimetics must be administered by injection, their place in antihyperglycaemic therapy is probably as addon treatment for patients who can no longer achieve blood glucose control with combinations of oral agents. Clarification of the potential role for exenatide and liraglutide dierefore awaits long-term studies comparing these agents with insulin in this patient group. Conclusions
Weight gain is a factor that may limit effective treatment in type 2 diabetes. Increased body weight affects not only the physiological capability of patients with diabetes to achieve glycaemic control, but also their psychological well-being, quality of life and persistence with antihyperglycaemic treatment. Weight gain in patients with type 2 diabetes may also be associated with increased healthcare resource burden including the increased use of weight management drugs. Current ADA/EASD treatment guidelines are based on evidence from large-scale clinical outcomes trials as to the benefits of metformin, sulphonylureas and insulin on long-term blood glucose control and macrovascular and microvascular outcomes in patients with type 2 diabetes. These guidelines recommend metformin as an effective first-line antihyperglycaemic drug without weight gain in patients with type 2 diabetes. When metformin fails, however, all recommended secondline treatment options (sulphonylureas, glitazones and insulin) can lead to significant weight gain. New agents that provide glycaemic control without increasing body weight would therefore be a welcome addition to the armamentarium of drugs for the treatment of type 2 diabetes. Initial clinical trial experience with oral DPP-4 inhibitors such as sitagliptin and vildagliptin suggest that these agents may represent an alternative treatment option to improve glycaemic control when added to metformin, witiiout the weight gain associated with existing antihyperglycaemic drugs. For the present, they lack outcome data and this is eagerly awaited, particularly from die point of view of durability of glycaemic control. GLP-I analogs such as exenatide, which must be administered by subcutaneous injection, have been shown to reduce body weight in clinical trials, and may be useful in patients who can no longer achieve blood glucose control with oral agents. Long-term clinical trials with the DPP-4 inhibitors and incretin mimetics are required to evaluate the relative risk/benefit profile of these drugs compared with the established antihyperglycaemic drug classes.
Acknowledgements
Declaration of interest: This work was supported by an unrestricted educational grant from Merck Sharp & Dohme Limited. The views expressed in this publication are those of the authors, and not necessarily those of the publisher or sponsor.
AB has received fees for lectures and advisory work from Bristol- Myers Squibb, GSK, Novartis, Merck, Sharp and Dohme, Novartis, Servier and Takeda, but was not paid for his role in the production of this manuscript. JA has been paid by Merck Sharp & Dohme Limited to provide assistance in the production of this review, and also works for other pharmaceutical companies. KJ is an employee of Merck, Sharp and Dohme. RM has been funded by Merck & Co. Inc., Whitehouse Station, NJ, USA to undertake a 1-year internship.
RM carried out the initial Medline search. This was repeated by JA to ensure all relevant papers were identified, given the time lapse between RM’s original search and the writing of the paper. RM and JA provided AB with an overview of the Medline search and the key issues arising from our findings. AB provided the strategic direction for this review article and contributed to its design and content. The review was subsequently prepared in manuscript form by JA. All authors (AB, JA, KJ, RM) commented on additional drafts, and JA managed the incorporation of comments to produce a final draft manuscript for submission.
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