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Summary

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References

Background:  Type 2 diabetes patients are usually overweight or obese. Further weight gain induced by antidiabetic treatment should be avoided if possible. Much attention has been focussed recently on the potential for GLP-1 mimetics, in particular, to reduce weight.

Aims:  Effects on weight are but one of several important criteria in selecting antidiabetic therapy, however. This review explores the effects on weight of older classes of antidiabetic agents (metformin, sulfonylureas, thiazolidinediones) and the newer drugs acting via the GLP-1 system. Other aspects of their therapeutic profiles and current therapeutic use are reviewed briefly to place effects on weight within a broader context.

Findings:  Comparative trials demonstrated weight neutrality or weight reduction with metformin, and weight increases with a sulfonylurea or thiazolidinedione. There was no clinically significant change in weight with DPP-4 inhibitors and a small and variable decrease in weight (about 3 kg or less) with GLP-1 mimetics. Improved clinical outcomes have been demonstrated for metformin and a sulfonylurea (cardiovascular and microvascular benefits, respectively, in the UK Prospective Diabetes Study), and secondary endpoints improved modestly with pioglitazone in the PROactive trial. No outcome benefits have been demonstrated to date with GLP-1-based therapies, and these agents exert little effect on cardiovascular risk factors. Concerns remain over long-term safety of these agents and this must be weighed against any potential benefit on weight management.

Conclusions:  Considering effects on weight within the overall risk-benefit profile of antidiabetic therapies, metformin continues to justify its place at the head of current management algorithms for type 2 diabetes, due to its decades-long clinical evidence base, cardiovascular outcome benefits and low cost.


Review criteria

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References
  • • PubMed search for articles on incretin-based therapies (review criteria are summarised in more detail in the article).

  • • Priority given to longer-term studies for weight regulation (6 months or longer duration of randomised treatment, where available).

  • • PubMed search, published guidelines and personal knowledge for properties of metformin.

Take-home messages for the clinician

  • • Body weight is an important treatment outcome for type 2 diabetes patients, who are usually overweight or obese.

  • • Effects on body weight differ between classes of antidiabetic therapies.

  • • Prescribing decisions are complex, however, and depend on the characteristics of each patient: they should not be swayed unduly by the relatively modest effects of GLP-1 mimetics on weight in randomised trials.

Introduction

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References

It is well established that the risk of a morbid cardiovascular event is increased by 2–4-fold in patients with type 2 diabetes, relative to their non-diabetic peers. This excess cardiovascular risk is multifactorial in aetiology, and risk factors associated with insulin resistance and the metabolic syndrome often coexist. Obesity is particularly problematic for type 2 diabetes patients. The prevalence of obesity is markedly higher among the type 2 diabetic population relative to the general population: Figure 1 shows the prevalence of overweight and obesity for the general and diabetic populations of the nationally-representative National Health and Nutrition Examination Survey) (1,2). Obesity, especially when characterised by abdominal adiposity, is a driver of adverse cardiovascular outcomes in diabetic and non-diabetic patients (3,4).

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Figure 1.  Prevalence of overweight and obesity in the general US population and in individuals with a diagnosis of diabetes in the 1999«2000 cohort of the National Health and Nutrition Examination Survey. Data from each population were standardised to the year 2000 US population. Drawn from data presented by the US Centers for Disease Control and Prevention (1) (diabetic patients) and Flegal et al (2)(general population)

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Maintaining adequate glycaemic control and optimising long-term clinical outcomes are each important foundations of the clinical management of type 2 diabetes, and an improved diet and regular exercise will contribute to both of these aims (5). However, it is notoriously difficult to persuade patients to maintain a lifestyle intervention over the long term, and most patients will require pharmacologic antidiabetic therapy. There are more options for initiating antidiabetic treatment than ever before, with numerous options for antidiabetic combination therapy as the patient’s declining β-cell function necessitates intensification beyond the initial monotherapy regimen.

The effects of available antidiabetic treatments on body weight vary markedly between classes. Effects on body weight are increasingly suggested as a key factor in influencing prescribing decisions, particularly with regard to the newer classes of agents acting via the glucagon-like polypeptide-1 (GLP-1) system. The purpose of this review is to examine the magnitude of additional benefits on weight regulation of established vs. novel classes of antidiabetic treatments, within the context of their overall risk:benefit profiles and the need to promote long-term improvements in clinical outcomes.

Antidiabetic therapies and body weight

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References

Trials reviewed

Most data presented originated from a PubMed search for type 2 diabetes, with drug names in article titles (limited to publication in English, with publication type randomised controlled trial or meta-analysis). Changes in body weight occur over the medium to long term, so that trials of short duration have limited relevance. Accordingly, in this section, priority was given to trials with a duration of randomised treatment of at least 1 year. Where trials of this duration were unavailable or scarce, consideration was given to the inclusion of randomised trials of shorter duration (at least 6 months). Meta-analyses including shorter trials were also reviewed briefly, for completeness, and information from these is included alongside a summary of the changes from individual trials in Table 1 (6–12).

Table 1.   Summary of weight changes and cost of treatment (UK perspective) with incretin-based therapies, sulfonylureas, metformin or acarbose
TreatmentMean weight change (kg)Cost for one year of treatment (UK)
Figures 2–5*Meta-analyses
  1. *Excludes data from trials where treatments were added to other treatments known to be associated with increased weight (sulfonylureas or thiazolidinediones). Costs (exclusive of value added tax) are from the UK British National Formulary or the MIMS prescription drug database and prescribing guide, estimated for one year of treatment at the maximum permitted dose or the recommended usual maximum daily dose as follows: exenatide 10 μg BID; liraglutide 1.8 mg QD; sitagliptin 100 mg QD or vildagliptin 50 mg BID; rosiglitazone 1 × 8 mg QD or pioglitazone 1 × 45 mg QD; gliclazide 4 × 80 mg (modified-release version 4 × 30 mg), glibenclamide 3 × 5 mg, glipizide 4 × 5 mg, or glimepiride 1 × 4 mg; acarbose 3 × 200 mg; metformin 4 × 500 mg or 2 × 850 mg (modified release versions 4 × 500 mg or 2 × 1000 mg). Lowest and highest costs among any of the various available preparations are shown where multiple formulations exist.

GLP-1 mimetic−3.1 to −2.5−2.7 (10)£830–1432
DPP-4 inhibitor−1.5 to +0.8+0.5 to +0.8 (11,12)£414–434
Thiazolidinedione+1.5 to +4.8+2.2–2.7 (8,10)£391–482
Sulfonylurea+0.8 to +2.6+2.8 (7)£34–173
Acarbose−1.7Weight neutral (9)£94
Metformin−2.9 to +1.5Weight neutral (6)£17–50 (£111–167)

This review concentrates on oral antidiabetic agents and the newer injectable GLP-1 mimetics, and a comparison of insulin-based regimens is beyond its scope. Recent large, randomised trials involving evaluation of the potential benefits of intensive glycaemic management are not reviewed here in detail. These inevitably involve multi-drug combinations or intensive insulin regimens for many patients, rendering it difficult to assess the contribution of single classes of agents on weight regulation. In addition, the effects of antidiabetic agents have been studied in non-diabetic overweight or obese populations, such as those with polycystic ovary syndrome or impaired glucose tolerance: these studies are again beyond the scope of this review.

Metformin, sulfonylureas and thiazolidinediones

Monotherapy

Figure 2 summarises the results of long-term, randomised evaluations of pharmacologic antidiabetic monotherapies on body weight (13–22). Given the predominant position of metformin at the head of management algorithms for type 2 diabetes, these have been divided into evaluations including, or not including, metformin. The adoption of a cut-off value of 1 year for this review effectively excluded most randomised evaluations of DPP-4 inhibitors or GLP-1 mimetics. Also, relatively few of these trials employed an active comparator. Accordingly, placebo-controlled trials, including those of shorter duration that evaluated incretin-based therapies, will be reviewed separately, later in this review.

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Figure 2.  Long-term evaluations of metformin, sulfonylureas or thiazolidinediones given as monotherapy. Trials involving at least 1 year of randomised treatment are shown here. Abbreviations: Glib: glibenclamide; Glic: gliclazide; Glim: glimepiride; Pio: pioglitazone; Rosi: rosiglitazone; Vilda: vildagliptin. aUK Prospective Diabetes Study; bA Diabetes Outcomes Progression Trial; Columns show mean changes from baseline except cchange vs. placebo.

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Most trials demonstrated a reduction in body weight with metformin. The longest comparison of antidiabetic agents conducted to date was in the 10-year UK Prospective Diabetes Study (UKPDS). All treatment groups gained some weight, on average. However, the weight gain with metformin (1.5 kg) was less than half of that with the sulfonylurea, and was similar to the 1.9 kg gained by patients randomised to diet (13). The difference between metformin and glibenclamide in the 5-year analysis from A Diabetes Outcomes Progression Trial (ADOPT) was more marked, with a treatment difference of 4.5 kg in favour of metformin (14). A further 1-year trial provided similar results (15). ADOPT and a 1-year trial in almost 1200 patients (16) confirm the adverse long-term effects of a thiazolidinedione on body weight. A long-term study randomised drug-naïve patients to metformin or to a DPP-4 inhibitor (vildagliptin): weight appeared to be reduced with metformin and unchanged with vildagliptin (17).

Other trials (not involving metformin) are shown in the lower panel of Figure 2 (18–22). In general, these show a similar pattern of effects on weight for sulfonylureas and thiazolidinediones. An additional analysis from the UKPDS showed that body weight was reduced modestly over 3 years of treatment with acarbose (these data are from an “allocated therapy” analysis conducted to take account of a high rate of withdrawals for gastrointestinal adverse events with acarbose; the intention-to-treat analysis showed a smaller effect of −3.0 kg over 3 years) (22).

A Cochrane meta-analysis dating from 2005 confirmed the significant weight reduction for metformin vs. sulfonylureas, although only two trials were available for a comparison with thiazolidinediones at that time (6). Also, this analysis did not find a significant difference for metformin vs. placebo, although it would be interesting if this analysis were repeated for trials of longer duration than the 3-month cut-off for trial duration used. Another meta-analysis that included trials of duration 6–52 weeks reported an average weight loss of 1.2 kg with metformin and a weight gain of 2.8 kg with any sulfonylurea (7).

Combination therapy

Most patients will require combination therapy at some time, given the apparently inexorable decline in β-cell function over time in patients with type 2 diabetes. The effects on body weight of combination therapies with traditional agents are shown in Figure 3 (23,24). Although relatively few long-term studies of these agents were available, a similar pattern of effects occurred in comparison to these agents used as monotherapy: body weight tended to decrease on metformin and increase on a sulfonylurea and, especially, a thiazolidinedione. Two further studies were not included in Figure 3 as only data on body mass index (BMI) were reported. One of these demonstrated small increases in BMI (+0.4 kg/m2) when metformin was added to the regimen following 1 month of treatment with nateglinide or glibenclamide (at which point sulfonylurea-induced weight gain was probably not maximal) (25). The second study, from the same group, reported large decreases in BMI following the addition of glimepiride (−1.6 kg/m2) or rosiglitazone (−1.7 kg/m2) to pre-existing metformin therapy in type 2 diabetes patients with metabolic syndrome (26). However, patients started on a −600 kcal/day diet at the start of the study, which complicates interpretation of the effects of study drugs on body weight.

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Figure 3.  Long-term combination therapy studies with metformin, sulfonylureas or thiazolidinediones. In the first study shown, combinations of nateglinide and either glibenclamide or metformin were compared in patients previously naive to oral antidiabetic therapy. Other studies involved addition of oral antidiabetic agents to existing therapy as shown. Glib: glibenclamide; Glic: gliclazide; Pio: pioglitazone; Met: metformin; Nat: nateglinide; SU: sulfonylurea

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DPP-4 inhibitors and GLP-1 mimetics

DPP-4 inhibitors

Fewer long-term trials are available for GLP-1-based therapies, and the main results from randomised trials of at least 6 months duration (Figure 4) have been included in this section for vildagliptin (17,27–35) and sitagliptin (36–42). The familiar increases in weight with a sulfonylurea (in one of two studies) and a thiazolidinedione were observed. Mean changes in weight with either DPP-4 inhibitor were small (generally < 1 kg), when administered to drug-naïve populations or as add-on therapy to metformin. In one study, changes in weight with vildagliptin and metformin differed little between those measured at 1 year and following a 1-year extension to a 1-year randomised comparison of these agents in previously drug-naïve subjects (17,43). Another study involving an 80-week extension to a 24-week comparison of vildagliptin and pioglitazone in oral antidiabetic agent-naïve patients (31) demonstrated no change in mean body weight for the DPP-4 inhibitor and a mean change of +4.7 kg with the thiazolidinedione (2 years of treatment overall) (44).

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Figure 4.  Effects on body weight of DPP-4 inhibitors (solid columns) in comparison with metformin (Met), placebo (Pbo), pioglitazone (Pio), rosiglitazone (Rosi), acarbose or glipizide (Glip) in comparative randomised trials with treatment durations of at least 6 months. Sitagliptin or vildagliptin are represented by filled columns in each case. Where multiple doses were evaluated only the maximum recommended dose for clinical use is shown for clarity. Mean weight change was 0 kg in patients randomised to avildagliptin or bglipizide. cPatients received sitagliptin for 54 weeks and glipizide for 46 weeks in a parallel-group study. TZD: thiazolidinedione. The comparison with metformin (17) is also included in Fig. 2a but is reproduced here also for completeness

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Two studies reported more marked weight gain when the DPP-4 inhibitor was added to pre-existing treatment with a thiazolidinedione. One reported an increase in weight of 1.4 kg with placebo, and a between-treatment difference in body weight of 1.3 kg for vildagliptin 100 mg/day vs. placebo at study end (35). However, there was almost no change on weight with vildagliptin 50 mg/day (+0.1 kg vs. placebo) in this study, and similar weight gain vs. placebo in an evaluation of sitagliptin as add-on therapy to a thiazolidinedione (45), so that these effects may represent mainly continued weight gain on the background thiazolidinedione treatment.

A Cochrane analysis that included randomised trials of at least 12 weeks’ duration (three trials each for sitagliptin and vildagliptin, relative to placebo) found a significant mean difference in weight of +0.7 kg (95% CI 0.3 to 1.1) for sitagliptin and of +0.8 kg (95% CI 0.3 to 1.3) for vildagliptin (12). Another meta-analysis found an average weight gain of 0.5 kg with DPP-4 inhibitors relative to placebo (11). Thus, even if a significant difference was found, this magnitude of weight gain is unlikely to be clinically significant.

GLP-1 mimetics

Studies with randomised treatment duration of about 6 months to 1 year reported losses in body weight of up to about 3 kg with the GLP-1 mimetics, exenatide and liraglutide (Figure 5) (45–53). A head-to-head trial showed that exenatide and liraglutide induced similar weight loss when added to metformin and/or a sulfonylurea (53). However, the magnitude of weight loss observed with these agents was inconsistent between trials, and it appeared that the observed weight loss may have been smaller when a GLP-1 mimetic was added to a sulfonylurea (one such trial failed to demonstrate significant weight loss after liraglutide was added to a sulfonylurea) (51).

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Figure 5.  Evaluations of exenatide and liraglutide (currently available GLP-1 mimetics) on body weight in trials with randomised treatment duration of at least 6 months. aPlacebo-corrected change (figure for placebo alone not available from source publication); bPlacebo omitted for clarity (mean change −0.1 kg). Met: metformin; SU: sulfonylurea; TZD: thiazolidinedione

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A meta-analysis of 22 trials involving addition of exenatide or a thiazolidinedione to oral antidiabetic therapy, with duration of at least 6 months, found similar results (mean weight loss with exenatide of −2.7 kg and mean weight gain with a thiazolidinedione of +2.2 kg) (10). A second meta-analysis found an average decrease in weight of −1.4 kg vs. placebo and −2.4 kg vs. all other comparators, including insulin (11). Only 3/29 of included studies had a duration as long as 30 weeks, so the lower placebo-corrected weight loss in this analysis was unsurprising, and these data are also not included in Table 1. A review of trials in this area (not a formal meta-analysis, so also not included in Table 1) found a decrease in weight with incretin mimetics of about −3.0 kg (54). Finally, a meta-analysis of 11 trials (55) found a mean decrease in BMI of −0.47 kg/m2 with a GLP-1 mimetic relative to placebo, when higher doses of these agents were used (changes in body weight per se were not reported).

A slightly larger decrease in body weight (−5.3 kg) has been observed in an open-label extension to exenatide trials involving a total of 3 years of treatment, although this study lacked a control group (56). A once-weekly formulation of exenatide, currently in clinical development, has been reported to induce slightly greater decreases in HbA1c compared with standard, twice-daily exenatide, although decreases in mean body weight were essentially identical (−3.6 kg and −3.7 kg, respectively) over 30 weeks of treatment (57).

Other factors influencing the choice of antidiabetic therapy

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References

Efficacy

The current (2009) ADA/EASD consensus statement on the management of type 2 diabetes rates the blood glucose lowering efficacy of antidiabetic therapies (5). Metformin and sulfonylureas are considered equally effective (expected decrease in HbA1c 1.0–2.0%). Considered less effective are meglitinides (expected decrease 0.5–1.5%), thiazolidinediones (0.5–1.4%), GLP-1 mimetics (0.5–1.0%), DPP-4 inhibitors (0.5–0.5%) and acarbose (0.5–0.8%). The level of antihyperglycaemic efficacy is likely to determine the effect on long-term microvascular complications, in particular.

Other cardiovascular risk factors

Metformin is associated with a modest improvement in the lipid profile, with a decrease in triglycerides and a small reduction in total or LDL-cholesterol (58,59). Improved fibrinolysis has also been observed following metformin treatment (60). A preliminary report of a CT scanning study suggests that metformin treatment may lead to redistribution of fat from metabolically active central compartment to the more quiescent subcutaneous compartment (61), a phenomenon also reported for thiazolidinediones (62). The main changes in the lipid profile with a thiazolidinedione are reduced triglycerides, increased HDL-cholesterol, with a tendency to increase LDL-cholesterol (62). Both metformin and thiazolidinediones have been reported to alter the subclass distribution of lipoprotein particles in a manner consistent with reduced cardiovascular risk (59,62). Sulfonylureas and DPP-4 inhibitors exert little or no effects on cardiovascular risk factors, although sitagliptin may lead to a small reduction in blood pressure. Modest improvements in cardiovascular risk factors have been observed during long-term treatment with exenatide in an uncontrolled study (56); liraglutide modestly reduces blood pressure, but this effect may be offset by an increased pulse rate (49–52,63). Finally, acarbose treatment reduced the risk of hypertension in pre-diabetic subjects (64).

Safety/tolerability

The tolerability issues associated with metformin (gastrointestinal symptoms, mainly diarrhoea) are well understood and their management is facilitated by decades of clinical experience. Many patients intolerant to standard metformin due to gastrointestinal side-effects successfully tolerate the prolonged-release formulation of this agent (65). Previous concerns relating to lactic acidosis with metformin have been laid to rest and it is clear that the risk of this serious adverse event is the same for metformin and other usual-care diabetes treatments when prescribed correctly (66,67). Sulfonylureas (and meglitinides) are associated with hypoglycaemia and weight gain, although the therapeutic profiles of sulfonylureas, especially is well understood. The effects of thiazolidinediones on cardiovascular outcomes remains unclear, and these agents remain associated with a risk of marked weight gain, oedema, heart failure, and distal limb fractures in women (5,62,68,69).

Incretin-based therapies have been less well studied. DPP-4 inhibitors are generally well tolerated, although uncertainty surrounds their potential to induce immune dysfunction (see above) (5). Skin reactions, sometimes severe, may be another concern with DPP-4 inhibitors, and may reflect insufficient selectivity for DPP-4 over other dipeptidyl peptidases (54). A transient nausea is the main side-effect of GLP-1 mimetics (this is generally not seen with DPP-4 inhibitors), although the long-term clinical significance of sporadic reports of pancreatitis with exenatide, or of adverse thyroid changes with liraglutide, remain to be determined (53).

Health outcomes

Overweight patients receiving metformin within the primary randomisation of the UKPDS benefited from a significantly reduced risk or a range of cardiovascular endpoints (13). Long-term follow-up of these patients for 10 years following the end of the randomised phase of the trial has demonstrated significant ‘legacy’ benefits, despite a rapid equalisation of HbA1c between patients formerly randomised to intensive glucose control or to diet-based therapy (70). A recent randomised, placebo-controlled controlled trial demonstrated improved cardiovascular outcomes in insulin-treated patients receiving metformin (71). Observational studies, and retrospective analyses of registries, also suggest significant cardiovascular protection with metformin (reviewed elsewhere) (59). Finally, registry data also suggest a significant anticancer effect of metformin (72–75). This effect is believed to arise from increased activation of the enzyme, AMP-kinase, an energy sensor within the cell that also controls an important tumour suppressor (59). Thus, AMP-kinase may represent a mechanistic link between metformin’s effects on glucose metabolism (and perhaps body weight) and a possible future clinical use in cancer prevention or therapy.

Randomisation to glibenclamide was also associated with a reduced risk of microvascular endpoints, again with a significant ‘legacy’ effect following the trial (11,70). The ADVANCE study also showed that intensive glycaemic management (including a sulfonylurea, gliclazide) reduced the risk of microvascular endpoints relative to less intensive management (76). The incidence of several secondary composite cardiovascular endpoints was reduced in patients randomised to pioglitazone vs. placebo in the PROactive trial, although the main endpoint was not affected significantly (77). A meta-analysis suggested a reduced risk of cardiovascular events with acarbose in patients with type 2 diabetes, although the number of events was relatively small (78). There are no data on long-term cardiovascular outcomes with DPP-4 inhibitors or GLP-1 mimetics.

Cost

The cost of treatments should not be underestimated as an important consideration during selection of therapy for patients in many countries. Table 1 provides an example of annual treatment costs from the perspective of the UK national health service. Although the availability of different products, and pricing strategies, will differ from country to country, similarly large relative differences between the branded and unbranded agents are likely to apply in most areas. Metformin and some sulfonylureas (e.g. glibenclamide) are generally available at low cost. Branded agents, particularly, thiazolidinediones, acarbose, DPP-4 inhibitors and, especially, a GLP-1 mimetic, are markedly more expensive.

Current guideline recommendations

A joint guideline proposed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (5), and a global guideline from the International Diabetes Federation (IDF) (79) represent the principal international guidelines currently in use. All guidelines stress the importance of an improved lifestyle throughout the course of treatment of type 2 diabetes. Also, all recommendations regarding the use of metformin relate to patients without contraindications for this agent.

The initial treatment recommendation in the IDF global guideline (80) is diet and exercise, followed by addition of metformin, and, when required a sulfonylurea. A thiazolidinedione represents the next intensification step, with meglitinides and α-glucosidase inhibitors included as further management options. This 2005 guideline does not cover DPP-4 inhibitors or GLP-1 mimetics. A separate and more recent (2007) IDF guideline on the management of post-meal glucose mentions DPP-4 inhibitors and GLP-1 mimetics, alongside meglitinides and α-glucosidase inhibitors, as pharmacologic therapies that are effective in lowering postprandial glucose and HbA1c.(80).

The ADA/EASD guideline, first published in 2006, has recently been updated for a second time (5). This guideline stratifies therapies into “well validated” and “less well validated” and, recognising the poor likelihood of long-term compliance with lifestyle interventions, recommends initial co-prescription of lifestyle intervention and metformin. Basal insulin or a sulfonylurea (followed by basal insulin) are the preferred, “well-validated” combination partners for further treatment intensification. Pioglitazone or a GLP-1 mimetic (for patients with relatively mild hyperglycaemia and for whom hypoglycaemia is a concern) represent “less well validated” options after metformin. Ultimately, all patients receive a combination of lifestyle intervention, metformin, and an intensive insulin regimen. DPP-4 inhibitors are not supported due to a theoretical concern over disturbed immune function (DPP-4 is involved in immune regulation in addition to the inactivation of GLP-1).

At present, therefore, current international guidelines are based largely on traditional antidiabetic therapies, while national guidelines provide strong support for the use of GLP-1-based agents. Support for GLP-1 mimetics is strongest where obesity is perceived as a particular problem for the patient.

Conclusions

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References

Weight increases in antidiabetic therapy are undesirable in principle and the intractable nature of weight gain in type 2 diabetes highlights the importance of selecting therapy to minimise further weight gain. Maintaining glycaemia and optimising long-term clinical outcomes are important considerations in antidiabetic therapy, and effects on weight must be viewed within this broader context.

Metformin is weight neutral or weight-reducing, inexpensive, and numerous studies have confirmed long-term cardiovascular outcome benefits associated with its use. Sulfonylureas and thiazolidinediones will have their place for specific patients, despite the weight gain encountered with these agents, for example within antidiabetic combinations or when metformin is contraindicated or not tolerated. Although much attention in the literature and at medical symposia is focussed on weight loss with GLP-1 mimetics, the magnitude of weight loss with these agents is modest, and equates to only about 2–4% of initial body weight in a typical overweight/obese type 2 diabetes patient. DPP-4 inhibitors, which also act via the GLP-1 system, are weight neutral and induce less nausea and vomiting than GLP-1 mimetics, but have few other benefits. There are no long-term outcome studies with either GLP-1 mimetics or DPP-4 inhibitors, and the benefit on weight regulation of these agents must be weighed against concerns arising from the lack of long-term safety data. Overall, considering effects on weight and broader benefits, the place of metformin at the head of current management algorithms for type 2 diabetes remains well justified and this agent should be retained in antidiabetic regimens wherever possible.

Acknowledgement

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References

While the opinions expressed in this manuscript are my own, editorial support was provided by Dr Mike Gwilt.

References

  1. Top of page
  2. Summary
  3. Review criteria
  4. Introduction
  5. Antidiabetic therapies and body weight
  6. Other factors influencing the choice of antidiabetic therapy
  7. Conclusions
  8. Acknowledgement
  9. References
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