Several new drugs designed to reduce hyperglycaemia in type 2 diabetes have been introduced into clinical practice in recent years. Established classes of oral blood glucose lowering agents, including biguanides, sulphonylureas, meglitinides, alpha-glucosidase inhibitors and thiazolidinediones (TZDs), as well as insulin, address hyperglycaemia in people with type 2 diabetes through a variety of mechanisms. While these agents compensate, in varying ways, for the diminished insulin secretion and enhanced insulin resistance that typify type 2 diabetes, their efficacy, to differing extents, is limited by hypoglycaemia, weight gain or both. In addition, each class of existing therapies has its own recognised contraindications, side-effects and interactions with other agents.
Improved understanding of pathophysiological processes underlying type 2 diabetes has enabled the development of glucose-lowering agents with new modes of action. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are examples of such developments (Munro et al, 2007; Munro and Levy, 2007). These agents are distinguished from many existing therapies by their glucose-dependent mode of action. They offer the possibility of glucose control with weight loss, or at least weight neutrality, and a diminished risk of significant hypoglycaemia.
This module describes the development path and licensing trials for the newer blood glucose lowering agents, with an emphasis on the agents currently available to prescribers in the UK. Post-marketing trial evidence is largely unavailable for these agents, although several multicentre trials are in their preliminary phases.
In addition, the module covers key mechanisms currently being explored that may result, over the next 10 years, in the emergence of therapies with novel modes of action, further expanding the palette of agents available for clinical use.
The incretin system
Incretin hormones are peptides released from the intestinal tract in response to mixed meals. They contribute to glucose homeostasis by promoting glucose-dependent insulin secretion. The incretin effect is observed experimentally when insulin responses to oral and intravenous glucose loads are compared. An enhanced response is seen with oral, as opposed to parenteral glucose.
The role of an incretin mechanism in glucose homeostasis was proposed as long ago as the 1930s (La Barre, 1932). It was not until the 1960s, however, that researchers demonstrated an increased stimulation of insulin secretion when glucose is given orally rather than intravenously at equivalent doses (Elrick et al, 1964; Perley and Kipnis, 1967). Results indicated the presence of gastrointestinal-hormone mediated action leading to enhanced postprandial insulin secretion in response to oral glucose loading. Eisentraut and Unger called this “intestinal secretion of insulin” the “incretin” effect (Creutzfeldt and Ebert, 1985).
Two hormones secreted from the gastrointestinal tract account for >50% of the incretin effect of a mixed meal. They rapidly stimulate insulin release in the presence of hyperglycaemia. These hormones are GLP-1, comprising 30 amino acids, and glucose-dependent insulinotropic polypeptide (GIP), comprising 42 amino acids (McIntyre et al, 1964; Nauck et al, 1986). GIP is derived from the K cells located in the jejunum and is secreted more readily in response to dietary fat than to glucose (Levy, 2006). In contrast, GLP-1 is secreted by the L cells in the ileum, predominantly in the presence of glucose.
The secretion of these hormones occurs in association with neural signalling arising from food stimulus. These mechanisms induce insulin secretion through direct activation of G-protein coupled receptors expressed on pancreatic beta-cells (Vilsboll and Holst, 2004). In people with type 2 diabetes the beta-cell response to GIP is largely lost, but GLP-1 receptor sensitivity remains (Munro and Feher, 2008). The reasons for reduced GIP responsiveness remain unclear but may be associated with reduced GIP receptor expression in people with significant insulin resistance (Rudovich et al, 2005). Drug developments have therefore focused on the role of GLP-1 in glucose homeostasis.
Native GLP-1
Insulin secretion in response to glucose metabolism is triggered by beta-cell membrane depolarisation. This raises intracellular calcium concentrations, which, in conjunction with calmodulin, causes insulin granules to fuse with the cell membrane, releasing their contents to the extracellular medium.
Cellular signalling mechanisms provide a rationale for incretin hormone effects. When GLP-1 binds to beta-cell surface receptors, cyclic adenosine monophosphate-dependent protein kinase activation results. This potentiates the insulin secretory pathway at many points, enhancing secretion. However, as GLP-1 cannot trigger insulin release by itself, its insulinotropic effect is dependent on ambient glucose. At glucose levels close to the threshold for the triggering of insulin secretion, GLP-1 has little effect (Triplitt et al, 2006).
In addition to its glucose-dependent action on insulin secretion, GLP-1 has been shown to suppress glucagon secretion, delay gastric emptying, and induce satiety and a sense of fullness, with a resultant reduction in food intake (Levy, 2006). Elevated glucagon levels are found in people with type 2 diabetes and contribute to background and postprandial hyperglycaemia. By direct action on islet alpha-cells, GLP-1 reduces excess glucagon secretion without impacting on its protective effect during hypoglycaemia.
The combination of delayed gastric emptying and a central nervous system effect on satiety, via GLP-1 mediated activation of receptors in the hypothalamus and area postrema, offers the potential for weight reduction (Orskov et al, 1996). In rodents suppression of apoptosis and proliferation of beta-cells has been demonstrated (Drucker, 2003). These properties are summarised in Box 1.
Exploiting the therapeutic potential of the incretin system
The effects of GLP-1 outlined above would clearly be useful in a blood glucose lowering therapy for type 2 diabetes. The potential for achieving glucose homeostasis with minimal risk of iatrogenic hypoglycaemia is clearly desirable, as is the possibility of weight loss. As the site of action of GLP-1 is distinct from those of other insulin secretagogues, it has the advantage of providing an additive, rather than competitive, effect (Zander et al, 2002). Furthermore, were the beta-cell protective properties observed in animal studies to be demonstrated in humans also, a treatment able to prevent the beta-cell decline that typifies type 2 diabetes would be represent a significant milestone.
Native GLP-1 is, however, not easily exploitable as a therapy for type 2 diabetes. Owing to its rapid degradation by DPP-4, the agent has a short half-life, and a native GLP-1 therapy would require continuous parenteral infusion. As such, efforts to therapeutically exploit the incretin system have focused on two drug classes – long-acting GLP-1 receptor agonists (also known as incretin “mimetics”) and DPP-4 inhibitors.
GLP-1 receptor agonists
GLP-1 receptor agonists mimic the action of native GLP-1, but are resistant to degradation by DPP-4.
Exenatide
History
The first GLP-1 receptor agonist to become commercially available is exenatide (Box 2). Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster, a poisonous Mexican lizard, which has a 50% homology with human GLP-1. Exenatide has been licensed in the USA for the treatment of type 2 diabetes since 2005. In the UK the agent has been commercially available since 2007.
Mode of action
Exenatide exhibits several of the antihyperglycaemic properties of GLP-1, and has been shown to bind to and activate the human GLP-1 receptor (Electronic Medicines Compendium, 2009). In common with GLP-1, the agent stimulates glucose-dependent insulin secretion, suppresses glucagon secretion and delays gastric emptying.
Indications and licence
Exenatide is indicated for the treatment of type 2 diabetes in combination with metformin, sulphonylureas, or both in people who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies.
The agent is administered via twice-daily subcutaneous injection. To reduce early side-effects such as nausea, the initial dose is 5 µg twice-daily. This can be increased to 10 µg after 1 month to further improve glycaemic control. Injections should be administered within the 60 minutes before morning and evening meals (or the two main meals of the day, providing that they are approximately >6 hours apart).
When used in combination with a sulphonylurea, it is recommended that a reduction in the dose of sulphonylurea be considered as a means of minimising the risk of hypoglycaemia (Electronic Medicines Compendium, 2009).
Key evidence: Placebo-controlled trials examining combination with oral agents
Phase III trials involving 1600 people with type 2 diabetes treated over a minimum of 6 months evaluated exenatide as additional therapy in those who had not achieved satisfactory glycaemic control with maximum doses of metformin, sulphonylureas or a combination of both agents (Buse et al, 2004; DeFronzo et al, 2005; Kendall et al, 2005). In all studies, exenatide 10 µg twice-daily reduced HbA1c by about 1% when compared with placebo over 30 weeks. When exenatide 10 µg twice-daily was added to metformin there was a 2.8 kg weight loss. This weight loss did not appear to plateau at the end of the study period (DeFronzo et al, 2005).
In a shorter 16-week study comparing exenatide with placebo when taken in combination with a TZD with or without metformin the agent was associated with a reduction of HbA1c approaching 1% (Zinman et al, 2007). Exenatide is not currently licensed for use in combination with TZDs.
Key evidence: Comparison with insulin
In a 26-week study, 549 people with type 2 diabetes and an HbA1c level of 7–10% on metformin and sulphonylurea were randomised to receive either exenatide or insulin glargine (titrated using a forced protocol aiming for a morning blood glucose level of 100 mg/dL [5.6 mmol/L]) (Heine et al, 2005). The percentages of patients achieving an HbA1c level of ≤7% (48% vs. 46%, respectively) and ≤6.5% (32% vs. 25%) were not significantly different. Weight loss in the exenatide arm was 2.3 kg, while weight gain in the insulin glargine recipients was 1.8 kg (P<0.001).
The therapeutic effects of insulin glargine and exenatide when added to either metformin or sulphonylurea monotherapy were compared in a 32-week crossover study (Barnett et al, 2007). On an intention-to-treat basis, 138 people with a mean BMI of 31 kg/m2, an HbA1c level of 9% and 7 years’ duration of diabetes were randomised to treatment with exenatide or insulin glargine plus either sulphonylurea (45%) or metformin (55%) therapy. After 16 weeks, participants’ treatment regimens were crossed over.
Similar percentages of trial participants reached an HbA1c target of ≤7% – 38% with exenatide and 40% with insulin glargine – with 22% and 14% achieving an HbA1c level ≤6.5%, respectively. Body weight changes observed in the first 16 weeks of the trials were effectively reversed when the treatments were crossed over (Barnett et al, 2007).
A comparison of exenatide and premixed insulin aspart exhibited similar results, with equivalence in HbA1c reductions (1.04% vs. 0.89%, respectively) and a divergence in weight effects (Nauck et al, 2007a). A higher percentage of people in the exenatide arm compared with the insulin aspart arm achieved an HbA1c level of ≤7% (32% vs. 24%, respectively).
Contraindications and side-effects
The most common side-effect in studies of exenatide in combination with other oral blood glucose lowering agents was mild to moderate nausea, with a prevalence of 36–39% (with 5 µg twice-daily) and 45–50% (with 10 µg twice-daily) (Riddle et al, 2006). However, this generally dissipated in the early weeks of therapy (Riddle et al, 2006). Overall, in the studies by Buse et al (2004), DeFronzo et al (2005) and Kendall et al (2005), 4% of exenatide recipients withdrew from the studies due to nausea.
There were reports of hypoglycaemia when exenatide was added to sulphonylurea but not to metformin. Adverse effects were related to dose, and slow titration reduced their incidence (Fineman et al, 2004).
Due to the increase in hypoglycaemia risk when exenatide is taken with a sulphonylurea, Group 2 (larger goods vehicle or passenger carrying vehicle) driving license holders treated with these agents in combination are required to inform the Driver and Vehicle Licensing Agency (DVLA, 2008).
In insulin comparator studies safety and tolerability were closely studied. Overall hypoglycaemia rates in the head-to-head comparison of exenatide and insulin glargine were low (7.3 vs. 6.3 events/year, respectively) (Heine et al, 2005). In the exenatide-treated people, this was thought to be attributable to concomitant sulphonylurea therapy. Low rates of hypoglycaemia were also observed in the comparison of exenatide and premixed insulin (daytime: 4.1 vs. 4.4 events/patient-year; nocturnal: 0.6 vs. 1.1 events/patient-year). One-third of people treated with exenatide experienced nausea; however, this resulted in a low drop out rate of 3.5%.
People with type 2 diabetes have a three-fold greater risk of developing pancreatitis compared with those without diabetes (Noel et al, 2009). In addition, those who are obese have a several-fold increased risk of developing severe complications of pancreatitis relative to non-obese people (Suazo-Barahona et al, 1998). Pancreatitis has been reported as an adverse effect of exenatide. As of March 2009, there have been approximately 800 000 patient-years of experience worldwide with the drug since it was licensed; in the period up to September 2008, there were 396 case reports of pancreatitis in people taking the agent (Medicines and Healthcare products Regulatory Agency [MHRA], 2009). According the MHRA (2009), nine reports of necrotising or haemorrhagic pancreatitis, two of which were fatal, have been received worldwide. Continuing advice is that if pancreatitis is suspected, treatment with exenatide should be suspended immediately; if pancreatitis is diagnosed, exenatide should be permanently discontinued (MHRA, 2009). There are no markers that determine whether pancreatitis associated with exenatide will be complicated by the haemorrhagic or necrotising forms.
Exenatide is not recommended for use in those with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) (MHRA, 2009).
GLP-1 receptor agonists: Future developments
Studies examining the impact of prolonged action of GLP-1 receptor agonists are currently under way. Additional research has focused on the development of GLP-1 receptor agonists based on modification of the amino acid sequence of human GLP-1 to increase resistance to enzymatic degradation by DPP-4.
While exenatide is administered twice daily, other GLP-1 receptor agonist preparations administered once-daily or once-weekly are being studied in an effort to improve adherence and acceptability. Furthermore, fortnightly and monthly injectable, as well as inhaled, GLP-1 agents are being investigated. Examples of agents in development are albiglutide (Matthews et al, 2008), liraglutide, exenatide once-weekly and taspoglutide.
Liraglutide
Liraglutide is a once-daily GLP-1 receptor agonist that is currently awaiting licensing approval for use in clinical practice. The agent is based on the human GLP-1 sequence linked to a fatty acid (Juhl et al, 2002). It binds to interstitial albumin at the injection site and is slowly absorbed. The albumin complex delays absorption and is resistant to DPP-4 degradation, having a half-life of 12.6 hours (Agerso et al, 2002).
The LEAD (Liraglutide Effect and Action in Diabetes) study programme has examined its use in combination with sulphonylureas, metformin, TZDs and insulin. The LEAD studies included around 4000 people with type 2 diabetes; five randomised, controlled, double-blind studies were initially conducted in more than 40 countries.
LEAD-1 (Marre et al, 2009) and LEAD-2 (Nauck et al, 2009) investigated the effect of different doses of liraglutide when combined with a single oral antidiabetes drug: glimepiride and metformin, respectively. LEAD-3 compared liraglutide with glimepiride when used as monotherapy (Garber et al, 2009), while LEAD-4 investigated the effect of different doses of liraglutide in combination with metformin and rosiglitazone (Zinman et al, 2009). LEAD-5 compared liraglutide with insulin glargine when used as add-on therapy in people inadequately controlled with metformin and glimepiride (Russell-Jones et al, 2008).
The most common adverse events in the trials were gastrointestinal in nature (i.e. nausea, diarrhoea and vomiting), and were mostly mild and transient. The rate of minor hypoglycaemia was low, at ≤0.5 events/patient-year. As with exenatide there were occasional reports of pancreatitis.
Exenatide once weekly
A once-weekly preparation of exenatide (exenatide QW) is currently in an advanced stage of development (Drucker et al, 2008). In a safety trial, exenatide QW lowered HbA1c levels by 1.9% over 30 weeks, compared with a 1.5% reduction for exenatide twice-daily over the same period (P=0.0023) (Drucker et al, 2008). A similar degree of weight loss was noted in both arms.
DPP-4 inhibitors (gliptins)
Mode of action
DPP-4 inhibitors are oral agents that block DPP-4-mediated inactivation of GLP-1. This results in prolongation of endogenous GLP-1 activity, with higher fasting and postprandial plasma levels being achieved in vivo (Idris and Donnelly, 2007). This, in turn, increases insulin secretion, reduces the proinsulin-to-insulin ratio, inhibits glucagon secretion and reduces postprandial hyperlipidaemia. In contrast to GLP-1 receptor agonists, DPP-4 inhibitors appear to have a limited effect on weight and gastric emptying.
In addition to their impact on GLP-1 and GIP action, these agents may potentially affect other peptides, including peptide YY, neuropeptide Y, growth hormone-releasing hormone and vasoactive intestinal polypeptide, which are involved in regulatory systems (Deacon, 2004). It is further recognised that DPP-4 is important in T-cell activation. Long-term data on the use of DPP-4 inhibitors remains limited.
There have been over 100 patent applications for DPP-4 inhibitors to be used either as a monotherapy or in other drug combinations for the treatment of type 2 diabetes, metabolic syndrome, osteoporosis and arthritis (Chyan and Chuang, 2007). Sitagliptin and vildagliptin are commercially available in the UK with additional agents expected in the near future.
Sitagliptin
History
Sitagliptin is a potent and highly selective inhibitor of DPP-4, and was the first DPP-4 inhibitor to become commercially available (Box 3). It was licensed for use in the USA in 2006, with its UK license following in 2007.
Indications and licence
Sitagliptin is indicated for improving glycaemic control in combination with metformin, a sulphonylurea, or both metformin and a sulphonylurea, when diet and exercise plus maximally tolerated doses of these agents do not provide adequate glycaemic control. It is also indicated for dual therapy with a TZD when glycaemic control is suboptimal with diet and exercise and the TZD alone.
The dose of sitagliptin is 100 mg once daily. When sitagliptin is used with a sulphonylurea, a reduction in the dose of sulphonylurea may be considered to minimise the risk of hypoglycaemia (Electronic Medicines Compendium, 2008b). Sitagliptin should not be used in people with moderate to severe renal insufficiency (creatinine clearance <50 mL/min) due to a lack of data.
Key evidence: Placebo-controlled trials
In a number of studies, sitagliptin has been shown to improve levels of HbA1c, fasting glucose and beta-cell function when compared with placebo. Aschner et al (2006) conducted a monotherapy study in which 741 patients were randomised to placebo, sitagliptin 100 mg daily or 200 mg daily over a 24-week period. HbA1c reductions of 0.61% and 0.76% were recorded for the 100 mg and 200 mg groups, respectively, while HbA1c increased by 0.18% in the placebo group. Additionally, fasting plasma glucose levels were reduced compared with placebo. Homeostasis model of assessment of beta-cell function (HOMA-B) showed an increase of 13% and a reduction in the proinsulin-to-insulin ratio, suggesting an improvement in beta-cell function with sitagliptin (Aschner et al, 2006). These findings were corroborated in another monotherapy study by Raz et al (2006). Sitagliptin is not currently licensed for use as a monotherapy.
Sitagliptin has also been investigated in combination therapy studies. Charbonnel et al (2006) randomised 701 people with type 2 diabetes and suboptimal glycaemic control (HbA1c ≥7 and ≤10%) with metformin alone to receive either placebo or sitagliptin 100 mg for 24 weeks. Sitagliptin was associated with a statistically significant placebo-subtracted reduction in HbA1c levels of 0.65%, and improvements in fasting and postprandial glucose levels. The proportion of participants achieving an HbA1c level of <7% was also significantly greater in those assigned to sitagliptin than those receiving placebo (47.0% vs. 18.3%, respectively; P<0.001). Significant improvements with sitagliptin were also noted for indexes of insulin secretion and beta-cell function. No significant differences were noted between the groups in terms of safety, including the risk of hypoglycaemia. Finally, changes in body weight were not significantly different.
Additional placebo-controlled studies have examined the use of the agent in combination with sulphonylurea, sulphonylurea and metformin (Hermansen et al, 2007), and a TZD (Rosenstock et al, 2006). In both studies, sitagliptin was associated with reductions in HbA1c and fasting glucose levels. There were modest increases in rates of hypoglycaemia with sitagliptin compared with placebo when the agent was added to sulphonylurea therapy, but not a TZD.
Key evidence: Comparator trials
Nauck et al (2007b) randomised 1172 people with type 2 diabetes and inadequate glycaemic control with metformin monotherapy to the addition of sitagliptin 100 mg once-daily or glipizide for 52 weeks. Similar reductions in HbA1c were achieved by participants in both arms. Rates of hypoglycaemia were lower in the group assigned sitagliptin than in the group receiving glipizide (5% vs. 32%; P<0.001).
Scott et al (2008) examined the relative effects of placebo, sitagliptin and rosiglitazone when added to ongoing metformin monotherapy. Similar reductions in HbA1c were observed in the active treatment arms; body weight increased in those assigned to rosiglitazone and decreased in those taking sitagliptin. The between treatment group difference in body weight change was statistically significant.
Further trials
Study data considering treatment with sitagliptin in children with type 2 diabetes aged 11–16 years, as well as treatment in combination with insulin in adults, are awaited.
Vildagliptin
History
Vildagliptin is a competitive and reversible inhibitor of DPP-4 that became commercially available for use in the UK in 2008 (Box 4). It is not currently licensed for use in the USA.
Indication and licence
Vildagliptin is currently licensed for the treatment of type 2 diabetes as dual oral therapy in combination with metformin, a sulphonylurea or a TZD. The recommended daily dose is 50 mg twice-daily when used with metformin or a TZD; 50 mg daily is the recommended dose when used with a sulphonylurea. There is also a fixed-dose combination of vildagliptin and metformin.
Prescribers are advised to monitor liver function at 3-month intervals during the first year of treatment with vildagliptin and periodically thereafter (Electronic Medicines Compendium, 2008a). Transient liver enzyme rises were noted during clinical trials with dosages higher than are available for clinical use.
Key evidence: Placebo-controlled trials
Bosi et al (2007) conducted a 24-week double-blind trial to evaluate the safety and efficacy of vildagliptin 50 mg daily and 100 mg daily compared with placebo, when added to metformin monotherapy in people with suboptimal glycaemic control. Placebo-subtracted reductions in HbA1c of –0.7% and –1.1% were observed with vildagliptin 50 mg and 100 mg, respectively (P<0.001 for both). Improvements in levels of fasting plasma glucose and measures of beta-cell function were also noted.
In a 6-week insulin clamp study comparing vildagliptin with placebo, the gliptin was associated with an improvement in islet function and glucose metabolism in peripheral tissues (Azuma et al, 2008).
Fonseca et al (2007) compared the addition of vildagliptin 50 mg twice-daily or placebo to insulin therapy in inadequately controlled people with type 2 diabetes (HbA1c 7.5–11%). A significant difference in the magnitude of HbA1c reduction was observed between the groups (vildagliptin: –0.5%, placebo: –0.2%; P=0.01). In addition, no difference in insulin dosages were noted and fewer and less severe hypoglycaemic episodes were recorded in the vildagliptin treated group. Vildagliptin is not currently licensed for use with insulin.
Garber et al (2008) compared the addition of vildagliptin (at doses of 50 mg once- or twice-daily) and placebo to sulphonylurea monotherapy. An improvement in glycaemic control was noted in those assigned vildagliptin. Rates of hypoglycaemia were low but slightly higher in the group receiving 50 mg twice-daily.
Key evidence: Comparator trials
In a 1-year study comparing vildagliptin 50 mg twice-daily with metformin 1 g twice-daily in drug-naïve people with type 2 diabetes and baseline HbA1c levels of 8.7%, the mean changes from baseline to endpoint HbA1c were –1% and –1.4%, respectively. While non-inferiority of vildagliptin compared to metformin was not confirmed, the DPP-4 inhibitor did result in early and sustained improvements in glycaemic control (Schweizer et al, 2007). Gastrointestinal side-effects were less frequent than with metformin, and there was no change in weight and a low rate of hypoglycaemia with vildagliptin. Vildagliptin is not currently licensed for use as a monotherapy.
A further study compared vildagliptin 50 mg twice-daily with rosiglitazone 8 mg daily in drug-naïve people with type 2 diabetes. The mean change in HbA1c for those on vildagliptin from baseline to endpoint was –1.1%, which satisfied the non-inferiority criterion of a ≤0.4% difference between treatments. Weight gain of 1.6 kg was observed over the 24-week study period in those treated with rosiglitazone, while those assigned vildagliptin did experience a change in body weight (Rosenstock et al, 2007).
Bolli et al (2008) performed a similar 24-week trial to compare the addition of vildagliptin 50 mg twice-daily and pioglitazone 30 mg daily to metformin monotherapy. The reduction in HbA1c achieved with vildagliptin was again non-inferior to that in the group receiving the TZD. Vildagliptin was not associated with a change in body weight, whereas those receiving pioglitazone gained weight.
Contraindications and side-effects
The DPP-4 inhibitors are generally regarded as weight neutral (Nathan et al, 2009). Hypoglycaemia is not a significant concern, although as described above, rates of hypoglycaemia may be increased when DPP-4 inhibitors are combined with a sulphonylurea. For this reason, drivers holding Group 2 licenses who are treated with a DPP-4 inhibitor and a sulphonylurea are required to inform the DVLA (DVLA, 2008).
DPP-4 inhibitors are otherwise generally well tolerated. Reported side-effects include infections of the upper respiratory tract as well as headache. Infrequently, the class can be associated with abdominal pain, nausea and diarrhoea.
DPP-4 inhibitors: Future developments
As with the GLP-1 receptor agonist class of agents, a number of additional DPP-4 inhibitors are in development. Examples include alogliptin (DeFronzo et al, 2008), linagliptin and saxagliptin (Rosenstock et al, 2008).
Clinical use of GLP-1 receptor agonists and DPP-4 inhibitors
Current guidance from NICE regarding the use of exenatide is illustrated in Box 5 (NCCCC, 2008). The agent is recommended as a third-line option for people meeting a range of clinical criteria. A short clinical guideline on the use of newer drugs for blood glucose lowering, including GLP-1 receptor agonists and DPP-4 inhibitors, is currently being prepared by NICE. At the time of going to press, a draft for consultation is accessible from NICE’s website, with publication of the final document expected later this year (NICE, 2008). Attention is focused on the cost-effectiveness as well as therapeutic utility in these guidelines.
Other algorithms have been published that include newer agents. Emphasis is placed on the need to control weight as well as hyperglycaemia and advocates a tailored approach to therapy escalation. Figure 1 illustrates one such example (Feher et al, 2008). Another algorithm was published in a recent supplement to this journal (Barnett et al, 2008). Box 6 presents a case study highlighting some of the practical considerations related to the use of exenatide and the DPP-4 inhibitors.
Other agents and future developments
In addition to the incretin system-based therapies, there are a number of other blood glucose lowering agents in development that impact on varying components of glucose homeostasis. These are considered below for completeness, along with information on pramlintide, a newer agent that is commercially available in the USA.
Pramlintide
Amylin, a neuroendocrine hormone, is released from the beta-cells of the pancreas in conjunction with insulin secretion (VanDeKoppel et al, 2008). It binds to cerebral receptors and lowers glucose levels by inhibiting the secretion of glucagon. It plays an important role in the early utilisation of ingested glucose (Ludvik et al, 2003). Diminished pancreatic beta-cell function leads to decreased insulin and amylin secretion and hyperglucagonaemia. This promotes endogenous glucose production and glycogen breakdown, the net result of which is hyperglycaemia.
Pramlintide, a synthetic form of amylin, is established as a co-agent with insulin in the management of people with type 1 and type 2 diabetes (Amylin Pharmaceuticals, Inc., 2008). It has been licensed for use in the USA since 2005. Pramlintide has a favourable effect on weight loss, which is an attractive feature, but it requires administration by subcutaneous injection. In addition, it must be used in combination with insulin at mealtimes, necessitating multiple additional injections daily. The most common side-effect with pramlintide is nausea. Although pramlintide does not cause hypoglycaemia by itself, it can enhance the hypoglycaemic effect of insulin (Amylin Pharmaceuticals, Inc., 2008).
Sodium glucose co-transporter type 2 (SGLT2) inhibitors
SGLT2 inhibition has been identified as a potential mechanism for managing hyperglyca
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