Several classes of agents are now available to reduce hyperglycaemia in type 2 diabetes. Established therapies including biguanides, sulphonylureas, meglitinides, thiazolidinediones and alpha-glucosidase inhibitors are now supplemented by therapies whose actions are mediated through the incretin effect – glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors.
No single agent, or class of drug, will suit all people. In selecting treatments for an individual with type 2 diabetes, a careful balance has to be drawn between efficacy, unwanted effects, including hypoglycaemia and weight gain, and adverse events. In licensing, drugs regulators have to draw a fine line between making new therapies available as quickly as possible and ensuring that the preparations lack significant adverse effects when used in routine clinical practice. The consequences of long-term use of glucose-lowering therapies, in terms of durability and safety, are difficult to predict accurately. Practical aspects, such as frequency of dosing, method of administration, monitoring requirements, drug interactions and cost-effectiveness also feed into this complex and individualised decision-making process. Straightforward management algorithms and protocols need increasingly to take account of wider choices and enable shared decisions on optimal therapy strategies between people with diabetes and their professional carers. The complexity of this decision-making is likely to increase as newer therapies with novel modes of action become available for use in routine clinical practice.
Intense post-marketing surveillance of some existing agents has provided further information on their utility and safety in clinical practice. The withdrawal of rosiglitazone following a review by Nissen and Wolski (2007) has heightened regulators’ concerns about drug safety both before and after licensing. Newer therapies now require ever more expensive phase III trials, including large cardiovascular safety studies, as intrinsic elements of the licensing process.
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 and 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 an incretin mechanism might play in glucose homeostasis was first proposed as far back as the 1930s (La Barre, 1932). It was not until the 1960s, however, that researchers demonstrated greater stimulation of insulin when glucose was given orally rather than intravenously at equivalent doses (Elrick et al, 1964; Perley and Kipnis, 1967). Results indicated the presence of gastrointestinal hormonal mediated action that enhanced postprandial insulin secretion in response to oral glucose loading. Eisentraut and Unger described this “intestinal secretion of insulin” as the “incretin” effect (Creutzfeldt and Ebert, 1985).
Two hormones secreted from the gastrointestinal tract account for over 50% of the incretin effect of a mixed meal. They rapidly stimulate insulin release in the presence of hyperglycaemia. The hormones are GLP-1, with 30 amino acids, and glucose-dependent insulinotropic polypeptide (GIP), with 42 amino acids (McIntyre et al, 1964; Nauck et al, 1986). GIP is derived from the K-cells located in the jejunum and responds more to dietary fat than to glucose (Levy, 2006). In type 2 diabetes the beta-cell response to GIP is largely lost, but GLP-1 receptor sensitivity remains. 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).
GLP-1 is secreted by the L-cells in the ileum, predominantly in the presence of glucose. This occurs in association with neural signalling arising from food stimulus. These mechanisms induce insulin secretion through direct activation of G-protein-coupled receptors (GPRs) expressed on pancreatic beta-cells (Vilsbøll and Holst, 2004). 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 very 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 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 in hypoglycaemia.
GLP-1 is degraded (and inactivated) in 1–2 minutes by DPP-4, a ubiquitous intracellular enzyme. This rapid degradation reduces the usefulness of human GLP-1 in clinical practice (since it would have to be continually infused in order to retain its biological action) and has led to the development of GLP-1 receptor agonists that are resistant to degradation by DPP-4 (owing to alterations in their molecular structure) and DPP-4 inhibitors, that promote physiological secretion of endogenous GLP-1.
Current and future GLP-1 receptor agonists
Three GLP-1 receptor agonists are currently available for use in clinical practice in the UK – exenatide twice daily, liraglutide and exenatide once weekly.
Exenatide was first launched in the USA in 2005 and in the UK in 2007. It is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster (a poisonous Mexican lizard) that has a 53% homology with human GLP-1. It is administered twice daily by subcutaneous injection given within an hour of morning and evening meals. There are two pen devices, one delivering a dose of 5 µg and the other 10 µg. Each will deliver a month’s worth of agent. Initiation in the first month is with 5 µg twice daily, increasing to 10 µg thereafter (Electronic Medicines Compendium, 2012e).
Liraglutide is an albumin-bound analogue of human GLP-1 that is DPP-4 resistant and has been in clinical use since July 2009. It has a duration of action that allows once-daily administration. It can be administered at any time during the day. It has dose regimen that escalates weekly, starting at 0.6 mg daily, and rising to 1.2 mg daily, or potentially 1.8 mg daily. All doses are delivered through a single pen device (Electronic Medicines Compendium, 2012f).
Exenatide once weekly is the first once-weekly GLP-1 receptor agonist to become available for clinical use in the UK. The formulation consists of injectable microspheres of exenatide (2 mg) and poly(D,L-lactic-co-glycolic acid), a biodegradable polymer, allowing slow and controlled drug release from the subcutaneous tissue (Tracey, 1999). The polymer has established use in other slow-release preparations and in absorbable sutures.
As with other glucose-lowering drugs there are responders and non-responders. The ability of the beta-cell to secrete insulin as a result of GLP-1 activation determines the glucose-lowering potential of this class of drug in individual people. A shorter duration of diabetes, in the author’s experience, may give some indication of a higher likelihood of response, although some people with long disease duration demonstrate insulin release following GLP-1 stimulation. It remains difficult, however, to accurately identify those who will respond optimally to this class of drug. There is some variation in the efficacy of these agents across phase III and post-licensing trials. Weight loss is noted consistently in study populations (Bailey, 2011). While this is not the licensed indication of the GLP-1 receptor agonists, it is a property that is attractive to both clinician and patient. Side effects are predominantly gastrointestinal but infrequently lead to cessation of therapy. Patient preference and prescriber experience play a large part in ensuring that therapies are tailored to the needs and expectations of each individual.
Recent licence extensions allow insulin detemir to be added to liraglutide (Electronic Medicines Compendium, 2012d) and exenatide twice daily to be added to basal insulin or to be continued when a basal insulin is added to existing therapy (Electronic Medicines Compendium, 2012e) in people with type 2 diabetes. These combinations are logical in terms of complementary modes of action and the potential for insulin sparing. However, care should be taken to avoid reducing insulin significantly in the presence of evolving beta-cell failure.
Several GLP-1 receptor agonists are in development including lixisenatide (daily administration), albiglutide, dulaglutide, LY2428757, semaglutide and CJC-1134-PC (all weekly administration). Taspoglutide is being reformulated following tolerability problems in phase III trials (UK Medicines Information).
As peptides, GLP-1 receptor agonists are destroyed by gastric acidity and currently need to be administered by subcutaneous injection. Novel mechanisms in development for administering GLP-1 receptor agonists include 3-monthly implants of exenatide using the Duros® implantable system, inhalation using Technosphere® delivery devices and transdermal patches (Qian et al, 2009).
Current and future DPP-4 inhibitors
Four DPP-4 inhibitors are currently available for use in clinical practice in the UK – sitagliptin, vildagliptin, saxagliptin and linagliptin.
Sitagliptin was the first in the class to become available for use in the UK following licensing approval in 2007 (Electronic Medicines Compendium, 2012a). Since then, vildagliptin, saxagliptin and, more recently, linagliptin have been added to the therapeutic armamentarium. Others in advanced development include alogliptin, dutogliptin and gemigliptin. Interestingly, berberine, a common herbal dietary supplement, inhibits DPP-4. This partly explains its glucose-lowering effect (Al-Masri et al, 2009).
As oral agents that inhibit degradation of endogenous GLP-1 by DPP-4, their glucose-lowering action is less pronounced than that of the GLP-1 receptor agonists, whose pharmacological dosing produces levels of GLP-1 receptor agonism several times greater than those seen with DPP-4 inhibitors (Holst et al, 2008). However, the side-effect profile is also less pronounced (probably as a result of lower levels of GLP-1 receptor agonism) and the class is, in general, well tolerated (Holst et al, 2008). In addition, DPP-4 inhibitors have the distinct advantage of being oral preparations.
Recent developments have seen extensions of licensed use in various levels of renal impairment. Whether there is a need to reduce drug dosage or perform additional monitoring with declining renal function depends on the route of elimination of the agent, and there are differences within the class in this regard (Table 1). There is some variation in the licence for co-administration with other glucose-lowering agents. In addition, some metformin combinations have become available for clinical use.
Selecting agents in practice
There is now an extensive range of glucose-lowering agents available for use in daily diabetes practice. Ideally decisions should be based on a balance between efficacy, utility and adverse effects.
Bailey (2011) has summarised the characteristics of the incretin agents in relation to existing glucose-lowering treatments (Table 2).
Reid (2012) has recently summarised some of the major trials comparing agents in the incretin class. The goals and designs of these are summarised in Table 3, and the principal findings are provided in Reid’s paper. The article appeared in the American journal Clinical Diabetes and the approval of exenatide once weekly in the USA (Amylin, 2012) came subsequent to its publication. In addition, vildagliptin has not been launched in the USA. Thus, the list of studies considered in the paper is not exhaustive. Readers should note, for instance, that exenatide once weekly has been compared with other incretin therapies (exenatide twice daily, liraglutide 1.8 mg and sitagliptin) in a series of head-to-head trials as part of the DURATION series (Drucker et al, 2008; Bergenstal et al, 2010; Buse et al, 2010b; Blevins et al, 2011; Buse et al, 2011; Taylor et al, 2011).
Current NICE guidance remains largely unchanged over the past 3 years. A guideline including exenatide twice daily, sitagliptin and vildagliptin was released shortly after the first version of this article was published (NICE, 2009). This includes an algorithm for blood glucose-lowering therapy in people with type 2 diabetes, which was reproduced in the previous CPD module. The guideline has been supplemented by technology appraisals for newer GLP-1 receptor agonists (NICE, 2010; 2012). This helpful structure enables clinicians to make prescribing decisions with patients based on the characteristics of the agents themselves as well as taking into account the challenges and aspirations of each individual. The guideline is currently undergoing revision.
Relevant documents for Scotland have been produced by the Scottish Intercollegiate Guidelines Network and the Scottish Medicines Consortium (some Welsh documentation also exists). The scope of these, and the NICE documents, in terms of therapies covered, is summarised in Table 4.
In austere times, however, the UK government has introduced QIPP (Quality, Innovation, Productivity and Prevention; Department of Health, 2011) savings within the NHS in England in a very short timeframe. Other nations have their own equivalents.
QIPP is a large-scale transformational programme for the NHS, involving staff, clinicians, patients and the voluntary sector. It is intended to improve the quality of care the NHS delivers while making up to £20 billion of efficiency savings by 2014–15. This has brought the cost of agents into sharp focus. In diabetes, the focus has included shifting away from analogue to human insulin usage in type 2 diabetes (National Prescribing Centre, 2012). In addition, the author has noticed that some primary care trusts have been insisting that high percentages of patients taking combinations of oral hypoglycaemic agents should be on sulphonylureas and metformin. The intention is to restrict access to more expensive newer drugs. Against this has to be balanced the recent European driving directive that disqualifies drivers for a year if they experience two or more hypoglycaemic episodes requiring third-party intervention (Drivers Medical Group, 2011). The tensions between political, economic and statutory requirements make individual prescribing decisions even more complex and threaten to undermine the trusting relationship between clinicians and the people they care for.
Future glucose-lowering agents
Sodium–glucose co-transporter 2 (SGLT2) inhibitors are under active development by several pharmaceutical companies. These agents block the action of SGLT2 in reabsorbing glucose and sodium from the renal tubules resulting in significant urinary glucose excretion, reduction in blood glucose and weight loss. Significant glucose lowering was observed in phase III trials (Ferrannini et al, 2010). The main side effects are an increase in genital infections (such as candidiasis and occasional urinary tract infection). Dapagliflozin is the first in the SGLT2 class to apply for licensing (Tahrani and Barnett, 2010). Others to follow include canagliflozin, empagliflozin, ipragliflozin and tofogliflozin.
A number of glucokinase activators are undergoing pre-licensing trials. These agents act by promoting intracellular phosphorylation of glucose, which, in turn, mediates cell membrane depolarisation, calcium influx and release of insulin from insulin granules (Matschinsky et al, 2011). Increased understanding of glucagon’s role in enhancing hepatic glucose output in type 2 diabetes has highlighted the glucose-lowering potential of glucagon receptor antagonists (Bagger et al, 2011). Several are in advanced stages of development.
Over-expression of sirtuin deacetylase receptors by resveratrol, found in the skin of red grapes, results in normalisation of blood glucose and weight loss in rodents (Imai and Guarente, 2010). Concentrated forms of resveratrol are being trialled in humans.
The link between bowel flora, microbiota, and glucose handling has been explored for its therapeutic possibilities (Kootte et al, 2012). Alterations in the constitution of bowel bacteria have been observed in patients with both type 1 and type 2 diabetes. Intraluminal secretion of lipopolysaccharides leads to activation of GPRs, enhanced GLP-1 release and reductions in blood glucose (Ahrén, 2009). GPR 119 and GPR 40 agonists are being actively studied.
As experience grows with newer agents, their use is likely to increase. Existing agents have their limitations but have the advantage of long-term use. As with any drug, new or old, constant surveillance is needed if rare long-term complications associated with their use are to be detected. Nevertheless, the continuing interest of researchers and pharmaceutical companies in elucidating the mechanisms underlying diabetes and developing better treatments is essential if the lives of those with diabetes are to be constantly improved.