emerging therapies in type 2 diabetes

IntroductionType 2 diabetes is a progressive con-dition that results from defective insu-lin secretion from the b-cell and insulinresistance at peripheral tissues. Thisresults in the development of hyper-glycaemia, which, if left uncontrolled,leads to microvascular and macrovascu-lar complications. Current antidiabetictherapy attempts to re-establish gly-caemic control with the aim of relief ofsymptoms and prevention of vascularcomplications. The therapeutic algor-ithm for type 2 diabetes begins withmodifications of lifestyle, e.g. takingexercise and changes in diet. This iscommonly followed by pharmacologi-cal intervention with an oral antidia-betic agent (OAA). The relentless pro-gression of the disease usually necessi-tates the addition of a second agent asthe efficacy of monotherapy declines.

This article reviews the mechanisms,benefits and limitations of currentOAAs and discusses the clinical poten-tial for new therapies for managementof type 2 diabetes.

Antihyperglycaemic agentsHistorically, very few classes of antihy-perglycaemic agent have been available.Until recently, only the sulphonylureas(SUs) and the biguanides, both firstdeveloped in the 1950s, were the onlyagents in common clinical usage.

Sulphonylureas: long-actinginsulin secretagoguesSulphonylureas (SU) have been a main-stay of type 2 diabetes treatment formore than 40 years. They are insulinsecretagogues (Figure 1) that bind toan SU receptor on the b-cells, whichleads to depolarisation of the b-cellmembrane and stimulates chronic insu-lin secretion. First generation (e.g.chlorpropamide) and second gener-ation (e.g. glibenclamide and gliclazide)SUs have both proven efficacious intype 2 diabetes as measured by reduc-

Emerging therapies in type 2 diabetesAnthony Barnett

Professor of Medicine, Birmingham Heartlands Hospital, Birmingham, UK

tions in HbA1c and FPG levels. Use ofSUs has also been associated with areduction in the risk of microvascular,but not macrovascular, complications.1

Sulphonylureas do not, however, con-trol the entire glycaemic profile: bystimulating chronic insulin secretion,they lower FPG levels, but do not targetacute episodes of post-prandial hyper-glycaemia. High postprandial glucoselevels are associated with poor gly-caemic control2 and cardiovasculardisease,3–5 so the lack of efficacy of SUson this feature of type 2 diabetes couldbe a significant limitation.

The hyperinsulinaemia produced bySUs can result in hypoglycaemia,6

which raises particular concern in theelderly. The first generation SUs areassociated with a large range of poten-tial drug interactions,7,8 which hasimplications particularly for olderpatients, who often require severaldrugs to manage various conditions.Sulphonylureas are also associated withweight gain, which minimises theirsuitability in obese patients. There isalso the suggestion that the prolongedinsulin secretion elicited by these agentscould, in the long term, cause compro-mise of b-cell function although thishas never been substantiated.

Biguanides: insulin sensitisersIn contrast to SUs, the biguanide classof OAAs (e.g. metformin) do not targetthe b-cell, but suppress hepatic glucoseproduction and enhance tissue sensi-tivity to insulin to promote uptake ofglucose into muscle (Figure 1). Becauseit has a different mechanism of action,metformin is often used in combi-nation with SUs. Like drugs of the SUclass, metformin lowers FPG, but haslittle effect on postprandial hyper-glycaemia.

Metformin is the drug of choice inoverweight diabetic patients because itis not associated with weight gain.There is also a suggestion from the

Figure 1. Oral therapies for type 2 diabetesand their sites of action

UKPDS that metformin might alsohave cardioprotective properties, per-haps through its insulin sensitisingaction.9 There are, however, significantsafety and tolerability issues with thisagent in a significant number ofpatients. Gastrointestinal discomfort,diarrhoea and nausea are common sideeffects. Moreover, it is contraindicatedin those with a history of renal, hepaticor cardiac impairment because of thepotential dangers of lactic acidosis.10

The a-glucosidase inhibitors –move to after metforminThe a-glucosidase inhibitors becameavailable in the 1990s.11 They areingested with meals and delay thedigestion of complex carbohydrates,thereby blunting postprandial glucosespikes. This is achieved through thecompetitive inhibition of enzymes inthe intestine that break down oligosac-charides and disaccharides into mono-saccharides (Figure 1). By delaying theincrease in postprandial blood glucose,the pancreatic b-cells have adequatetime to secrete the appropriate amountof insulin. This mode of action doesmean, however, that a-glucosidaseinhibitors are less effective if a patienthas a diet low in carbohydrate or highin monosaccharides.a-glucosidase inhibitors have a good

safety profile, as they are not associatedwith hypoglycaemic events. Their usedoes produce frequent gastrointestinalside effects, however, such as flatulence,abdominal bloating and diarrhoea,

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Current perspectives and future treatment options in type 2 diabetes

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which are caused by undigested dietarycarbohydrate. These adverse events aredescribed as mild and transient but areassociated with a relatively poor rateof compliance. In a study of UKMediPlus data from 4539 patients withtype 2 diabetes, discontinuation ratesof 51% were reported in patientstaking acarbose within the first 12months of treatment (1998).

Emerging pharmaco-therapeutic optionsA number of new therapeutic optionsfor type 2 diabetes have, or will shortly,become available. These new therapiesare all distinct from SUs and thebiguanides in both structure and func-tion. Their development has arisenfrom increased understanding aboutthe pathophysiology of type 2 diabetes,which emphasises the contribution ofboth insulin resistance and b-cell dys-function to disease development. Anadditional fundamental characteristicthat manifests early in the disease pro-cess is the loss of early-phase insulinsecretion. This defect has importantconsequences for both postprandialhyperglycaemia and overall glycaemiccontrol. It has recently been shownthat postprandial hyperglycaemia (glu-cose spikes or peaks) is closely associ-ated with HbA1c levels,2 and that it isan independent predictor for riskof macrovascular complications.12,4,13

The new agents available for type 2diabetes treatment have been devel-oped, therefore, to address both insulininsensitivity and loss of early-phaseinsulin secretion.

Thiazolidinediones – insulinsensitisersThe thiazolidinediones (or glitazones)combine with an intranuclear receptor,peroxisome proliferator activated re-ceptor c (PPAR-c), and target theinsulin resistance defect of type 2 dia-betes, increasing the sensitivity ofperipheral tissues to insulin anddecreasing hepatic glucose production(Figure 1). This is achieved via a com-plex mode of action, which involvesup-regulation of transcription of genesthat are critical in fat cell proliferation,lipid metabolism and glucose trans-

Figure 2. An algorithm for the pharmacological management of type 2 diabetes. Adaptedfrom reference 10

port. Glitazones increase expression oftransmembrane glucose transporters(GLUT-1 and GLUT-4) and increasestorage of triglycerides. This results inreduced output of hepatic glucose andimproved insulin-mediated glucoseuptake.

They are efficacious in managingchronic hyperglycaemia as demon-strated by decreases in FPG and HbA1c

using troglitazone14 – the first glita-zone to become available commercially.This compound was withdrawn fromuse in the United Kingdom and theUnited States, however, followingseveral cases of death from liver failure.

Pioglitazone and rosiglitazone areboth available in the US and both havevery recently become available in theUK. In the UK and Europe they areonly licensed for use in combinationwith metformin or SUs. They arestructurally different from troglitazoneand are efficacious in reducing bothFPG and HbA1c levels.15,16 There isno evidence for hepatotoxicity eitherin the clinical trial programme orpost-marketing surveillance of over2 000 000 people already treated withthese agents in the US. Despite this,the licensing authorities have rec-ommended that patients on treatmentwith pioglitazone or rosiglitazone mustundergo regular liver function testing.

Use of glitazones may be associatedwith weight gain and fluid retention,16

and in a few patients note peripheraloedema. Because of fluid retentionthey are contra-indicated in those witha history of heart failure. They do not,however, increase risk of hypoglycae-mia and do not cause the gastrointesti-nal side effects so commonly seen with

metformin. By targeting a primarydefect of type 2 diabetes they mayhave the potential to alter diseaseprogression.

Short-acting insulinsecretagoguesEarly-phase insulin release is stimulatedby prandial glucose and is lost early inthe development of type 2 diabetes.Short-acting insulin secretagoguestarget postprandial glucose spikes andcan therefore improve overall glycaemiccontrol. As the stimulatory effect onthe b-cell is relatively short lived com-pared with that of the SUs, the risk ofhypoglycaemia is reduced.

It is postulated that restoring early-phase insulin release and avoiding pro-longed second-phase insulin secretionwill lead to reduced b-cell stress. Thepossibility exists, therefore, that short-acting insulin secretagogues may main-tain efficacy compared with conven-tional antidiabetic agents. Such studiesto determine the sustained long-termefficacy of this therapeutic class areunderway.

There are two distinct types – themeglitinides which are derived fromthe non-SU moiety of glibenclamideand a new class, the amino acidderivatives.

MeglitinidesRepaglinide is a meglitinide (Figure 1),which if taken shortly before meals isactive during the prandial phase.18 Itis absorbed and eliminated rapidlycompared with SUs, although insulinlevels do not return to baseline levelsfor up to 4–6 hours post-dose. This pro-longed hyperinsulinaemia may account

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for the fact that hypoglycaemia maystill be a problem with this agent.19

Amino acid derivativesThe amino acid derivatives, which,unlike repaglinide, bear no relation tothe SUs, improve early-phase insulinrelease.20,21 They interact with recep-tors coupled to KATP channels on thebeta-cell plasma membrane (Figure 1).The chain of events initiated by thisbinding results in a rapid and transientrelease of insulin.

Early-phase insulin secretion isimproved with these agents withoutinducing the prolonged hyperinsulina-emia seen with other agents insulin-secretion agents.22 Hanefeld et al. dem-onstrated that the amino acid derivativesproduced significant decreases in post-meal glucose spikes.20 In addition,when administered in the absence ofglucose (i.e. in a missed meal situation),they stimulate very little insulinsecretion. In the presence of glucose,however, the amino acid derivativesstimulate a comparatively large secre-tion of insulin. This synergistic effectmay also lower the risk of hypogly-caemic episodes,23 and these agentsmay be associated with less weight gaincompared with sulphonylureas.

Combination therapyMost type 2 diabetes patients willeventually require treatment with morethan one OAA. The progressive natureof the disease means that patients whoinitially respond well to monotherapywill require the addition of at least oneother OAA to their existing therapeuticregimen. At present, the most widelyused combination is that of metforminand an SU.24 These two therapieshave complementary modes of action,which explains the additive effect ofcombining these agents on glycaemiccontrol. Adverse events and contra-indications associated with these twotherapies may, however, limit theircombined use. In addition, the combi-nation of SUs with a-glucosidaseinhibitors improves glycaemic con-trol,24 but again there may be problemsbecause of side effects.

The arrival of new OAAs provides

new options for pharmacotherapeuticcombinations – including their combi-nation with conventional treatments.Improved glycaemic control has beendemonstrated for a combination ofSUs and thiazolidinediones25 andmetformin and thiazolidinediones.26

Further benefits may arise from thecombination of short-acting insulinsecretagogues with other classes ofagent with complimentary mechan-isms of action, for example, with met-formin or glitazones.

ConclusionsUse of the older oral antidiabetictherapies, SUs and metformin, pro-duces significant reductions in FPGand HbA1c levels in type 2 diabeticpatients. These therapies may, however,be associated with adverse effects aswell as eventual treatment failure as thedisease progresses. As our knowledge ofthe pathogenesis of type 2 diabetesimproves, the criteria for efficacioustreatment evolves; new therapies areexpected to directly target the under-lying defects associated with this dis-ease. There is an increasing demand fortreatments that will sustain control oftotal glycaemia and prevent the devel-opment of diabetic complications. Assuch, agents that effectively target theprimary defects in type 2 diabetes (insu-lin resistance and loss of early-phaseinsulin secretion), as both monotherapyand combination regimens, are likelyto assume a pivotal position in themanagement of type 2 diabetes. Theymay also have the potential to improveon areas of weakness identified withconventional antidiabetic treatments.

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emerging therapies in type 2 diabetes

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