Fixed-dose single tablet antidiabetic combinations

Fixed-dose single tablet antidiabetic combinations School of Life and Health Sciences, Aston University, Birmingham, UK Combinations of two or more oral agents with different mechanisms of action are often used for the management ofhyperglycaemia in type 2 diabetes. While these combinations have customarily been taken as separate tablets, severalfixed-dose single tablet combinations are now available. These are based on bioequivalence with the separate tablets,giving similar efficacy to the separate tablets and necessitating the same cautions and contraindications that apply toeach active component. Fixed-dose combinations can offer convenience, reduce the pill burden and simplifyadministration regimens for the patient. They increase patient adherence compared with equivalent combinations ofseparate tablets, and this is associated with some improvements in glycaemic control. Presently available antidiabeticfixed-dose combinations include metformin combined with a sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor or meglitinide as well as thiazolidinedione–sulphonylurea combinations, each at a range of dosagestrengths to facilitate titration. Anticipated future expansion of multiple drug regimens for diabetes management islikely to increase the use of fixed-dose single tablet combinations.
Keywords: antidiabetic agents, bioequivalence, compliance, fixed-dose combinations, hypoglycaemic agentsReceived 19 August 2008; accepted 15 September 2008 to demonstrate that better glycaemic control, especially dur- ing early stages of the disease process, helps to reduce long- The management of hyperglycaemia in type 2 diabetes often term morbidity and mortality [8–10]. Most treatment algo- requires a combination of two or more glucose-lowering rithms for type 2 diabetes acknowledge this as a basis for therapies [1,2]. These can be used to improve glycaemic their choice of target [2,5–7]. They also emphasize lifestyle control by addressing different pathophysiological aspects (diet and exercise) advice as initial and ongoing therapy of the disease, such as insulin resistance, b-cell dysfunc- and generally suggest metformin as a first-line pharmaco- tion, a-cell dysfunction and defects of nutrient metabolism logical agent, provided there are no contraindications or affecting liver, muscle and adipose tissue [3,4]. With in- tolerability issues [2,5–7]. If appropriate, another type of creased attention focussed towards glycaemic targets and antidiabetic agent such as an insulin secretagogue, thiazo- the prevention of complications [2,5–7], there has been lidinedione or an a-glucosidase inhibitor could be used.
heightened interest in combination therapy, particularly However, one antidiabetic agent alone is rarely sufficient ‘fixed-dose’ single tablet combinations of antidiabetic to maintain acceptable glycaemic control. For example, in agents. This review takes stock of the current use and future the United Kingdom Prospective Diabetes Study, less than opportunities for antidiabetic single tablet combinations.
one-quarter of patients treated with a single oral antidia-betic agent maintained a glycosylated haemoglobin A1c(HbA1c) level below 7% after 9 years [1]. When one agent does not achieve or sustain the desired glycaemic target, it Although the most desirable target for good glycaemic is customary to add a second agent. If patients exhibit control remains in contention, there is much evidence severe hyperglycaemia, this usually indicates the need for Correspondence:Prof. Clifford J. Bailey, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
E-mail:[email protected] Diabetes, Obesity and Metabolism, 11, 2009, 527–533 insulin therapy which can be introduced while continu- peutic breadth to combat the progressive nature of type ing one or more oral agents (figure 1).
2 diabetes. Where lower doses of two agents can be used Prescription databases in the UK such as DINLink and instead of a high dose of one agent, this can reduce the MAT indicate that in 2007 about one-third of all patients side effects that often occur with a high dose of the one with diagnosed type 2 diabetes are treated with two or agent [12,13]. However, combination therapy requires more oral antidiabetic agents. A recent survey of 154 gen- that the contraindications, precautions and monitoring eral practices in the UK (covering 1.2 million people, associated with each agent must be respected. Risk of 3.1% diagnosed type 2 diabetes) noted that 36.8% of type hypoglycaemia, possible drug interactions and special 2 patients were being treated with two or more oral anti- care during dose titration must also be appreciated.
diabetic agents [11]. The oral combination therapy In practice, metformin can be combined with any other ‘bought’ a median 7.7 years of time after monotherapy therapy (unless contraindications exist). Commonly, an until initiation of insulin therapy. Prescription data- agent that reduces insulin resistance (e.g. metformin or bases for the UK in 2007 indicate that among type 2 dia- a thiazolidinedione) is combined with an oral insulin betes patients who are receiving oral antidiabetic drugs, secretagogue, such as a sulphonylurea or meglitinide just over 50% are treated with monotherapy, just over [2,5]. Combination with one of the newly available sec- 40% are treated with a combination of two oral agents retagogues, namely a dipeptidylpeptidase-4 (DPP-4) and about 4–5% are prescribed three types of agents.
inhibitor or an injectable glucagon-like peptide-1 (GLP-1) agonist, is also a viable option [14]. Additionally,because metformin and thiazolidinediones counter insulin resistance by different cellular mechanisms, The potential benefits and extra cautions associated with these agents can be combined with additive anti- a combination of two or three antidiabetic agents have hyperglycaemic efficacy [15]. Where extra postprandial been rehearsed in detail previously [12,13]. As a rule of control is required, or interprandial glycaemic troughs thumb antidiabetic agents with different modes of are too low, an a-glucosidase inhibitor can be combined action can be used in combination to achieve additive or with any other antidiabetic therapy [12]. Because sul- possibly synergistic glucose-lowering effects. In princi- phonylureas act on the beta-cell by a different cellular ple, these differently acting agents should address mechanism to GLP-1, sulphonylureas have also been different pathological factors, thereby increasing thera- combined with a GLP-1 agonist or DPP-4 inhibitor [14].
The effect of adding a second antidiabetic agent has been assessed in many prospective randomized double-blinded Lifestyle + metformin
placebo-controlled or parallel group comparator studies:these are summarized and reviewed elsewhere [12–16].
When interpreting these studies, it is pertinent to bear inmind the variability of individual responses and disease Add insulin
Add insulin
status. Thus, the falls in HbA1c vary with recruited pop- secretagogue*
ulation, baseline HbA1c, obesity, drug doses and treat-ment duration as well as the actual agents involved,making it difficult to compare add-on efficacy betweenstudies [12,13,16]. Oral combinations are sometimes con- Add insulin
Add insulin
tinued with the introduction of insulin in type 2 diabetes sensitizer
[17]. These usually include an agent to reduce insulinresistance, but an insulin secretagogue can increaseendogenous insulin delivery into the portal vein to target Further intensify insulin or add insulin
the liver. This complements the higher peripheral insulin and continue one or two oral agents
levels achieved with subcutaneous injections.
Reassuringly, most treatment guidelines offer some Fig. 1 Simplified algorithm for the treatment of hyper- practical advice about individualizing combination ther- glycaemia in type 2 diabetes. Modified from the American apy, heeding exclusion criteria and minimizing risk of Diabetes Association - European Association for the Study hypoglycaemia if close to a low glycaemic target. Other pro- of Diabetes (ADA-EASD) consensus statement [2].
minent considerations include weight gain, co-existing *Insulin sectetagogue could be a sulphonylurea, meglitinide,DPP-4 inhibitor or GLP-1 agonist. An a-glucosidase inhihitor morbidity, vascular risk, patient lifestyle and potential can be added with any of the other antidiabetic therapies interactions with other medications [2,5–7].
j Diabetes, Obesity and Metabolism, 11, 2009, 527–533 also impose the same cautions associated with separate Although oral combination therapy has mostly beenundertaken with separate tablets for each agent, this increases the pill burden for a group of patients who arealready likely to be treated with several other medications Single tablet combinations of antidiabetic agents can [18]. Many type 2 patients take more than 10 medi- increase adherence compared with separate tablets. For cations daily and some take in excess of 20 [18–20]. Sev- example, a US prescription database was used to assess eral studies involving agents to treat hypertension and adherence (proportion of days for which tablets were col- dyslipidaemia have noted that patient adherence de- lected) during 1 year by 1618 diabetic patients switched clines as the number of prescribed medications increa- from monotherapy with metformin or rosiglitazone to ses [21,22]. Careful tracking of antihypertensive therapy a combination of these agents. Patients receiving using containers with electronic date–time recorded a fixed-dose combination (Avandamet) showed greater dispensing noted that compliance (percentage of days adherence (86%) than those receiving a combination of on which the prescribed numbers of doses were separate tablets (61%) [30]. In a study of 6525 newly removed) decreased from 83 to 57% when comparing diagnosed patients treated with either glibenclamide once-daily vs. thrice-daily therapy [23].
(glyburide) or metformin monotherapy, adherence (pro- Adherence to oral antidiabetic therapies is similarly portion of days for which tablets were collected) over prone to decline with increases in dosage frequency and 6 months was similar for the two agents at 71% [31].
number of daily medications [24–26]. For example, in 91 However, when patients required combination therapy, type 2 patients, compliance (defined as percentage of those given separate tablets showed only 54% adherence, prescribed doses reportedly taken by patients) with oral whereas adherence was maintained (77%) among those antidiabetic therapy fell from 79% for a once-daily dose given a fixed-dose combination. Moreover, improved to 38% for three times daily [27]. In the Diabetes Audit adherence translates into improved glycaemic control: Research in Tayside (DARTS, Scotland) study of 2849 thus, when 72 patients receiving metformin and gly- type 2 diabetic patients, adherence (measured as refill- buride as separate tablets were switched to a fixed-dose ing 90% of prescribed medication for >1 year) to sul- single tablet regimen, HbA1c was reduced by 0.6% [32].
phonylurea or metformin as monotherapy was 31 and Improved adherence implies less drug wastage and 34%, respectively, corresponding to about 300 days of greater opportunity for added agents to achieve their treatment per year. When a combination of these two therapeutic potential. Indeed, increased adherence to drugs was prescribed, adherence was reduced to 13%, antidiabetic medication correlated with fewer hospital corresponding to 266 days of treatment per year [28]. A admissions and reduced overall healthcare costs among similar study in the USA tracked 6995 type 2 patients type 2 patients [33]. Also, a recent retrospective study of for 2 years and noted that compliance (defined as the adherence (proportion of days for which tablets were number of days for which tablets were collected) for sul- collected) to all therapies in 11 532 diabetic patients phonylurea or metformin as monotherapy was 60.5 and noted higher HbA1c, higher blood pressure and higher 63%, respectively, corresponding to 435 and 454 days LDL cholesterol levels in non-adherent patients (<80% of treatment over 720 days. However, compliance was of tablets collected), and this coincided with increased only 35.7% (corresponding to 257 days of treatment risk of hospitalization and increased mortality [34].
over 720 days) when the drugs were prescribed as Because many individual antidiabetic drug therapies a combination [29]. One might anticipate therefore that are administered with the same dosing schedules, there improvements in glycaemic control expected by treat- is a pharmacokinetic rationale for their combination ment intensification could be at least partially offset by within single tablets. It is sometimes argued that fixed- dose combinations reduce prescriber flexibility andconstrain the titration process, but there are several dif-ferent dosage strengths of most fixed-dose combinations(table 1), which facilitate and simplify dose titration.
Also, as with combinations of separate tablets, fixed- dose combinations can facilitate similar or greater gly- Fixed-dose single tablet combinations of antidiabetic caemic control with lower doses of two agents than with agents offer several potential advantages over separate a large dose of one agent. For example, a fixed-dose tablets, particularly associated with compliance. They metformin–glipizide combination (Metaglip) produced Diabetes, Obesity and Metabolism, 11, 2009, 527–533 Table 1 Fixed-dose single tablet antidiabetic combinations*,y available as a separate tablet at much lower cost. Thus,fixed-dose combinations are generally competitively priced compared with the same combinations as separate All forms of combination therapy require special vigi- lance to comply with the contraindications, precautions and monitoring that apply to both agents. Interactions between the different classes of antidiabetic agents are rare [16], but a potentially heightened risk of hypo- glycaemia must be appreciated, especially when aiming for near-normal levels of glycaemia. Appropriate selec- tion of the combination and the starting dose should take this into account, noting that agents that do not usually precipitate hypoglycaemia as monotherapy may nevertheless act together to lower glycaemia into thesubnormal range. Subtle adjustments to the dose or tim- ing of administration of one of the agents to avoid such yAvailability of tablets and component strengths differ betweencountries.
events cannot be made with fixed-dose combinations.
Marketing approval of fixed-dose antidiabetic combi- **Names vary between Europe and USA.
nations has been based on pharmacokinetic and pharma- yyFood and Drug Administration (FDA) approval June 2008.
codynamic equivalence to the two active components asseparate tablets. Although bioavailabilities of the active more than twice the reduction of HbA1c compared with components may have been adjusted slightly to facilitate similar or greater dosages of metformin or glipizide as administration within the same tablet, the range of dosage monotherapy [35]. Similarly, a fixed-dose combination strengths available has ensured that concerns about a lack of metformin–glibenclamide (Glucovance) achieved a of flexibility for dose titration are seldom a practical lim- greater reduction in HbA1c with half or less than half of itation. Thus, the dosage increments are generally the the amounts of metformin or glibenclamide as mono- same for a fixed-dose combination as separate tablet com- therapy [36]. The extra glucose-lowering effect seen binations. The titration steps are dictated by the compo- with the Glucovance fixed-dose combination may have nent that exerts the faster blood glucose-lowering effect, been achieved in part through a small adjustment in the noting that the slowly generated antihyperglycaemic formulation (discussed below), indicating a further action of thiazolidinediones warrants some extended opportunity to increase the efficacy gain from fixed- Certain intercurrent illnesses or investigations may As reported with combinations of separate tablets, require temporary withholding of one component of lower doses of two agents in a fixed-dose combination a fixed-dose combination, or the emergence of a contrain- can reduce the side effects associated with a high dose dication may necessitate permanent cessation of one of one agent. Thus, uptitrating metformin to improve gly- component. In each case, stopping the fixed-dose tablet caemic control may be limited by onset of diarrhoea, but inconveniently stops both components, but the continu- this was avoided while achieving a similar improvement ing component can still be given as a single tablet at the in glycaemic control by addition of rosiglitazone in same dosage or where appropriate, an alternative combi- nation can be substituted at a comparable strength.
From a pharmacoeconomic perspective [38], some drug cost reimbursement procedures may enable patients and/ or their healthcare providers to use fixed-dose combina- tions to receive two drugs for approximately the price ofone. Many fixed-dose combinations are priced little The main fixed-dose single tablet combinations of antidi- higher than the more expensive component of the combi- abetic drugs are listed in table 1. Not all combinations or nation: the cheaper component is usually generic and dosage strengths are available in all countries, and there j Diabetes, Obesity and Metabolism, 11, 2009, 527–533 are some variations in the names and approved formin and glibenclamide as separate tablets [36]. How- ever, to provide bioequivalence with the separate Combination therapy with a biguanide and a sulpho- tablets, the formulation of Glucovance contains suffi- nylurea as separate tablets has been used in Europe for cient very small particles of glibenclamide that there is over 40 years, and some early fixed-dose combinations rapid absorption of a small proportion of the glibencla- involving phenformin or metformin together with a sul- mide. When the combination tablet is taken with or phonylurea receive minority use in some countries.
immediately before a main meal, this increases the However, these combinations were mostly designed prandial insulin response, adding particularly to the around the sulphonylurea component, whereas the reduction in postprandial hyperglycaemia [36,48].
introduction of Glucovance (metformin–glibenclamide) Thus, minor adaptations in the formulation of fixed- as a fixed-dose combination in the USA in 2000 dose combinations can provide efficacy gains.
provided a more equitable balance of dosages [36,39].
Formulation adjustments can also be used to assist tol- Glucovance generated a new interest in antidiabetic erability: for example, use of a slow release fixed-dose fixed-dose combinations and accounted for about 6% formulation that combines metformin–pioglitazone can of oral antidiabetic prescriptions in the USA for 2006, delay absorption of the metformin component and reduce with much higher usage in some countries of central and South America (
Following in the wake of Glucovance, a metformin–glipizide combination (Metaglip, 2002) received much With regard to the treatment of diabetes and related cardiometabolic disorders, the UK and other European Fixed-dose combinations of metformin with the countries have embraced the concept of fixed-dose com- thiazolidinedione rosiglitazone (Avandamet, 2002) or binations with less enthusiasm than the USA. Neverthe- pioglitazone (Competact/Actoplusmet, 2005) have re- less, fixed-dose combinations of antihypertensive drugs ceived considerable use in North America. The single have been reported to improve compliance and increase tablet combinations show bioequivalence to the two efficacy with fewer side effects [50–52]. Multiple thera- drugs given as separate tablets, affording similar levels pies are often required to treat dyslipidaemia [53], of glycaemic control and fewer tolerability issues when and several fixed-dose combinations of lipid-lowering used instead of a high dose of one [40,41]. Fixed-dose agents are approved in various countries, for example combinations of a thiazolidinedione with a sulphony- Vytorin (ezetimibe–simvastatin), Advicor (lovastatin– lurea have recently been produced, again showing niaspan), Simcor (simvastatin–niaspan) and Tredap- similar properties to the separate tablet combina- tive (nicotinic acid plus laropiprant – to reduce the tions (Avaglim/Avandaryl and Tandemact/Duetact) nicotinic acid flush). In recent years, the prospect has emerged that fixed-dose combinations could be used The DPP-4 inhibitors sitagliptin and vildagliptin to treat across different indications. For example, increase glucose-stimulated insulin secretion, reduce Caduet (atorvastatin–amplodipine) provides a single glucagon secretion and improve glycaemic control tablet to address lipid-lowering and antihypertensive without weight gain [44]. Fixed-dose combinations of sitagliptin–metformin (Janumet) and vildagliptin–metformin (Eucreas) have been developed [45,46].
Janumet is available in the USA (2007) and due forlaunch soon in Europe, while Eucreas is available in Development of fixed-dose combinations containing an parts of Europe (2008) but not in the USA. Recently antidiabetic agent plus a statin has been investigated, (2008), Food and Drug Administration (FDA) approved and there is ongoing research into combinations of anti- a fixed-dose combination of metformin with repaglinide obesity agents. It is generally appreciated that the treat- ment of type 2 diabetes requires attention to myriadcardiovascular risk factors, and several long-term trialshave demonstrated the benefits of adopting this approach [54]. This has fostered the concept of a multiple combi- In some trials, the glucose-lowering effect of Glucovance nation pill (so-called polypill) for diabetes that might be (noted above) appeared to be slightly more than additive anticipated to include a statin, an antihypertensive, pos- (sometimes described as synergistic) compared with met- sibly an anticoagulant and one or more antidiabetic Diabetes, Obesity and Metabolism, 11, 2009, 527–533 agents in a single tablet. Other ingredients have also lar disease in diabetes mellitus. Ann Intern Med 2004; been considered in a similar manner to a multivitamin and mineral supplement, but the concept remains futur- 10 ADVANCE Collaborative Group. Intensive blood glu- istic [55]. Since some potential components such as cose control and vascular outcomes in patients withtype 2 diabetes. N Engl J Med 2008; 358: 2560–2572.
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Diabetes, Obesity and Metabolism, 11, 2009, 527–533


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