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Incretin-based therapy: how do incretin mimetics and DPP-4 inhibitors fit into treatment algorithms for type 2 diabetic patients?
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 513–523
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Incretin-based therapy: how do incretin mimetics and DPP-4 inhibitors fit into treatment algorithms for type 2 diabetic patients? M. Nauck, Prof. Dr. med. a, *, U. Smith, MD, PhD b a b
Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany Department of Internal Medicine, University of Gothenburg, Sweden
Keywords: oral anti-diabetic drugs incretin-based antidiabetic medication GLP-1 receptor agonists incretin mimetics DPP-4 inhibitors incretin enhancers
Incretin-based antidiabetic medications have been approved for clinical use for approximately two to three years. While their major clinical characteristics have been known from clinical trials, the discussion now focuses on the best clinical use of GLP-1 receptor agonists (incretin mimetics) and inhibitors of the protease dipeptidyl peptidase-4 (DPP-4). Any novel drug will not fully disclose its spectrum of beneficial and adverse activity before long-term trials with clinical endpoints are available. This, typically, will last 5-8 years. Nevertheless, there are convincing reasons to use incretin mimetics and DPP-4 inhibitors even in the absence of such results. This decision should be based on specific patient characteristics and (expected) treatment results, in comparison to other available treatment options. The present manuscript tries to describe the current state-of-the-art of using incretin mimetics and DPP-4 inhibitors in clinical practice, including an attempt to suggest their place in treatment algorithms for type 2-diabetic patients. Ó 2009 Elsevier Ltd. All rights reserved.
Type 2 diabetes is a condition developing later in life in most cases and progressing from a pre-diabetic stage to manifest diabetes and further to advanced stages with increasing demands on anti-diabetic therapy.1–3 This progressive nature is the reason that treatment recommendations cannot be uniform for every patient with type 2 diabetes; the physician will have to take into account patient specifics, for example, disease duration and the presence or absence of obesity, and experiences with previous therapy, both concerning lifestyle modification and anti-diabetic drugs. Therefore, treatment algorithms making
* Corresponding author. Tel.: þ49 5524 81218; Fax: þ49 5524 81398. E-mail address: [email protected] (M. Nauck). 1521-690X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.03.002
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recommendations for type 2 diabetic patients usually suggest a cascade of therapeutic measures, starting with initial therapy (when the diagnosis is made and educational measures are initiated), monotherapy with single anti-diabetic agents, later changing to combination therapy, if a single medication does not lead to satisfactory results, and even later introducing injectable agents like insulin.4 The overall principle is to suggest the form of therapy that promises the most benefit in terms of reducing the risk of diabetic complications and premature death, while requesting the least necessary effort to achieve these goals. The number of available medications suitable for the treatment of type 2 diabetic patients at different stages of their condition will determine the number of treatment options one will have to consider. With the advent of novel medications that have properties very different from ‘conventional’ anti-diabetic drugs, the number of choices has greatly increased (Fig.1). With this background, it is reasonable to attempt to modify treatment algorithms for the treatment of type 2 diabetes to include recommendations regarding incretinbased anti-diabetic agents, for example, inhibitors of dipeptidyl peptidase-4 (DPP-4) and glucagon-like peptide-1-receptor agonists (incretin mimetics). The present approach will concentrate on type 2 diabetic patients with representative characteristics, for example, obesity, aged 40–70 years with no peculiar associated disease that will impose further restrictions on drug prescriptions. Some subgroups with special circumstances (elderly type 2 diabetic patients, patients with significant renal functional impairment) will be mentioned separately. Treatment goals The ultimate goal of treating type 2 diabetes is to prevent the development or worsening of diabetic complications and premature death. This requires a multifactorial approach as exemplified by the Steno 2 study5,6 targeting not only uncontrolled hyperglycaemia, but also hypertension, LDL cholesterol and triglycerides, and cardiovascular disease already present (ACE inhibitors, aspirin, etc.). The present recommendations concern the anti-hyperglycaemic therapy of type 2 diabetes. While ultimate treatment goals guide our decisions about when and how to treat patients with type 2 diabetes, the intermediate measure of successfully achieving glucose control is blood glucose and glycated haemoglobin (HbA1c). Unfortunately, the relationship between mean updated HbA1c and the risk for both microvascular and macrovascular diabetic complications is steadily rising from the normal range up to uncontrolled, decompensated diabetes.7 There is no certain threshold value below which a further reduction in glycaemic levels would not reduce the probability of diabetic complications. On the other hand, increasing efforts would be necessary to achieve normoglycaemia, the closer one gets to the normal glycaemic range. Furthermore, lowering glucose under such circumstances may prompt hypoglycaemic events or other untoward reactions. Thus, a recommendation of a realistic intermediate treatment goal has to take into account both the benefit it brings and the effort it takes, including the costs of treatment and treatment surveillance. Commonly suggested HbA1c goals are <7% (American Diabetes Association) or <6.5% (European Association for the Study of Diabetes, International Diabetes Federation, American College of Endocrinologists). Action should be taken whenever HbA1c goals are not met in a given patient.4 Often this means considering a change of treatment, that is, to advance in the treatment cascade. Treatment algorithms for type 2 diabetes based on ‘conventional’ anti-diabetic drugs There is uniform agreement that the diagnosis of diabetes mellitus should prompt educational measures to enable patients to live with their diabetes, take control of those determinants that predict diabetic complications and premature death, learn about the choices for a healthier lifestyle (healthy eating, body weight control – in most cases with the aim of reducing weight – and regular physical exercise aiming at a better physical fitness). Whereas earlier recommendations suggested observing the success of such measures (that can have an enormous impact on body weight and glycaemic control) for 3–6 months, and add an anti-diabetic drug only if lifestyle modifications alone fail to reach the glycaemic goals, recent recommendations advocate starting drug treatment at this stage.4 The main first-line medication recommended for the typical obese type 2 diabetic patients is metformin, and this is mainly based on experiences from the United Kingdom Prospective Diabetes Study (UKPDS) indicating that metformin treatment (in contrast to the consequences of initiating other anti-diabetic
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therapies) is not associated with weight gain, it does not provoke hypoglycaemic episodes, and has reduced the proportion of patients experiencing cardiovascular complications during a 15-year followup by approximately 35%, leading to a significant reduction in mortality in overweight patients.3 Since none of the other classes of anti-diabetic agents have shown comparable benefits to the patients, metformin should be used, if there is no contraindication and if the patient can tolerate it. In 5–15% of the patients, metformin treatment is not tolerated, mostly because of gastrointestinal side effects. The strong arguments in favour of metformin have made it difficult for other candidates to be accepted as first-line treatment for patients with type 2 diabetes. The recent A Diabetes Outcome Progression Tria (ADOPT) study described advantages of rosiglitazone in terms of time to failure and disease progression (the slope of rising fasting glucose and HbA1c concentrations), but on the other hand, this was only slightly better than with metformin and with an associated weight gain of almost 7 kg relative to metformin treatment.8 Recommendations for the stage of diabetes when metformin monotherapy no longer leads to adequate glycaemic control are less uniform. In fact, the guidelines issued by the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) as well as national organisations such as the Deutsche Diabetes-Gesellschaft (DDG) (German Association for the Study of Diabetes), as an example, listed all available drug classes in alphabetical order, with no specific recommendation in favour or against certain combinations.9 This leaves the decision to be taken depending on the individual situation. Specific patient characteristics and problems have to guide these decisions. Keeping this in mind, it is important to note that four out of five drug classes that were available by 2007 have the potential to promote weight gain (sulphonylurea compounds, meglitinides, thiazolidinediones and insulin), the only exception being a-glucosidase inhibitors (Fig. 1). This poses a significant problem: obese type 2 diabetic patients know that their diabetes is – at least in part – a consequence of their overweight. Most likely, they have tried to reduce their body weight and have failed. They receive recommendations to control their body weight and, at the same time, get prescriptions of anti-diabetic agents that will most likely make them gain weight. The same dilemma is true from the perspective of the prescribing physician, who needs to evaluate the consequences of uncontrolled diabetes against better glycaemic control with some additional weight gain. A second problem that is inherent in three out of five classes of anti-hyperglycaemic agents (sulphonylurea compounds, meglitinides and insulin) is the potential to bring out situations with inadequately high insulin concentrations leading to hypoglycaemic episodes (Fig. 1). While the overall proneness to hypoglycaemia is considerably lower in patients with type 2 diabetes2 compared to type 1-diabetic patients10, introducing drugs that raise the probability of hypoglycaemic episodes may limit
Fig. 1. Treatment algorithm for initiating anti-hyperglycaemic treatment in patients with type 2 diabetes. This algorithm is based on the ‘stepped approach’ to respond to disease progression. In contrast to recommendations issued by the ADA and EASD, the present algorithm lists all available drug classes including incretin-based medications. Abbreviations: CV: cardiovascular; SU: sulfonylurea; hypo: hypoglycaemia; TZD: thiazolidinediones; Gluc.: Glucosidase; DPP-4: Dipeptidyl peptidase-4; BW: body weight; Ev.: events; AE: adverse events.
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our ability to take patients to their glycaemic goals, because hypoglycaemia prompts dose reductions for the responsible agents, which will limit the overall effectiveness of such treatment policy. Reasons in favour of using incretin-based medications Both DPP-4 inhibitors and incretin mimetics have shown efficacy in terms of reducing fasting and postprandial glucose concentrations and glycated haemoglobin.11 Of particular relevance are the studies comparing glucose control on a background of oral anti-diabetic agents (preferably metformin) with other accepted anti-diabetic medications. Along these lines, sitagliptin has been shown to be noninferior with respect to lowering HbA1c and fasting glucose concentrations when compared to glipizide in patients no longer adequately controlled by metformin.12 Body weight increased with glipizide but not with sitagliptin. Only glipizide treatment was associated with hypoglycaemia (in approximately onethird of the patients). For vildagliptin, similar results have been obtained when compared to a thiazolidinedione, but without any difference in hypoglycaemia.13 Exenatide (injected twice daily) had similar efficacy in controlling HbA1c when compared to insulin glargine (injected once daily)14,15 or pre-mixed insulin aspart (twice daily)16; all these patients had been on metformin and sulphonylureas. With insulin, body weight increased, whereas with exenatide, weight loss was initiated. The difference in body weight – on average – was >5 kg between patients treated with insulin and exenatide for 1 year.16 No weight gain Reasons to recommend the use of incretin mimetics or DPP-4 inhibitors in combination with metformin include no apparent weight gain (DPP-4 inhibitors) and even the potential to lower body weight (incretin mimetics).11 In this respect, incretin mimetics and DPP-4 inhibitors are the only classes of insulinotropic drugs that do not promote weight gain. Low risk of hypoglycaemia The low risk of provoking hypoglycaemic episodes that has been observed in clinical studies is compatible with our understanding of the mode of action of glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion in a strictly glucose-dependent manner, and only above a permissive level of glycaemia.17 Therefore, even high concentrations of GLP-1 are unable to cause hypoglycaemia.18,19 However, this advantage is lost when incretin mimetics or DPP-4 inhibitors are combined with sulphonylurea compounds.20–23 The biological reason is that sulphonylureas are able to close the ATPdependent potassium channel at lower glucose concentrations, whereas GLP-1 alone is unable to achieve this.24,25 Practically speaking, in the absence of sulphonylureas lowering the level of glycaemia with incretin mimetics or DPP-4 inhibitors does not increase the risk for hypoglycaemia, whereas in combination with sulphonylureas (or, by inference, meglitinides), any lowering of blood glucose concentrations will increase the probability of hypoglycaemic episodes.11,26 Absence of threatening adverse events The main adverse events reported in studies with incretin mimetics have been ‘gastrointestinal’ in nature, and typically include mild-to-moderate nausea, and sometimes vomiting, diarrhoea, abdominal fullness or pain.11 The likelihood of such side effects are higher upon first exposure and usually their probability declines over time.27 Of all the patients receiving exenatide, 5–10% could not tolerate these symptoms and were withdrawn from the randomised controlled trials due to such adverse events.21,26,28,29 Nevertheless, such gastrointestinal side effects do not expose the patients to any substantial risk, and usually, the problems related to these adverse events can be dealt with by educating them and offering transient anti-emetic medication. Recent reports of cases with acute pancreatitis including severe cases with a lethal outcome have raised the questions of whether there may be a causal relationship to exenatide treatment. Until now, alternative risk factors (gall stones, alcohol abuse) have been identified in most cases, and the number of cases reported in relation to the number of patient years experience with exenatide treatment does
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not result in more than the expected number of bouts of acute pancreatitis. Due to the severity of this disease and because the numbers reported so far are neither sufficient to exclude nor to prove any causal relationship, more studies are needed to make a final judgement. At the time of writing, it appears too early to draw firm conclusions that would include recommendations against using exenatide. Regarding DPP-4 inhibitors, a specific side effect profile cannot be defined based on the reports from studies with sitagliptin and vildagliptin. A slightly higher rate of upper respiratory tract symptoms compatible with infections reported for sitagliptin30 is of uncertain clinical significance and has no longer been described in a more recent analysis including more studies and patients.31 Therefore, both incretin mimetics and DPP-4 inhibitors are not known to cause any potentially severe or even life-threatening diseases or events. As far as can be said from analyses of phase 3 studies and post-marketing surveillance over 1–2 years after receiving approval, both classes overall have to be considered safe. In addition, some animal experiments and preliminary clinical studies raise hopes related to specific cardiac and endocrine pancreatic (b-cell) effects, which may translate into some clinical benefit.32–34 Potential cardiovascular benefits Beneficial effects of GLP-1 have been shown in both animal and human studies of coronary ischaemia35,36 and in left-ventricular failure due to cardiomyopathy.37 In rats, myocardial necroses occurred when ligating coronary arteries were found to be smaller after GLP-1 was administered.35 In patients with acute myocardial infarction treated by angioplasty, both type 2 diabetics and nondiabetics, an intravenous infusion of GLP-1 led to less wall-motion abnormality and better overall left-ventricular function.36 Since GLP-1 receptors are present in cardiomyocytes and vascular endothelial cells, these effects point to a potential cardiovascular benefit of incretin-related anti-diabetic therapies, which remain to be demonstrated in future clinical studies. Effects on b-cell health In line with GLP-1 effects on b-cell proliferation and differentiation34, insulin content, apoptosis, functional status including recruitment of individual b-cells to the insulin secretory process, treatment with incretin mimetics32,33,38 and DPP-4 inhibitors39,40 has improved b-cell numbers and function in animal models of type 2 diabetes. Since a steady decline in b-cell numbers and function characterises the natural history of type 2 diabetes8,41,42, counteracting these processes using incretin-based therapy may provide a rationale for halting the progression of the disease. Studies focus on demonstrating ‘durability’ of treatment success and b-cell function. So far, many studies have used HOMA-b, proinsulin to insulin molar ratios, or ‘modelling’ (relating observed insulin secretory rates to absolute values or changes in glucose concentrations) to characterise insulin secretory function. Favourable results have been reported with both incretin mimetics28,43,44 and DPP-4 inhibitors45–55 while the patients were receiving their respective drug treatment. Recent studies looking for persisting effects after discontinuing exenatide44 or vildagliptin56 respectively after 1 year of treatment, have failed to demonstrate lasting effects after withdrawing the treatment for 12 weeks. Based on estimates of human islet b-cell turnover, a longer duration of treatment may be necessary before beneficial effects can be observed. However, it must be concluded that the potential b-cell protective effect of incretins in humans still needs to be clearly documented. Reasons for hesitating to recommend incretin-based anti-diabetic drugs Lack of long-term studies describing hard clinical end points Until now, no long-term clinical study has described effects of exenatide, sitagliptin or vildagliptin on micro- or macrovascular complications of type 2 diabetes, including any potential to prevent premature death. Therefore, the clinical benefits to patients today can only be described at the level of
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surrogate end points like HbA1c, other parameters characterising glycaemic control, body weight, number of hypoglycaemic episodes etc. Lack of databases to conclude long-term safety Along the same lines, the long-term safety of using any of the incretin-based anti-diabetic medications cannot be assessed today, given the absence of studies with a design, size, and duration allowing such conclusions, and the limited duration of exposure from clinical practice since the introduction into the market of the first-in-class incretin mimetics and DPP-4 inhibitors. Treatment costs Like any other novel medication, incretin mimetics and DPP-4 inhibitors are offered at higher prices than traditional anti-diabetic drugs, especially those that are available as generic drugs (like metformin and most sulphonylurea compounds). The exact pricing may be different in individual countries, but the general phenomenon is representative of the overall situation. In Germany, for example, metformin and glibenclamide are available at 25–30 cents per day, while 100 mg sitagliptin cost roughly 2 V per day, and the price for exenatide (10 mg twice daily) is approximately 4 V per day. A careful cost–benefit analysis needs to take into account not only pure drug costs, but overall treatment expenses that will include costs such as for blood glucose monitoring. Due to the low risk for hypoglycaemia, there is only a limited need for self-monitoring of glycaemia when incretin mimetics or DPP-4 inhibitors are used. Comparing injectable treatment with exenatide to insulin treatment, the costs can be similar or even lower for exenatide, if a patient needs large amounts of insulin in case of extreme insulin resistance. Recommendations of official bodies representing health-care systems Largely driven by the fear of exploding costs in health-care systems, ministers of health, other official bodies within health-care systems, health insurance companies, physicians’ associations and others have issued recommendations for a restricted use of novel medications including incretin-based anti-diabetic drugs. Often, long-term studies with clinical end points are stated to be a necessary prerequisite before a novel medication can be recommended for use and before reimbursement seems to be justified. This level of discussion sometimes ignores that for all newly approved drugs there is a period of several years before results from longer-term studies can be expected, even if they are started at the earliest possible time. In addition, as exemplified by thiazolidinediones, such studies do not always provide unequivocal evidence. Last, even the traditional anti-diabetic medications that are often recommended for use because of lower costs (e.g., sulphonylureas, meglitinides, a-glucosidase inhibitors and even various approaches for insulin treatment) have not – so far – provided this level of ‘evidence’, although they have been available for a long time (e.g., since the 1970s in the case of glibenclamide). Suggestions for a place in treatment algorithms for type 2 diabetes for DPP-4 inhibitors and incretin mimetics By indication Incretin mimetics Exenatide is an injectable drug. Therefore, any combination of oral anti-diabetic agents will be the preferred treatment as long as it provides safe and effective glycaemic control without the need to inject drugs. As a consequence, exenatide is approved for use in addition to oral anti-diabetic agents (metformin, sulphonylureas, thiazolidinediones (in some countries), or combinations hereof). This makes it an alternative to any of those oral anti-diabetic drugs that can be added to metformin (or any other first-line oral anti-diabetic drug) or insulin (combination of insulin and oral anti-diabetic drugs or insulin-only regimens). With future incretin mimetics (like liraglutide) the approved indication probably will be similar, but the situation is less clear.
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DPP-4 inhibitors Sitagliptin and vildagliptin are approved for use in addition to oral anti-diabetic agents (metformin, sulphonylureas, thiazolidinediones (in some countries), or combinations hereof). This makes DPP-4 inhibitors also an alternative to any of those oral anti-diabetic drugs that can be added to metformin (or any other first-line oral anti-diabetic drug) or insulin (combination of insulin and oral anti-diabetic drugs or insulin-only regimens). Just to decide based on approved indications does not give clear guidance and leaves open a number of possibilities that need to be weighed against each other. By comparative evaluation Incretin mimetics Exenatide has been compared to insulin regimens administered on a background of metformin and/ or sulphonylureas. Two studies involved insulin glargine administered once daily14,15, and one study involved pre-mixed insulin aspart (twice daily).16 Exenatide was used in a predetermined dosage for all patients (5 mg per dose for the initial month followed by 10 mg per dose, before breakfast and dinner), while insulin was titrated by established algorithms. Uniformly, the efficacy to control glycaemia was not different; insulin treatment prompted weight gain and exenatide treatment was associated with substantial weight loss. There was no difference in the incidence of hypoglycaemic episodes but this was probably due to the concomitant sulphonylurea medication. Liraglutide was tested against insulin glargine and was found to be slightly superior to insulin as far as HbA1c reductions versus baseline were concerned.57 Otherwise the findings were similar to those described with exenatide treatment, although the effect on fasting plasma glucose was stronger. Based on these results of comparing incretin mimetic treatment with insulin, similar glycaemic control can be achieved, with the additional benefit of weight loss. Most likely, hypoglycaemia would be different if no sulfonylurea co-medication was administered, which, however, has not been tried in such comparator trials. Such treatment may be of particular value in patients with weight-associated health problems or in patients with a particular awareness for obesity-related issues. DPP-4 inhibitors In direct comparison, sitagliptin has been tested against glipizide, a sulfonylurea, both on a background of metformin treatment12, and vildagliptin has been tested against pioglitazone (concomitant medication: metformin)13 as well as metformin (both as monotherapy).58 Sitagliptin was non-inferior (in fact, no difference at all) to glipizide concerning HbA1c reduction, and the patients treated with sitagliptin did not increase their body weight during 52 weeks of treatment, while glipizide-treated patients gained 1–2 kg. More patients (approximately 33% vs. 5%) experienced hypoglycaemic episodes with glipizide.12 Vildagliptin was non-inferior with respect to glycaemic control in comparison to pioglitazone treatment over 24 weeks.13 Again, there was a weight difference favouring vildagliptin. Hypoglycaemia was no problem with both treatments. The fact that vildagliptin did not lower quite as much as did metformin in a 52-week monotherapy trial58 may be interpreted as supporting evidence to use DPP-4 inhibitors as a second-line rather than as a first-line treatment, with metformin being recommended as the first anti-diabetic drug. Taken together, DPP-4 inhibitors are as effective as any other oral anti-diabetic drug that they have been compared to on a metformin background, with the additional benefit of not promoting hypoglycaemia and weight gain. Costs It needs to be acknowledged that incretin mimetics (exenatide: approximately 4 V per day) and DPP-4 inhibitors (sitagliptin and vildagliptin: approximately 2 V per day) are more expensive than sulfonylureas (approximately 0.30 V per day). DPP-4 inhibitors and glitazones have similar prices (all costs based on current prices in Germany, September 2008). These numbers provide only direct expenses for these drugs, and do not take into account any ‘return on investment’ like avoiding
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hospitalisation (e.g., for severe hypoglycaemia) or other benefits like less need to perform glucose selfmonitoring, etc. A detailed calculation of cost-effectiveness is not currently available. It is obvious that recommendations in favour or against these novel anti-diabetic agents critically depend on the economic conditions of the particular environment and can vary widely between countries and individuals, for example, related to their health insurance status. Special considerations for patient groups with peculiarities Renal functional impairment There are many restrictions on using traditional oral anti-diabetic agents in patients with renal functional impairment. Accordingly, metformin is contraindicated at more advanced stages59, sulphonylureas can cause severe problems regarding prolonged hypoglycaemic episodes60, fluid retention with thiazolidinediones61 can be a problem etc. Sitagliptin and exenatide can be used with a dose reduction in mild and moderate degrees of renal functional impairment. This recommendation is based on some published experiences and pharmacokinetic reasoning.62 It should be noted, that the incretin hormones gastric inhibitory polypeptide (GIP) and GLP-1 are eliminated renally63,64 and that concentrations can be expected to vary with the degree of reduction in glomerular filtration. Nevertheless, incretin mimetics may be especially suited for the treatment of type 2 diabetic patients with mild-to-moderate renal functional impairment. However, since metformin is often contraindicated in such patients, more studies are needed to develop strategies for their use (e.g., in combination with which other agent(s)) in this particular patient group. Elderly patients Patients with type 2 diabetes in older age groups are common, and provide particular challenges, in that there often are cognitive impairments and other associated conditions. Unnoticed renal functional impairment is one (vide supra). It probably is of special importance in this patient segment to avoid hypoglycaemia (danger of injury) and to provide simple therapeutic regimens (e.g., avoiding the need for glucose self-monitoring; low frequency of administration, hopefully independent from meal schedules). Therefore, there might be advantages of using DPP-4 inhibitors65–67 or incretin mimetics in this patient group. Outlook Incretin-based therapy, that is, incretin mimetics and DPP-4 inhibitors, have interesting properties that make them different from traditional anti-diabetic drugs. They will most likely be used as a treatment added to metformin therapy when monotherapy alone does not provide adequate control. Whether or not there is an advantage for choosing incretin-based therapy (e.g., taking into account costs) must be determined in the individual situation, based on patient characteristics and individual needs. This judgement may change, if studies reporting a robust effect on b-cell health or clinical outcomes (prevention of diabetic complications) become available, in which case a more prominent recommendation within the treatment algorithm needs to be discussed.
Practice points Definition of patient groups who most likely profit from incretin-based antidiabetic therapy versus other available antidiabetic treatment options Post-marketing surveillance for rare adverse events not disclosed by clinical trials Collection of individual patients’ experiences with unexpected responses to treatment with incretin-based antidiabetic medications (non-responders?)
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Research agenda Effects of incretin mimetics and DPP-4 inhibitors in specific subgroups of type 2-diabetic patients Direct comparison of incretin-based antidiabetic medications and comparator drugs Earlier use of combination antidiabetic therapy (including incretin-based antidiabetic drugs) and its effect on long-term glycaemic exposure and diabetic complications Long-term treatment with incretin mimetics and DPP-4 inhibitors and b-cell function and mass Long-term treatment with incretin mimetics and DPP-4 inhibitors and cardiovascular complications
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22. Hermansen K, Kipnes M, Luo E et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes, Obesity & Metabolism 2007; 9: 733–745. 23. Garber AJ, Foley JE, Banerji MA et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes, Obesity & Metabolism 2008; 10: 1047–1056. 24. Gromada J, Dissing S, Bokvist K et al. Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting ßTC3-cells by enhancement of intracellular calcium mobilization. Diabetes 1995; 44: 767–774. 25. Gromada J, Dissing S, Kofod H et al. Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium channels and cytosolic calcium levels in ß TC3 cells and rat panceatic beta cells. Diabetologia 1995; 38: 1025–1032. 26. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083–1091. 27. Fineman MS, Shen LZ, Taylor K et al. Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes. Diabetes/Metabolism Research and Reviews 2004; 20: 411–417. *28. DeFronzo RA, Ratner RE, Han J et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092–1100. 29. Zinman B, Hoogwerf BJ, Duran Garcia S et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Annals of Internal Medicine 2007; 146: 477–485. 30. Stein PP, Williams-Herman D, Khatami H et al. Sitagliptin, a selective DPP-4 inhibitor, is well tolerated in patients with Type 2 diabetes: pooled analysis of 5141 patients in clinical trials for up to 2 years (abstract). Diabetes 2007; 56(Suppl.1): A142–A143. *31. Williams-Herman D, Round E, Swern AS et al. Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis. BMC Endocrine Disorders 2008; 8: 14. 32. Xu G, Stoffers DA, Habener JF et al. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48: 2270–2276. 33. Tourrel C, Bailbe D, Meile MJ et al. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocintreated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 2001; 50(7): 1562–1570. 34. Brubaker PL & Drucker DJ. Minireview: glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004; 145: 2653–2659. 35. Bose AK, Mocanu MM, Carr RD et al. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 2005; 54: 146–151. 36. Nikolaidis LA, Mankad S, Sokos GG et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004; 109: 962–965. 37. Nikolaidis LA, Elahi D, Hentosz T et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 2004; 110: 955–961. 38. Prazak R, Ru¨tti S, Ellingsgaard H et al. Liraglutide induces cell proliferation and protects from interleukin 1-beta induced beta-cell apoptosis in human islets [abstract]. Diabetes 2008; 57(Suppl. 1): A440–A441. 39. Mu J, Woods J, Zhou YP et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic ß-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006; 55: 1695–1704. 40. Duttaroy A, Voelker F, Zhang X et al. The DPP-4 inhibitor vildagliptin increases pancreatic beta cell mass in rodents [abstract 481]. Diabetologia 2005; 48(Suppl. 1): A178. 41. U.K. Prospective Diabetes Study Group. U.K prospective diabetes study 16: Overview of 6 years therapy of type II diabetes: a progressive disease (Perspectives in diabetes). Diabetes 1995; 44: 1249–1258. 42. Butler AE, Janson J, Bonner-Weir S et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102–110. *43. Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 84–90. *44. Bunck MC, Diamant M, Corner A et al. One-year treatment with exenatide improves beta-cell function, compared to insulin glargine, in metformin treated type 2 diabetes patients: a randomized, controlled trial. Diabetes Care 2009. 45. Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29: 2638–2643. 46. Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006; 49: 2564–2571. 47. Nonaka K, Kakikawa T, Sato A et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Research and Clinical Practice 2008; 79: 291–298. 48. Raz I, Chen Y, Wu M et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Current Medical Research and Opinion 2008; 24: 537–550. 49. Scott R, Wu M, Sanchez M et al. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. International Journal of Clinical Practice. Supplement 2007; 61: 171–180. 50. Åhren B, Pacini G, Foley JE et al. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care 2005; 28: 1936–1940. 51. Pratley RE, Jauffret-Kamel S, Galbreath E et al. Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes. Hormone and Metabolic Research 2006; 38: 423–428. 52. Azuma K, Radikova Z, Mancino J et al. Measurements of islet function and glucose metabolism with the dipeptidyl peptidase 4 inhibitor vildagliptin in patients with type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism 2008; 93: 459–464. 53. Garber AJ, Schweizer A, Baron MA et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes, Obesity & Metabolism 2007; 9: 166–174.
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54. Mari A, Scherbaum WA, Nilsson PM et al. Characterization of the influence of vildagliptin on model-assessed -cell function in patients with type 2 diabetes and mild hyperglycemia. The Journal of Clinical Endocrinology and Metabolism 2008; 93: 103–109. 55. Rosenstock J, Foley JE, Rendell M et al. Effects of the dipeptidyl peptidase-IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance. Diabetes Care 2008; 31: 30–35. *56. Scherbaum WA, Schweizer A, Mari A et al. Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. Diabetes, Obesity & Metabolism 2008; 10: 1114–1124. 57. Russell-Jones D, Vaag A, Schmitz O et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP-1 analog, compared with insulin glargine: all as add-on to metformin and a sulfonylurea in type 2 diabetes (abstract). Diabetes 2008; 57(Suppl. 1): A159. 58. Schweizer A, Couturier A, Foley JE et al. Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1 year in drug-naive patients with Type 2 diabetes. Diabetic Medicine 2007; 24: 955–961. 59. Lalau JD, Race JM & Brinquin L. Lactic acidosis in metformin therapy. Relationship between plasma metformin concentration and renal function. Diabetes Care 1998; 21: 1366–1367. 60. Krepinsky J, Ingram AJ & Clase CM. Prolonged sulfonylurea-induced hypoglycemia in diabetic patients with end-stage renal disease. American Journal of Kidney Diseases 2000; 35: 500–505. 61. Kiryluk K & Isom R. Thiazolidinediones and fluid retention. Kidney International 2007; 72: 762–768. 62. Bergman AJ, Cote J, Yi B et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007; 30: 1862–1864. 63. Ørskov C, Andreasen J & Holst JJ. All products of proglucagon are elevated in plasma of uremic patients. The Journal of Clinical Endocrinology and Metabolism 1992; 74: 379–384. 64. Meier JJ, Nauck MA, Kranz D et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 2004; 53: 654–662. 65. Williams-Herman D, Swern AS, Davies MJ et al. In patients with type 2 diabetes, sitagliptin effectively lowers A1c regardless of patient age, gender, or body mass index (abstract). Diabetes 2008; 57(Suppl. 1): A148. 66. He YL, Sabo R, Campestrini J et al. The effect of age, gender, and body mass index on the pharmacokinetics and pharmacodynamics of vildagliptin in healthy volunteers. British Journal of Clinical Pharmacology 2007. 67. Pratley RE, Rosenstock J, Pi-Sunyer FX et al. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care 2007; 30: 3017–3022.
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10
Incretin-based therapy: how do incretin mimetics and DPP-4 inhibitors fit into treatment algorithms for type 2 diabetic patients? M. Nauck, Prof. Dr. med. a, *, U. Smith, MD, PhD b a b
Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany Department of Internal Medicine, University of Gothenburg, Sweden
Keywords: oral anti-diabetic drugs incretin-based antidiabetic medication GLP-1 receptor agonists incretin mimetics DPP-4 inhibitors incretin enhancers
Incretin-based antidiabetic medications have been approved for clinical use for approximately two to three years. While their major clinical characteristics have been known from clinical trials, the discussion now focuses on the best clinical use of GLP-1 receptor agonists (incretin mimetics) and inhibitors of the protease dipeptidyl peptidase-4 (DPP-4). Any novel drug will not fully disclose its spectrum of beneficial and adverse activity before long-term trials with clinical endpoints are available. This, typically, will last 5-8 years. Nevertheless, there are convincing reasons to use incretin mimetics and DPP-4 inhibitors even in the absence of such results. This decision should be based on specific patient characteristics and (expected) treatment results, in comparison to other available treatment options. The present manuscript tries to describe the current state-of-the-art of using incretin mimetics and DPP-4 inhibitors in clinical practice, including an attempt to suggest their place in treatment algorithms for type 2-diabetic patients. Ó 2009 Elsevier Ltd. All rights reserved.
Type 2 diabetes is a condition developing later in life in most cases and progressing from a pre-diabetic stage to manifest diabetes and further to advanced stages with increasing demands on anti-diabetic therapy.1–3 This progressive nature is the reason that treatment recommendations cannot be uniform for every patient with type 2 diabetes; the physician will have to take into account patient specifics, for example, disease duration and the presence or absence of obesity, and experiences with previous therapy, both concerning lifestyle modification and anti-diabetic drugs. Therefore, treatment algorithms making
* Corresponding author. Tel.: þ49 5524 81218; Fax: þ49 5524 81398. E-mail address: [email protected] (M. Nauck). 1521-690X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.03.002
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recommendations for type 2 diabetic patients usually suggest a cascade of therapeutic measures, starting with initial therapy (when the diagnosis is made and educational measures are initiated), monotherapy with single anti-diabetic agents, later changing to combination therapy, if a single medication does not lead to satisfactory results, and even later introducing injectable agents like insulin.4 The overall principle is to suggest the form of therapy that promises the most benefit in terms of reducing the risk of diabetic complications and premature death, while requesting the least necessary effort to achieve these goals. The number of available medications suitable for the treatment of type 2 diabetic patients at different stages of their condition will determine the number of treatment options one will have to consider. With the advent of novel medications that have properties very different from ‘conventional’ anti-diabetic drugs, the number of choices has greatly increased (Fig.1). With this background, it is reasonable to attempt to modify treatment algorithms for the treatment of type 2 diabetes to include recommendations regarding incretinbased anti-diabetic agents, for example, inhibitors of dipeptidyl peptidase-4 (DPP-4) and glucagon-like peptide-1-receptor agonists (incretin mimetics). The present approach will concentrate on type 2 diabetic patients with representative characteristics, for example, obesity, aged 40–70 years with no peculiar associated disease that will impose further restrictions on drug prescriptions. Some subgroups with special circumstances (elderly type 2 diabetic patients, patients with significant renal functional impairment) will be mentioned separately. Treatment goals The ultimate goal of treating type 2 diabetes is to prevent the development or worsening of diabetic complications and premature death. This requires a multifactorial approach as exemplified by the Steno 2 study5,6 targeting not only uncontrolled hyperglycaemia, but also hypertension, LDL cholesterol and triglycerides, and cardiovascular disease already present (ACE inhibitors, aspirin, etc.). The present recommendations concern the anti-hyperglycaemic therapy of type 2 diabetes. While ultimate treatment goals guide our decisions about when and how to treat patients with type 2 diabetes, the intermediate measure of successfully achieving glucose control is blood glucose and glycated haemoglobin (HbA1c). Unfortunately, the relationship between mean updated HbA1c and the risk for both microvascular and macrovascular diabetic complications is steadily rising from the normal range up to uncontrolled, decompensated diabetes.7 There is no certain threshold value below which a further reduction in glycaemic levels would not reduce the probability of diabetic complications. On the other hand, increasing efforts would be necessary to achieve normoglycaemia, the closer one gets to the normal glycaemic range. Furthermore, lowering glucose under such circumstances may prompt hypoglycaemic events or other untoward reactions. Thus, a recommendation of a realistic intermediate treatment goal has to take into account both the benefit it brings and the effort it takes, including the costs of treatment and treatment surveillance. Commonly suggested HbA1c goals are <7% (American Diabetes Association) or <6.5% (European Association for the Study of Diabetes, International Diabetes Federation, American College of Endocrinologists). Action should be taken whenever HbA1c goals are not met in a given patient.4 Often this means considering a change of treatment, that is, to advance in the treatment cascade. Treatment algorithms for type 2 diabetes based on ‘conventional’ anti-diabetic drugs There is uniform agreement that the diagnosis of diabetes mellitus should prompt educational measures to enable patients to live with their diabetes, take control of those determinants that predict diabetic complications and premature death, learn about the choices for a healthier lifestyle (healthy eating, body weight control – in most cases with the aim of reducing weight – and regular physical exercise aiming at a better physical fitness). Whereas earlier recommendations suggested observing the success of such measures (that can have an enormous impact on body weight and glycaemic control) for 3–6 months, and add an anti-diabetic drug only if lifestyle modifications alone fail to reach the glycaemic goals, recent recommendations advocate starting drug treatment at this stage.4 The main first-line medication recommended for the typical obese type 2 diabetic patients is metformin, and this is mainly based on experiences from the United Kingdom Prospective Diabetes Study (UKPDS) indicating that metformin treatment (in contrast to the consequences of initiating other anti-diabetic
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therapies) is not associated with weight gain, it does not provoke hypoglycaemic episodes, and has reduced the proportion of patients experiencing cardiovascular complications during a 15-year followup by approximately 35%, leading to a significant reduction in mortality in overweight patients.3 Since none of the other classes of anti-diabetic agents have shown comparable benefits to the patients, metformin should be used, if there is no contraindication and if the patient can tolerate it. In 5–15% of the patients, metformin treatment is not tolerated, mostly because of gastrointestinal side effects. The strong arguments in favour of metformin have made it difficult for other candidates to be accepted as first-line treatment for patients with type 2 diabetes. The recent A Diabetes Outcome Progression Tria (ADOPT) study described advantages of rosiglitazone in terms of time to failure and disease progression (the slope of rising fasting glucose and HbA1c concentrations), but on the other hand, this was only slightly better than with metformin and with an associated weight gain of almost 7 kg relative to metformin treatment.8 Recommendations for the stage of diabetes when metformin monotherapy no longer leads to adequate glycaemic control are less uniform. In fact, the guidelines issued by the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) as well as national organisations such as the Deutsche Diabetes-Gesellschaft (DDG) (German Association for the Study of Diabetes), as an example, listed all available drug classes in alphabetical order, with no specific recommendation in favour or against certain combinations.9 This leaves the decision to be taken depending on the individual situation. Specific patient characteristics and problems have to guide these decisions. Keeping this in mind, it is important to note that four out of five drug classes that were available by 2007 have the potential to promote weight gain (sulphonylurea compounds, meglitinides, thiazolidinediones and insulin), the only exception being a-glucosidase inhibitors (Fig. 1). This poses a significant problem: obese type 2 diabetic patients know that their diabetes is – at least in part – a consequence of their overweight. Most likely, they have tried to reduce their body weight and have failed. They receive recommendations to control their body weight and, at the same time, get prescriptions of anti-diabetic agents that will most likely make them gain weight. The same dilemma is true from the perspective of the prescribing physician, who needs to evaluate the consequences of uncontrolled diabetes against better glycaemic control with some additional weight gain. A second problem that is inherent in three out of five classes of anti-hyperglycaemic agents (sulphonylurea compounds, meglitinides and insulin) is the potential to bring out situations with inadequately high insulin concentrations leading to hypoglycaemic episodes (Fig. 1). While the overall proneness to hypoglycaemia is considerably lower in patients with type 2 diabetes2 compared to type 1-diabetic patients10, introducing drugs that raise the probability of hypoglycaemic episodes may limit
Fig. 1. Treatment algorithm for initiating anti-hyperglycaemic treatment in patients with type 2 diabetes. This algorithm is based on the ‘stepped approach’ to respond to disease progression. In contrast to recommendations issued by the ADA and EASD, the present algorithm lists all available drug classes including incretin-based medications. Abbreviations: CV: cardiovascular; SU: sulfonylurea; hypo: hypoglycaemia; TZD: thiazolidinediones; Gluc.: Glucosidase; DPP-4: Dipeptidyl peptidase-4; BW: body weight; Ev.: events; AE: adverse events.
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our ability to take patients to their glycaemic goals, because hypoglycaemia prompts dose reductions for the responsible agents, which will limit the overall effectiveness of such treatment policy. Reasons in favour of using incretin-based medications Both DPP-4 inhibitors and incretin mimetics have shown efficacy in terms of reducing fasting and postprandial glucose concentrations and glycated haemoglobin.11 Of particular relevance are the studies comparing glucose control on a background of oral anti-diabetic agents (preferably metformin) with other accepted anti-diabetic medications. Along these lines, sitagliptin has been shown to be noninferior with respect to lowering HbA1c and fasting glucose concentrations when compared to glipizide in patients no longer adequately controlled by metformin.12 Body weight increased with glipizide but not with sitagliptin. Only glipizide treatment was associated with hypoglycaemia (in approximately onethird of the patients). For vildagliptin, similar results have been obtained when compared to a thiazolidinedione, but without any difference in hypoglycaemia.13 Exenatide (injected twice daily) had similar efficacy in controlling HbA1c when compared to insulin glargine (injected once daily)14,15 or pre-mixed insulin aspart (twice daily)16; all these patients had been on metformin and sulphonylureas. With insulin, body weight increased, whereas with exenatide, weight loss was initiated. The difference in body weight – on average – was >5 kg between patients treated with insulin and exenatide for 1 year.16 No weight gain Reasons to recommend the use of incretin mimetics or DPP-4 inhibitors in combination with metformin include no apparent weight gain (DPP-4 inhibitors) and even the potential to lower body weight (incretin mimetics).11 In this respect, incretin mimetics and DPP-4 inhibitors are the only classes of insulinotropic drugs that do not promote weight gain. Low risk of hypoglycaemia The low risk of provoking hypoglycaemic episodes that has been observed in clinical studies is compatible with our understanding of the mode of action of glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion in a strictly glucose-dependent manner, and only above a permissive level of glycaemia.17 Therefore, even high concentrations of GLP-1 are unable to cause hypoglycaemia.18,19 However, this advantage is lost when incretin mimetics or DPP-4 inhibitors are combined with sulphonylurea compounds.20–23 The biological reason is that sulphonylureas are able to close the ATPdependent potassium channel at lower glucose concentrations, whereas GLP-1 alone is unable to achieve this.24,25 Practically speaking, in the absence of sulphonylureas lowering the level of glycaemia with incretin mimetics or DPP-4 inhibitors does not increase the risk for hypoglycaemia, whereas in combination with sulphonylureas (or, by inference, meglitinides), any lowering of blood glucose concentrations will increase the probability of hypoglycaemic episodes.11,26 Absence of threatening adverse events The main adverse events reported in studies with incretin mimetics have been ‘gastrointestinal’ in nature, and typically include mild-to-moderate nausea, and sometimes vomiting, diarrhoea, abdominal fullness or pain.11 The likelihood of such side effects are higher upon first exposure and usually their probability declines over time.27 Of all the patients receiving exenatide, 5–10% could not tolerate these symptoms and were withdrawn from the randomised controlled trials due to such adverse events.21,26,28,29 Nevertheless, such gastrointestinal side effects do not expose the patients to any substantial risk, and usually, the problems related to these adverse events can be dealt with by educating them and offering transient anti-emetic medication. Recent reports of cases with acute pancreatitis including severe cases with a lethal outcome have raised the questions of whether there may be a causal relationship to exenatide treatment. Until now, alternative risk factors (gall stones, alcohol abuse) have been identified in most cases, and the number of cases reported in relation to the number of patient years experience with exenatide treatment does
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not result in more than the expected number of bouts of acute pancreatitis. Due to the severity of this disease and because the numbers reported so far are neither sufficient to exclude nor to prove any causal relationship, more studies are needed to make a final judgement. At the time of writing, it appears too early to draw firm conclusions that would include recommendations against using exenatide. Regarding DPP-4 inhibitors, a specific side effect profile cannot be defined based on the reports from studies with sitagliptin and vildagliptin. A slightly higher rate of upper respiratory tract symptoms compatible with infections reported for sitagliptin30 is of uncertain clinical significance and has no longer been described in a more recent analysis including more studies and patients.31 Therefore, both incretin mimetics and DPP-4 inhibitors are not known to cause any potentially severe or even life-threatening diseases or events. As far as can be said from analyses of phase 3 studies and post-marketing surveillance over 1–2 years after receiving approval, both classes overall have to be considered safe. In addition, some animal experiments and preliminary clinical studies raise hopes related to specific cardiac and endocrine pancreatic (b-cell) effects, which may translate into some clinical benefit.32–34 Potential cardiovascular benefits Beneficial effects of GLP-1 have been shown in both animal and human studies of coronary ischaemia35,36 and in left-ventricular failure due to cardiomyopathy.37 In rats, myocardial necroses occurred when ligating coronary arteries were found to be smaller after GLP-1 was administered.35 In patients with acute myocardial infarction treated by angioplasty, both type 2 diabetics and nondiabetics, an intravenous infusion of GLP-1 led to less wall-motion abnormality and better overall left-ventricular function.36 Since GLP-1 receptors are present in cardiomyocytes and vascular endothelial cells, these effects point to a potential cardiovascular benefit of incretin-related anti-diabetic therapies, which remain to be demonstrated in future clinical studies. Effects on b-cell health In line with GLP-1 effects on b-cell proliferation and differentiation34, insulin content, apoptosis, functional status including recruitment of individual b-cells to the insulin secretory process, treatment with incretin mimetics32,33,38 and DPP-4 inhibitors39,40 has improved b-cell numbers and function in animal models of type 2 diabetes. Since a steady decline in b-cell numbers and function characterises the natural history of type 2 diabetes8,41,42, counteracting these processes using incretin-based therapy may provide a rationale for halting the progression of the disease. Studies focus on demonstrating ‘durability’ of treatment success and b-cell function. So far, many studies have used HOMA-b, proinsulin to insulin molar ratios, or ‘modelling’ (relating observed insulin secretory rates to absolute values or changes in glucose concentrations) to characterise insulin secretory function. Favourable results have been reported with both incretin mimetics28,43,44 and DPP-4 inhibitors45–55 while the patients were receiving their respective drug treatment. Recent studies looking for persisting effects after discontinuing exenatide44 or vildagliptin56 respectively after 1 year of treatment, have failed to demonstrate lasting effects after withdrawing the treatment for 12 weeks. Based on estimates of human islet b-cell turnover, a longer duration of treatment may be necessary before beneficial effects can be observed. However, it must be concluded that the potential b-cell protective effect of incretins in humans still needs to be clearly documented. Reasons for hesitating to recommend incretin-based anti-diabetic drugs Lack of long-term studies describing hard clinical end points Until now, no long-term clinical study has described effects of exenatide, sitagliptin or vildagliptin on micro- or macrovascular complications of type 2 diabetes, including any potential to prevent premature death. Therefore, the clinical benefits to patients today can only be described at the level of
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surrogate end points like HbA1c, other parameters characterising glycaemic control, body weight, number of hypoglycaemic episodes etc. Lack of databases to conclude long-term safety Along the same lines, the long-term safety of using any of the incretin-based anti-diabetic medications cannot be assessed today, given the absence of studies with a design, size, and duration allowing such conclusions, and the limited duration of exposure from clinical practice since the introduction into the market of the first-in-class incretin mimetics and DPP-4 inhibitors. Treatment costs Like any other novel medication, incretin mimetics and DPP-4 inhibitors are offered at higher prices than traditional anti-diabetic drugs, especially those that are available as generic drugs (like metformin and most sulphonylurea compounds). The exact pricing may be different in individual countries, but the general phenomenon is representative of the overall situation. In Germany, for example, metformin and glibenclamide are available at 25–30 cents per day, while 100 mg sitagliptin cost roughly 2 V per day, and the price for exenatide (10 mg twice daily) is approximately 4 V per day. A careful cost–benefit analysis needs to take into account not only pure drug costs, but overall treatment expenses that will include costs such as for blood glucose monitoring. Due to the low risk for hypoglycaemia, there is only a limited need for self-monitoring of glycaemia when incretin mimetics or DPP-4 inhibitors are used. Comparing injectable treatment with exenatide to insulin treatment, the costs can be similar or even lower for exenatide, if a patient needs large amounts of insulin in case of extreme insulin resistance. Recommendations of official bodies representing health-care systems Largely driven by the fear of exploding costs in health-care systems, ministers of health, other official bodies within health-care systems, health insurance companies, physicians’ associations and others have issued recommendations for a restricted use of novel medications including incretin-based anti-diabetic drugs. Often, long-term studies with clinical end points are stated to be a necessary prerequisite before a novel medication can be recommended for use and before reimbursement seems to be justified. This level of discussion sometimes ignores that for all newly approved drugs there is a period of several years before results from longer-term studies can be expected, even if they are started at the earliest possible time. In addition, as exemplified by thiazolidinediones, such studies do not always provide unequivocal evidence. Last, even the traditional anti-diabetic medications that are often recommended for use because of lower costs (e.g., sulphonylureas, meglitinides, a-glucosidase inhibitors and even various approaches for insulin treatment) have not – so far – provided this level of ‘evidence’, although they have been available for a long time (e.g., since the 1970s in the case of glibenclamide). Suggestions for a place in treatment algorithms for type 2 diabetes for DPP-4 inhibitors and incretin mimetics By indication Incretin mimetics Exenatide is an injectable drug. Therefore, any combination of oral anti-diabetic agents will be the preferred treatment as long as it provides safe and effective glycaemic control without the need to inject drugs. As a consequence, exenatide is approved for use in addition to oral anti-diabetic agents (metformin, sulphonylureas, thiazolidinediones (in some countries), or combinations hereof). This makes it an alternative to any of those oral anti-diabetic drugs that can be added to metformin (or any other first-line oral anti-diabetic drug) or insulin (combination of insulin and oral anti-diabetic drugs or insulin-only regimens). With future incretin mimetics (like liraglutide) the approved indication probably will be similar, but the situation is less clear.
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DPP-4 inhibitors Sitagliptin and vildagliptin are approved for use in addition to oral anti-diabetic agents (metformin, sulphonylureas, thiazolidinediones (in some countries), or combinations hereof). This makes DPP-4 inhibitors also an alternative to any of those oral anti-diabetic drugs that can be added to metformin (or any other first-line oral anti-diabetic drug) or insulin (combination of insulin and oral anti-diabetic drugs or insulin-only regimens). Just to decide based on approved indications does not give clear guidance and leaves open a number of possibilities that need to be weighed against each other. By comparative evaluation Incretin mimetics Exenatide has been compared to insulin regimens administered on a background of metformin and/ or sulphonylureas. Two studies involved insulin glargine administered once daily14,15, and one study involved pre-mixed insulin aspart (twice daily).16 Exenatide was used in a predetermined dosage for all patients (5 mg per dose for the initial month followed by 10 mg per dose, before breakfast and dinner), while insulin was titrated by established algorithms. Uniformly, the efficacy to control glycaemia was not different; insulin treatment prompted weight gain and exenatide treatment was associated with substantial weight loss. There was no difference in the incidence of hypoglycaemic episodes but this was probably due to the concomitant sulphonylurea medication. Liraglutide was tested against insulin glargine and was found to be slightly superior to insulin as far as HbA1c reductions versus baseline were concerned.57 Otherwise the findings were similar to those described with exenatide treatment, although the effect on fasting plasma glucose was stronger. Based on these results of comparing incretin mimetic treatment with insulin, similar glycaemic control can be achieved, with the additional benefit of weight loss. Most likely, hypoglycaemia would be different if no sulfonylurea co-medication was administered, which, however, has not been tried in such comparator trials. Such treatment may be of particular value in patients with weight-associated health problems or in patients with a particular awareness for obesity-related issues. DPP-4 inhibitors In direct comparison, sitagliptin has been tested against glipizide, a sulfonylurea, both on a background of metformin treatment12, and vildagliptin has been tested against pioglitazone (concomitant medication: metformin)13 as well as metformin (both as monotherapy).58 Sitagliptin was non-inferior (in fact, no difference at all) to glipizide concerning HbA1c reduction, and the patients treated with sitagliptin did not increase their body weight during 52 weeks of treatment, while glipizide-treated patients gained 1–2 kg. More patients (approximately 33% vs. 5%) experienced hypoglycaemic episodes with glipizide.12 Vildagliptin was non-inferior with respect to glycaemic control in comparison to pioglitazone treatment over 24 weeks.13 Again, there was a weight difference favouring vildagliptin. Hypoglycaemia was no problem with both treatments. The fact that vildagliptin did not lower quite as much as did metformin in a 52-week monotherapy trial58 may be interpreted as supporting evidence to use DPP-4 inhibitors as a second-line rather than as a first-line treatment, with metformin being recommended as the first anti-diabetic drug. Taken together, DPP-4 inhibitors are as effective as any other oral anti-diabetic drug that they have been compared to on a metformin background, with the additional benefit of not promoting hypoglycaemia and weight gain. Costs It needs to be acknowledged that incretin mimetics (exenatide: approximately 4 V per day) and DPP-4 inhibitors (sitagliptin and vildagliptin: approximately 2 V per day) are more expensive than sulfonylureas (approximately 0.30 V per day). DPP-4 inhibitors and glitazones have similar prices (all costs based on current prices in Germany, September 2008). These numbers provide only direct expenses for these drugs, and do not take into account any ‘return on investment’ like avoiding
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hospitalisation (e.g., for severe hypoglycaemia) or other benefits like less need to perform glucose selfmonitoring, etc. A detailed calculation of cost-effectiveness is not currently available. It is obvious that recommendations in favour or against these novel anti-diabetic agents critically depend on the economic conditions of the particular environment and can vary widely between countries and individuals, for example, related to their health insurance status. Special considerations for patient groups with peculiarities Renal functional impairment There are many restrictions on using traditional oral anti-diabetic agents in patients with renal functional impairment. Accordingly, metformin is contraindicated at more advanced stages59, sulphonylureas can cause severe problems regarding prolonged hypoglycaemic episodes60, fluid retention with thiazolidinediones61 can be a problem etc. Sitagliptin and exenatide can be used with a dose reduction in mild and moderate degrees of renal functional impairment. This recommendation is based on some published experiences and pharmacokinetic reasoning.62 It should be noted, that the incretin hormones gastric inhibitory polypeptide (GIP) and GLP-1 are eliminated renally63,64 and that concentrations can be expected to vary with the degree of reduction in glomerular filtration. Nevertheless, incretin mimetics may be especially suited for the treatment of type 2 diabetic patients with mild-to-moderate renal functional impairment. However, since metformin is often contraindicated in such patients, more studies are needed to develop strategies for their use (e.g., in combination with which other agent(s)) in this particular patient group. Elderly patients Patients with type 2 diabetes in older age groups are common, and provide particular challenges, in that there often are cognitive impairments and other associated conditions. Unnoticed renal functional impairment is one (vide supra). It probably is of special importance in this patient segment to avoid hypoglycaemia (danger of injury) and to provide simple therapeutic regimens (e.g., avoiding the need for glucose self-monitoring; low frequency of administration, hopefully independent from meal schedules). Therefore, there might be advantages of using DPP-4 inhibitors65–67 or incretin mimetics in this patient group. Outlook Incretin-based therapy, that is, incretin mimetics and DPP-4 inhibitors, have interesting properties that make them different from traditional anti-diabetic drugs. They will most likely be used as a treatment added to metformin therapy when monotherapy alone does not provide adequate control. Whether or not there is an advantage for choosing incretin-based therapy (e.g., taking into account costs) must be determined in the individual situation, based on patient characteristics and individual needs. This judgement may change, if studies reporting a robust effect on b-cell health or clinical outcomes (prevention of diabetic complications) become available, in which case a more prominent recommendation within the treatment algorithm needs to be discussed.
Practice points Definition of patient groups who most likely profit from incretin-based antidiabetic therapy versus other available antidiabetic treatment options Post-marketing surveillance for rare adverse events not disclosed by clinical trials Collection of individual patients’ experiences with unexpected responses to treatment with incretin-based antidiabetic medications (non-responders?)
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Research agenda Effects of incretin mimetics and DPP-4 inhibitors in specific subgroups of type 2-diabetic patients Direct comparison of incretin-based antidiabetic medications and comparator drugs Earlier use of combination antidiabetic therapy (including incretin-based antidiabetic drugs) and its effect on long-term glycaemic exposure and diabetic complications Long-term treatment with incretin mimetics and DPP-4 inhibitors and b-cell function and mass Long-term treatment with incretin mimetics and DPP-4 inhibitors and cardiovascular complications
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