Introduction: beyond glycemic control in type 2 diabetes

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Aug 14, 2006 - Current Medical Research and Opinion, 22:sup2, S1-S4, DOI: 10.1185/ ... Clinical Director, Diabetes and Endocrinology, Heart of England NHS.

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Introduction: beyond glycemic control in type 2 diabetes A. H. Barnett To cite this article: A. H. Barnett (2006) Introduction: beyond glycemic control in type 2 diabetes, Current Medical Research and Opinion, 22:sup2, S1-S4, DOI: 10.1185/030079906X112705 To link to this article:

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Introduction: beyond glycemic control in type 2 diabetes A. H. Barnett Professor of Medicine, University of Birmingham and Consultant Physician/ Clinical Director, Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK Address for correspondence:  Professor A. H. Barnett, Undergraduate Centre, Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham B9 5SS, UK. Tel.: +44‑121‑424‑3587; Fax: +44‑121‑424‑0593; email: [email protected] Key words:  Cardiovascular risk – Glycemic control – Type 2 diabetes

Introduction When I first started out in diabetes in the 1970s the whole focus of diabetes management was on glucose control. We were aware of the importance of diet and exercise as part of the holistic approach to management. We also had two different drug classes, the sulfonylureas and biguanides, as oral pharmacotherapy to treat type 2 diabetes. Insulin injections were normally reserved as a treatment of last resort! It is interesting to note that although insulin was first isolated in 1921, it was not until the 1940s that the hypoglycemic effect of sulfonamides was first reported and we did not see the advent of sulfonylureas until the mid-1950s, followed soon after by the first biguanide. In the 1980s, the α‑glucosidase inhibitors came on the scene and since the late 1990s there has been a significant increase in the numbers of new oral anti-diabetic drugs coming to market, or ones in development that will soon be with us. These include the thiazolidinediones (glitazones) and the meglitinide class of rapid-acting insulin secretagogues, with the likelihood of other agents, such as dipeptidyl peptidase‑4 (DPP4) inhibitors and endocannabinoid receptor‑1 blockers in the near future. There have also been major developments in insulin therapy, including insulin analogues, both rapid-acting and long-acting, and the recent licensing of inhaled insulin. The development of (injectable) glucagon-like peptide‑1 (GLP‑1) agonists has also been greeted with interest. Paper 3448B

The development of new anti-diabetic agents has also changed the focus of our thinking concerning best management practice. Drugs have been developed to target specifically the underlying pathophysiology of type 2 diabetes – either directed at insulin resistance, β‑cell dysfunction, or a combination of the two. It has also been appreciated that the ideal anti-diabetic agent, in addition to being efficacious in lowering glucose and with a good safety/tolerability profile, should also provide durability of glycemic control and reduce cardiovascular risk. These additional properties are very relevant in the management of type 2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) showed not only that type 2 diabetes is a progressive condition, but also that traditional agents used to treat the condition do not affect progression1. The UKPDS also emphasized the virtues of combination anti-diabetic treatment if patients are to get even close to glycemic targets! An interesting sub-study of the UKPDS also demonstrated the cardioprotective properties of the biguanide, metformin 2. This latter was an interesting and unexpected finding – the possibility of developing anti-diabetic agents that also have cardioprotective properties has since gained much interest. We now know that type 2 diabetes is a cardiovascular risk equivalent3–5 and indeed the new (pragmatic) definition of this form of diabetes could be stated as follows: ‘Type 2 diabetes is a cardiovascular disease diagnosed on the basis of a raised blood glucose’. If we are to make a major impact on type 2 diabetes we really must tackle the associated cardiovascular S1

disease (remembering that around 80% of all patients with type 2 diabetes will die, many prematurely, from this complication). In addition, there has been an explosion in the evidence base for different aspects of management. We now have an overwhelming weight of evidence, not just for the benefits of improving glycemia in reducing microvascular risk1, but also for the profound benefits of blood pressure 6 and lowdensity lipoprotein (LDL) cholesterol lowering 7,8 to dramatically reduce cardiovascular risk and mortality. Management has now moved even further, through single cardiovascular risk intervention (e.g. antihyper­tensives or a statin), to multiple cardiovascular risk factor intervention, providing an additive or event synergistic effect in dramatically reducing cardiovascular risk9. While trials have shown conclusively the benefits of blood pressure lowering in patients with type 2 diabetes, around 80% of whom are hypertensive, they also emphasize that to get down to the required tight blood pressure targets a combination of antihypertensive drugs from different classes will be required. A further reduction in risk can be achieved by the addition of low-dose aspirin once blood pressure is controlled10. In addition, recent statin trials have not only shown conclusively the benefits of these agents in dramatically reducing cardiovascular risk and mortality in diabetes patients, but also suggest that even diabetes patients with relatively normal LDL cholesterol will show similar risk reduction benefits7,8. Indeed, they strongly suggest that all patients with type 2 diabetes should normally be on a statin at an evidence-based dose. This approach to multiple cardiovascular risk factor intervention using relevant anti-diabetic agents, statins, antihypertensives, and low-dose aspirin, is clearly an important way forward in dramatically reducing cardio­vascular events and mortality. There is a price to pay, however, in the fact that patients may have to take many drugs every day, leading to problems of compliance, tolerability and side effects. There is also the overarching responsibility of health professionals in ensuring that adequate systems of care are set up to allow best practice to take place (which itself presents many challenges). The importance of single risk factor intervention has now been recognized by many authorities and indeed, in the UK, general practitioners are actually paid to hit individual blood pressure and lipid targets in their diabetic patients. The value of multiple cardiovascular risk factor intervention is also increasingly being appre­ciated even by non-specialists, although there is still a long way to go. There has been much written about the challenges involved in achieving good patient compliance with medication and the difficulties of setting up adequate S2  Introduction

systems of care to ensure best practice. Simple measures, such as explaining to the patient why they need their blood pressure or cholesterol to be lowered will certainly help (health professionals in the past have not always been very good at this!) and clearly there needs to be adequate resources to enable all this to happen. The costs of diabetes are high, and increasing, and in some health economies represent greater than 10% of the total health service budget. It should be pointed out, though, that 80% of these costs relate to managing the long-term complications, rather than the costs of preventative treatment, which is much cheaper. Health providers need to be aware of this to avoid rationing, which in the long term is in nobody’s interest! Attempts have also been made to tackle the compliance issue by the pro­vision of fixed-dose combinations of drugs from different classes, which have an additive or synergistic effect on relevant parameters, such as glycemia, blood pressure, or indeed cholesterol. We now have fixed combinations of different antihypertensives, statins with a cholesterol absorption inhibitor, and antidiabetic agents. In addition, there seems to be a logic in combining agents which have an additive or synergistic effect, but work by different mechanisms. This may allow reduced doses of each drug to be used, perhaps improving tolerability and safety with even more profound benefits compared with just increasing the dose of a single drug. While the above issues are appreciated in principle, particularly by specialists, there does still seem to be an antagonism in certain quarters (particularly, for example, in the UK among our prescribing advisers) towards fixed-dose combination drugs. This latter provides a significant educational challenge, which it should be possible to overcome. It is instructive to chart the changing focus of type 2 diabetes management through, from the treatment of glycemia with only a limited number of drugs available, to the present day, with a much larger range of anti-diabetes agents and a logical approach to cardiovascular risk management consequent on the trials of antihyper­tensives, statins, etc. This has led to single, followed by multiple, cardiovascular risk factor intervention. The emphasis on the development of drugs that tackle the primary defects of diabetes itself is clearly to be welcomed, but can we go even further? Can drugs be developed which, in addition to having a primary effect on a single parameter such as glycemia, also have beneficial effects on other cardiometabolic parameters such as blood pressure, lipids, hemostatic factors, inflam­matory markers, adipocytokines, and so on? Indeed, do we already have such a drug? The thiazolidinediones (glitazones) are agonists of an intra-nuclear hormone receptor – peroxisome © 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22(Suppl. 2)

proliferator activated receptor‑γ 11. Simplistically, their actions promote effects on carbo­hydrate and lipid metabolism similar to that which occurs when insulin combines with its receptor. The result is an improvement in insulin sensitivity, thereby reducing insulin resistance, the latter being a primary defect in type 2 diabetes and perhaps in the development and progression of the metabolic syndrome. Improve­ ment in insulin resistance and glycemia also results in reduction in glucose toxicity with (assumed) improve­ ment in pancreatic β‑cell dysfunction. These agents have been shown to have beneficial effects not just on glycemia, but also on blood pressure and the lipid profile (e.g. an increase in high-density lipoprotein [HDL] cholesterol and, in the case of pioglitazone, a reduction in triglycerides, accompanied by a move from small dense lipoprotein particles to larger, less dense, less atherogenic fractions11. Improve­ ments in inflammatory markers (e.g. C‑reactive protein), adipocytokines (e.g. adiponectin) and microalbuminuria (the latter is a very good predictor of cardiovascular risk and mortality) have also been demonstrated. These observations have suggested that these agents may have beneficial effects beyond glycemia, specifically improvement in other parameters related to the meta­ bolic syndrome and reduction of cardiovascular risk. This has been tested in hard outcome trials and the first of these has recently been reported. The PROactive trial demonstrated reduction in cardiovascular event rates in high-risk patients with type 2 diabetes with the use of pioglitazone12. Other studies have also suggested that the use of glitazones may be associated with more sustained glycemic control compared with traditional agents – the results of more definitive studies from the point of view of both prevention of type 2 diabetes and early inter­vention are awaited. Sustainability of glycemic control long-term and the possibility of cardiovascular protection are thus the subject of important trials using glitazone agents. Further results of clinical trials are awaited with interest. For all the above reasons, it has been a particular pleasure for me to write the introduction for this series of papers. Each can be read in its own right and all are written by experts in their field. The first paper from Massimo Massi-Benedetti looks at changing targets in the treatment of type 2 diabetes13. He emphasizes that, while correction of raised glucose is a central feature of diabetes management, one must go beyond this to address other cardiovascular risk factors if we are to improve outcomes for our patients. He covers in detail the current guidelines for management of glycemia and cardiovascular risk reduction and considers other markers of risk as areas for future study. He emphasizes © 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22(Suppl. 2)

that efforts need to be made to increase the proportion of patients achieving current treatment targets (which in many studies has been abysmally low!). He also emphasizes that the poly-pharmacy ‘pill burden’ may be helped by using drugs that are effective against multiple aspects of the metabolic syndrome, and by co-formulation of agents with established efficacy. Christian Schneider then focuses on outcome studies in cardiovascular risk and metabolic control14. Using a MEDLINE literature search he covers all of the major trials in diabetes and points out that, despite the wealth of information we have concerning the use of combin­ ation treatment, there still remains an excess residual risk of cardiovascular events in patients with type 2 diabetes. He suggests that emerging data and ongoing trials will provide better guidance on new therapeutic opportun­ities in this high-risk group. The third paper, by Bart Staels, addresses the use of a biguanide and a glitazone (specifically metformin and pioglitazone) as an effective combination treatment for insulin resistance15. He outlines the pathophysiology of the problem, what we know about the mechanism of action of these two types of agent, and the potential benefits of combination treatment. He emphasizes that these agents not only combine to reduce glycemia more effectively than the single agent alone, but that they also have distinct effects on levels of mediators involved in inflammation and endothelial dysfunction, with a suggestion that both may be useful in combination to further reduce macrovascular events. The final paper, by Jochen Seufert, considers the new fixed combination of metformin and pioglitazone – pointing out that, given the additive effects of a glitazone and metformin, a fixed combination of the two (specific­ally pioglitazone and metformin – Competact (Takeda, Osaka, Japan) is a rational way forward16. The beneficial effects of these two agents in combination on glycemia are accompanied by improvements in diabetic dyslipidemia and other biomarkers of atherosclerosis, such as inflammatory mediators and coagulation/throm­ bosis components. The potential is that by combining these agents, there may be a further reduction in cardiovascular risk, compared with the use of the single agent alone. Studies with this combination show good tolerability, with low rates of hypoglycemia and the hope of improved patient compliance. The above series of articles nicely summarize the literature in this important area. They are well written and follow a logical format. They should provide practical advice which can be used by health pro­ fessionals dealing with patients with diabetes. This is an extremely exciting time in the field, with the promise of a whole range of new studies and information which will have an important effect on clinical practice in the near future. Introduction  Barnett  S3

References 1. United Kingdom Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53 2. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;353:854-65 3. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. New Eng J Med 1998;339:229-34 4. Evans JM, Wang J, Morris AD. Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction. BMJ 2002;324:939-42 5. Juutilainen A, Lehto S, Ronnemaa T, et al. Type 2 diabetes as a ‘coronary heart disease equivalent’: an 18‑year prospective population-based study in Finnish subjects. Diabetes Care 2005;28:2901-7 6. United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13 7. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22

8. Calhoun HM, Betteridge DJ, Durrington PN, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet 2004;364:685-96 9. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Eng J Med 2003;348:383-93 10. Hansson L, Zanchetti A, Carruthers SG, et al. Effect of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-62 11. Murphy E, Nolan JJ. What is the role of the thiazolidinediones (glitazones) in clinical practice? In: Diabetes Annual 2002. Barnett AH, editor. London: Martin Dunitz, 2002. pp.119-40 12. Dormandy JA, Charbonnel B, Eckland EJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes: a randomised trial of pioglitazone. The PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events). Lancet 2005;366:1279-89 13. Massi-Benedetti M. Changing targets in the treatment of type 2 diabetes. Curr Med Res Opin 2006;22:S5-S13 14. Schneider CA. Improving macrovascular outcomes in type 2 diabetes: outcome studies in cardiovascular risk and metabolic control. Curr Med Res Opin 2006;22:S15-S26 15. Staels B. Metformin and pioglitazone: effectively treating insulin resistance. Curr Med Res Opin 2006;22:S27-S37 16. Seufert J. Competact: a promising alternative in metabolic control. Curr Med Res Opin 2006;22:S39-S48

CrossRef links are available in the online published version of this paper: Paper CMRO-3448B_2, Accepted for publication: 04 July 2006 Published Online: 14 August 2006 doi:10.1185/030079906X112705

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