- Email: [email protected]
The impact of glucose-lowering therapy on cardiovascular outcomes
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
Contents lists available at ScienceDirect
Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem
9
The impact of glucose-lowering therapy on cardiovascular outcomes Eberhard Standl, Professor *, Martin Mu¨ller, MD, Oliver Schnell, Professor ¨dter Landstrasse 1, 85 764 Munich Neuherberg, Germany Munich Diabetes Research Institute at the Munich Helmholtz Center, Ingolsta
Keywords: diabetes blood glucose lowering HbA1c hypoglycaemia weight gain cardiovascular morbidity and mortality
Despite some controversies, especially in 2008, evidence is mounting by a number of randomised controlled trials in recent years that blood-glucose-lowering therapy (as an integral part of multifactorial therapy) reduces cardiovascular disease (CVD) for longer term, both in type 1 and type 2 diabetes. In particular, cardiovascular events are reduced by approximately 10–15% per 1% absolute reduction of HbA1c, on top of other CVD-risk-reducing therapies. With regard to mortality, the situation is less clear, as those intervention studies need at least a 10-year follow-up. In fact, some risks involved with blood-glucose-lowering therapy, for example, hypoglycaemia and weight gain, especially in patients with prior CVD, may also impact unfavourably on (cardiovascular) mortality. Therefore, blood glucose lowering is a highly individualised therapy with a target for HbA1c 7.0% or 6.5%, which takes time to tailor (poly-)pharmacotherapy gently to the patient’s needs. Drug-specific effects, both advantageous and disadvantageous, of blood-glucose-lowering therapy cannot be excluded currently and warrant further studies. Ó 2009 Elsevier Ltd. All rights reserved.
In theory, it nearly sounds like a ‘no-brainer’ that blood-glucose-lowering therapy should have a beneficial impact on the outcome of patients with diabetes and heart disease, given the overwhelming evidence of an excessive and massive risk of cardiovascular disease (CVD) associated with diabetes mellitus in human subjects. In fact, diabetes mellitus has been rated as an equivalent of coronary artery disease by several scientific associations and the corresponding guidelines.1–6 In reality, however, the linkage between heart disease and diabetes seems to be much more complex and,
* Corresponding author. Tel.: þ49 89 3187 3173; Fax: þ49 89 3081733. E-mail address: [email protected] (E. Standl). 1521-690X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.03.010
402
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
indeed, multifactorial beyond the issues of glycaemic control, such that an exclusive ‘glucocentric’ therapy may not suffice to ensure an improved cardiovascular (CV) prognosis.7 Furthermore, the results of several long-term intervention trials released recently have reminded us that potential risks associated with blood-glucose-lowering therapy, in particular, the risk of serious hypoglycaemia, may outweigh the benefits of blood-glucose-lowering therapy in certain patients and that this downside may be drug specific.8,9 In all, a highly individualised blood-glucose-lowering therapy as an integral component of multifactorial therapy appears to be key to maximise benefits in terms of an improved outcome and to avoid serious side effects.10,11 This article attempts to evaluate the present evidence of pros and cons of blood-glucose-lowering therapy and to provide some guidance for a successful approach to glycaemic control in patients with heart disease and diabetes mellitus. Hyperglycaemia and cardiovascular disease (CVD): epidemiological observations Compelling evidence has been accumulated that hyperglycaemia is closely and independently related with excessive morbidity and mortality of CVD.12,13 This involves all components of the ‘glucotriade’, that is HbA1c, fasting plasma glucose and postprandial or post-load plasma glucose.14–21 The relationship has to be seen as a continuum and starts already within the glycaemic range below the present cut-off for the definition of (ouvert) diabetes mellitus. The latter notion poses a particular challenge for early diagnosis of asymptomatic diabetes (and the related treatment) and contrasts with the findings as for the more diabetes-specific microvascular changes, for example, retinopathy and nephropathy, which rarely emerge before the manifestation of diabetes mellitus.22–25 The overall risk of CVD for people with diabetes increased two- to threefold in men, and three- to fivefold in women when compared to people without diabetes.26 Approximately 50–70%, depending on the methodology of assessment, of all people with diabetes (both type 1 and type 2), die due to CVD.26,27 As type 1 diabetes appears to be a more ‘pure’ paradigm of exclusive hyperglycaemia, it is not surprising that the relationship of hyperglycaemia not only with microangiopathy, but also with macroangiopathy seems to be stronger in type 1 diabetes compared to type 2 diabetes.26,28 Recent results from a large Finnish database showed that for every 1% increase of HbA1c, CVD mortality increased by about 50% in type 1 diabetes, whereas only by about 10% in type 2 diabetes.26 The landmark United Kingdom Prospective Diabetes Study (UKPDS) of a large cohort of newly diagnosed people with type 2 diabetes has indicated a 16% increased risk of myocardial infarction for every unit (%) increase of HbA1c.16 A global meta-analysis of all worldwide available epidemiological data for mortality from ischaemic heart disease in relation to fasting plasma glucose (FPG) has demonstrated an overall increase of 20% for every 1 mmol l1 increase of FPG above the optimum level.29 This excessive risk went up even to 40% in the age group below 60 years.29 Another analysis revealed that both men and women with diabetes develop the same rates of acute myocardial infarction at an age 20 years earlier compared to their non-diabetic gender counterparts.13 Extrapolating from these epidemiological observations, it is clear that blood-glucose-lowering therapy inducing a 1% decrease of HbA1c or a 1 mmol l1 decrease of FPG (and even this modest decrease of glycaemia seems to be a high hurdle in many randomised prospective studies) cannot achieve more than a 10–20% reduction of serious CVD events.28 In view of the high event rates of CV complications in diabetes, this may still represent a clinically meaningful outcome improvement, in terms of randomised studies; however, large patient numbers are required to detect statistically significant differences and – very crucial – a sufficiently long follow-up observation period. Based on the epidemiological evidence, one can conclude that it takes at least 8–10 years of treatment to find significant effects – if not longer.16,19,30 The recently published ‘Legacy effect’ of blood-glucoselowering therapy in preventing myocardial infarction and mortality in the UKPDS was unquestionable after a mean observation period of 18.5 years, an advantageous effect on macrovascular disease which had been heavily debated 10 years earlier.16 The time/effect relationship of improved blood glucose control on macrovascular disease seems to be similar in type 1 diabetes, as seen in the cohort of the Diabetes Control and Complication Trial (DCCT) after a mean observation period of 17 years.19 Even with the multifactorial approach, including blood-glucose-lowering-therapy as applied in the Steno 2 trial, it takes time: after 4 years in the study, only microvascular complications were reduced; it needed 7.8 years to substantiate the macrovascular benefits; and an observation time of 13 years to reveal an
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
403
impressively reduced mortality.10 This dependence on rather long-term studies poses a high challenge for randomised controlled trials to explore macrovascular outcomes. On the other hand, CVD alterations may be present, and to an abundant extent, at diagnosis of diabetes. In fact, epidemiological evaluations have indicated that up to 15 years prior to the diagnosis of diabetes the risk of macrovascular morbidity is already elevated.24 The causes for this excessive risk again seem to be complex: long-time undiagnosed diabetes, the association of type 2 diabetes with metabolic syndrome and the impact of especially impaired glucose tolerance (IGT), to name just a few. It is very clear from analysis of huge databases from many sources that the higher the 2-h post-load glucose levels, though below the threshold of ouvert diabetes, the higher the risk for macrovascular disease. This association has been found to be significantly stronger than in the event of an increasing elevation of fasting blood glucose level in relation to macrovascular disease.20,31 Of late, this notion has also sparked the debate over whether the present criteria for diagnosing diabetes should be lowered or not. Several intervention trials, therefore, have looked into whether the prevention of diabetes at the level IGT is also preventive for CVD.32 Most of the larger trials are still ongoing (see below). Finally, and astoundingly, the concentration of a single, random blood glucose measurement in the acute condition of macrovascular complications, for example, acute myocardial infarction, was found highly predictive whenever investigated, both for the short-term prognosis during hospital stay and long term over several years.33 Again, although somewhat controversial, IGT seems to carry an increased risk, especially in longer term.22,34 Results of intervention trials Presently, it is beyond doubt that lowering blood glucose is highly successful to prevent microangiopathy, for example, retinopathy, nephropathy and neuropathy, both in type 1 and type 2 diabetes. It may, however, take a longer time than expected, and there may be even some worsening early on in patients with pre-existing disease, but it clearly pays off over time in terms of preventing and reducing microvascular diabetic complications.16,19 Therefore, sufficient glycaemic control is warranted in every diabetes patient with some degree of life expectancy. Evidence suggests that maintaining glycaemic control at an HbA1c range of at least 7.5% will prevent most patients from developing serious microangiopathic sequelae. Care should be taken to avoid too rapid, overaggressive lowering of blood glucose, especially in patients with pre-existing significant retinopathy or neuropathy and/or with a tendency to encounter more severe hypoglycaemia. Recently, the results of ADVANCE have demonstrated that aiming at and attaining even lower HbA1c values in patients with type 2 diabetes, that is 6.5%, yields additional microvascular renal outcome benefits, and can be achieved safely and with very little risk of hypoglycaemia and weight gain, and certainly without any risk of excessive mortality.9 Interestingly enough, this additional benefit compared to a more conventionally treated randomised control group with an average HbA1c value of about 7.3% was fully additive to intensive blood-pressure-lowering therapy and also apparent in the subgroup on statin therapy. The number needed to treat, however, to achieve this additional benefit was not overly impressive and was approximately 50 for the 5-year observation period.9 The landmark studies to underpin the effectiveness of blood-glucose-lowering therapy to reduce not only microvascular, but also CV complications of diabetes have already been introduced: the DCCT for type 1 diabetes and UKPDS for (newly diagnosed) type 2 diabetes.16,19 The most striking long-term ‘legacy effects’ of lowering blood glucose, however, evolved in both the studies during the open poststudy observation period. On the other hand, all the available prospective randomised data sources in 2006 have been subjected to a meta-analysis and clearly showed a significant effect in both types of diabetes: some 60% reduction for any macrovascular end point in type 1 diabetes and a still significant reduction of approximately 15% in type 2 diabetes.29 Therefore, clearly, the effectiveness in type 1 diabetes can be taken as a proof of principle, whereas the effect was also detectable in type 2 diabetes, and actually within the expected range for a 1% decrease of HbA1c. It seems noteworthy that, according to this meta-analysis, the effectiveness in type 2 diabetes apparently varied across the main target areas of macrovascular complications: it was more marked for cerebrovascular and peripheral vascular disease, and only of borderline significance for CVD. In the latter context, recently published results of the Euro Heart Survey ‘Diabetes and the Heart’ seem to be more reassuring.34 Patients with established
404
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
coronary artery disease, be it acute or chronic, and newly diagnosed diabetes on this occasion showed a much better prognosis over the next year when (usually oral) blood-glucose-lowering pharmacotherapy was implemented at that time compared to the chance group of patients with identical baseline characteristics, but whose diabetes was not treated (by drugs) and only followed up.34 These results are highly suggestive that blood-glucose-lowering therapy can make a beneficial difference even rather short term in some group of patients with newly diagnosed diabetes and a high risk for further complications of CVD, although the limitations of these survey data are also clear in that they were not obtained from a randomised controlled trial with no information available about metabolic control and adherence to non-pharmacological lifestyle therapy. Therefore, undoubtedly more and longer-term randomised trials were and are urgently needed to further explore the CVD benefits of blood-glucose-lowering therapy in type 2 diabetes, whereas most scientific associations and the according ‘evidence-based guidelines’ had recently settled to recommend an overall glycaemic target range of an HbA1c value either 7.0% or 6.5% (DCCT standard), and the corresponding target ranges for blood glucose.1–6 In 2008, however, a triade of randomised studies, that is, studies with the acronyms ACCORD (Action to Control CardiOvascular Risk in Diabetes), VADT (Veterans Affairs Diabetes Trial) and ADVANCE, based on a total of about 23 000 type 2 diabetic patients and a mean follow-up between 3.5 and 6.5 years, have reported conflicting results on macrovascular outcomes, including mortality in the context of various blood-glucose-lowering regimes.9,11,19,35 ACCORD/VADT/ADVANCE: have the targets for HbA1c changed? Disturbing news have come particularly from ACCORD where the intensive treatment arm had to be stopped after a mean of 3.5 years in the study due to excessive mortality (1.4% vs. 1.1% annually in the less intensive arm, hazard ratio 1.22, confidence interval (CI) 1.01–1.46).9 Although the overall mortality was unusually low for a group of diabetes patients of this age and CVD risk, this borderline difference was of concern, as it was also reflected in an increased CV mortality.9 The intensive group had followed the intention to avoid failure of attaining glycaemic goals as in UKPDS, in which also the so-called intensive treatment arm exhibited a mean HbA1c value of approximately 8% at the end of the randomised study period.9 In fact, a perhaps overaggressive treatment algorithm was enforced in ACCORD aiming at a rather ambitious goal for HbA1c 6.0%. Indeed, the HbA1c levels fell dramatically in a short period of time from a mean of 8.1% to 6.4%. Table 1 lists the macrovascular outcomes assessed in all the three intervention trials together with the achieved hazard ratios for the primary macrovascular outcomes and for total mortality. Although non-significant for the individual study, there was a consistent trend across all the three studies for a favourable reduction of the respective composite macrovascular outcomes in
Table 1 Hazard ratios: overview VADT, ADVANCE, ACCORD.
VADT
ADVANCE
ACCORD
Definition of primary outcome
Hazard ratio for primary outcome (95% CI)
Mortality findings
Non-fatal MI, Non-fatal stroke, CVD death, hospitalization for CHF Revascularization Microvascular plus macrovascular outcomes (Non-fatal MI, Non-fatal Stroke, CVD)
0.87% (0.73 to1.04)
Hazard ratio 1.065 (0.801, 1.416)
0.9 (0.82 to 0.98) Macrovascular: 0.94 (0.84 to 1.06) 0.90 (0.78 to 1.04)
Hazard ratio 0.93 (0.83 to 1.06)
Non-fatal MI Non-fatal Stroke CVD Death
Hazard ratio 1.22 (1.01 to 1.46)
VADT: Duckworth W, Abraira C, Moritz T, et al. (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360: 129–139. ADVANCE: Patel A, MacMahon S, Chalmers J, et al. (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358: 2560–2572. ACCORD: Nathan et al. (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353: 2643–2653.
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
405
relation to more intensive blood glucose therapy and lower HbA1c levels, with a hazard ratio of about 0.9.9,19,35 In light of this uniform trend, one would like to see the result of an appropriate meta-analysis of all the three studies. At variance, however, were the observed total mortality rates, which was – as mentioned – unfavourable in ACCORD (despite the fact that CVD death was also a component of the overall beneficial trend for macrovascular outcomes there), more or less neutral in VADT and advantageous in ADVANCE.9,19,35 Table 2 compares some features of the most diverse studies, ACCORD and ADVANCE.36 As can be seen, as a consequence of the perhaps overaggressive treatment algorithm, most patients were on a quintuple therapy with intensified insulin therapy (multiple injections of short-acting and longacting insulins), a sulphonylurea, metformin and an insulin sensitiser in the intensive arm of ACCORD. In contrast, polypharmacy was much less pronounced in ADVANCE with a less ambitious HbA1c goal of 6.5%, much less insulin usage and very little use of insulin sensitisers (only 17% of patients in the intensive arm of ADVANCE vs. 92% in ACCORD). Hence, it does not seem surprising that assistance requiring hypoglycaemia amounted to an astronomically high 16.2% over the study period in the intensive arm of ACCORD (a figure which is some 2.5 times higher compared to the experience in UKPDS), and 28% of all patients gained more than 10-kg weight, whereas assistance requiring hypoglycaemia was below 1% per year in ADVANCE with no weight gain present on average.9,19 It has been stated that no single factor in ACCORD could be sorted out and made accountable for the excess CVD and total mortality, including hypoglycaemia.19 Perhaps the smallest of the three studies, VADT, might give clues to the conflicting results seen in those studies.9 Again, VADT was heavily leaning towards high usage of intensified insulin therapy in conjunction with an insulin sensitiser, a sulphonylurea and metformin; once again hypoglycaemia was a problem, and severe hypoglycaemia was tracked down as an independent predictor of both CV death and the primary macrovascular outcomes with the highest hazard ratio of all predictors.9 In addition, the VADT investigators found an interesting relationship between known diabetes duration and the hazard ratios for CVD events with intensive therapy (p < 0.0001).9 While with a short duration of diabetes at baseline, there clearly was a beneficial trend, which seemed to vanish over time, however, and reached a break-even point after 15 years of known diabetes duration at baseline, beyond which the potential downsides of intensive therapy seemed to outweigh the benefits. In a subset of patients, VADT investigators also assessed coronary calcifications and observed that at low calcium scores intensive treatment was advantageous, whereas at high calcium scores the opposite was found.9 This notion also seems to have a reflection in a subgroup analysis in ACCORD: the two-thirds of the 10 251 patients without a prior history of CV events clearly seemed to benefit from intensive therapy, in contrast to the one-third with known prior CV events.9 In addition, patients with lower HbA1c levels at baseline did seem to benefit the most, whereas patients with a higher HbA1c at start did not.9 All this combined raises the possibility that especially the ‘vulnerable’, pre-injured heart is at risk for the potential complications and downsides of Table 2 Differences between the ACCORD and ADVANCE studies. Characteristic
ACCORD
ADVANCE
Baseline N Mean age (Y) Duration of diabetes (Y) Median HbA1c at baseline History of macrovascular disease (%)
10,251 62 10 8.1 35
11,140 66 8 7.2 32
<6.0 3.4
6.5 5.0
77 95 87 92
41 vs 24 74 vs 67 94 vs 62 17 vs 11
Intervention Target HbA1c (%) Median duration (Y) Medical treatment at study completion (intensive vs standard) (%) Insulin Metformin Secretagoue (sulphonylurea or glinide) Thiazolidinedione Dluhy et al. N Engl J Med 2008; 358: 2630–3.
vs 55 vs 87 vs 74 vs 58
406
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
a too aggressive blood-glucose-lowering therapy, in particular, hypoglycaemia which seems to be mainly driven by a high-dose insulin therapy, perhaps in conjunction with an insulin-sensitising agent or a sulphonylurea. Of course, all these deliberations are only to generate hypothesis since they were made post hoc and based on subgroup analysis. They fit, however, in the context of recent results from the DIGAMI 2 Trial and the Euro Heart Survey ‘Diabetes and the Heart’.22,37 DIGAMI 2 patients with diabetes and an acute coronary syndrome have been randomly assigned to new insulin therapy. The 2-year follow-up results indicated that the patients on insulin were associated with a higher risk for non-fatal myocardial infarction and stroke and also for the composite of death and non-fatal myocardial infarction or stroke.37 The impact of in-hospital hypoglycaemia during the acute condition was also evaluated in terms of the longer-term mortality and CV events. Although there was a connection, it was thought that hypoglycaemia was mainly a surrogate of other high-risk factors for CVD and mortality and the effect, therefore, inconclusive. On the other hand, metformin-based therapy was associated with the most favourable outcomes.37 Similarly, in the Euro Heart Survey, noninsulin-based therapies were related to a more advantageous 1-year outcome compared to insulinbased therapies.22 Therefore, in summary of the discussions over the findings in ACCORD/VADT/ADVANCE, it may be stated that, although the need for further well-planned randomised trials has become even more evident, the initially conflicting results seem to follow a currently widely accepted logic. The practical implications for the present-day blood-glucose-lowering therapy may be outlined as follows: 1) In particular, in view of the prevention of microvascular complications, there is no need for a change of HbA1c targets (7% or 6.5%, respectively), but there is a need to go slow, especially in patients with pre-existing CVD and very high baseline HbA1c levels - Side effects, such as hypoglycaemia and weight gain, need to be avoided. 2) Early treatment and prevention appears to give the best results 3) Drug-specific effects, both advantageous and disadvantageous, of blood-glucose-lowering pharmacotherapy cannot be excluded currently and therefore warrant further studies 4) The beneficial effects of improved blood glucose control on CVD do emerge in longer term and there is a ‘legacy effect’ (metabolic memory) Does prevention of diabetes prevent CVD? The jury is still out whether prevention of diabetes, particularly at the level of IGT, also prevents CVD. At present, this is more a research-oriented question of high theoretical interest, and awaits further substantiation, before it could lead to a practical indication. The first study to underpin this possibility was the randomised StopNIDDM trial which sought to prevent the manifestation of type 2 diabetes by the use of acarbose and where CVD outcomes were also a pre-specified secondary objective.32 After a mean follow-up of 3 years, there was an absolute risk reduction not only for diabetes of 11%, but also for any CVD end point, especially myocardial infarction.32 Overall event numbers were low, however, and no such observation was made in other prevention trials, for example, DPP2 or DPS37,38 Interestingly enough, in 2008, the 20-year outcome results of the entirely lifestyle-based DaQuing prevention trial was made available.25 Although vanishing during the second decade, still a highly significant preventive effect of the lifestyle intervention earlier on was detectable in terms of diabetes manifestation, while in terms of prevention of CVD death a rather suggestive preventive effect emerged over the second decade which was reminiscent of the legacy effect of glucose control in UKPDS.16 Again, unfortunately, due to small overall numbers this effect failed to reach statistical significance. Therefore, the onus would be on the still-ongoing or recently started prevention trials, such as Outcome Reduction with Initial Glargine Intervention (ORIGIN), Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) or Acarbose Cardiovascular Evaluation (ACE), to prove whether prevention of type 2 diabetes – it is often said that this is only ‘masking’ diabetes by pharmacotherapy – materialises in the prevention of CVD as well.38,39
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
407
Drug-specific cardiac issues of blood-glucose-lowering therapies ‘Reach and maintain glycaemic goals safely and gently, avoid serious side effects’, must be the current policy for blood-glucose-lowering therapy. Often, this leads to a highly individualised therapy, as there is no ‘golden’ algorithm. This was also the main recommendation of the First Joint EASD/ESC Guidelines ‘Diabetes, Pre-Diabetes and Cardiovascular Diseases’.40 Depending on the conditions of the individual with regard to specific organ damage, metabolic phenotype and stage of diabetes, the appropriate mix of non-pharmacological and pharmacological options should be tailored to the particular needs (Table 3). As may be seen and already discussed in this article in detail, heart-related issues may play an important modifying role for the appropriate choice. Adequate lifestyle, self-control and empowerment are the foundation good treatment. Metformin, although not uncriticised, has been associated with the most favourable cardiac outcomes, for example, in UKPDS, Digami 2 and others.16,37 It holds the pole position in monotherapy. It may have some unpleasant gastrointestinal side effects, is contraindicated in patients with a GFR < 50 ml or high risk of severe hypoxaemia and has to be stopped 1 day prior to the exposure to contrast media. It can be re-instituted later, provided there is a stable and sufficient circulatory function. All remaining options, including insulin, are for (early) combination with metformin or an alternate option, when metformin is contraindicated or not tolerated (some 50% of all cases with type 2 diabetes). Sulphonylureas, in particular glibenclamide, are often burdened with some degree of hypoglycaemic risk (about 30% of all treated cases) and weight gain. The combination with metformin and a potential influence on cardiac K-channels and on ischaemic remodelling have been under debate. Compared to metformin, epidemiological evaluations have yielded less favourable outcomes. On the other hand, the positive effects in ADVANCE and the ‘legacy effect’ in UKPDS have been substantiated in randomised trials with sulphonylureas.9,16 Short-acting sulphonylurea analogues, that is ‘gliptins’, are also available. In theory, they should offer a lesser risk of hypoglycaemia, but appropriate randomised trials are lacking, and especially studies demonstrating a long-term CVD benefit. The alpha-glucosidase-inhibitor acarbose seems to have a rather advantageous risk/benefit ratio. The CVD benefits are opposed only by a few gastrointestinal side effects (in about 30% of all treated cases), which do afford ‘gentle’ skills when introducing or stepping up this therapy, but certainly not by serious side effects such as hypoglycaemia or weight gain.32 Insulin sensitisers (thiazolidindiones (TZDs) or glitazones) are well tolerated by patients and do not induce hypoglycaemia but are noted for inducing weight gain, which seems to be a mix of true (subcutaneous) weight gain and some fluid retention in prone patients. TZDs are contraindicated in patients with heart failure. Pioglitazone has been shown associated with significant CVD benefits in the Prospective Pioglitazone Clinical Trial in Macro Vascular Events (PROACTIVE) trial and in a large metaanalysis, though the risk to develop signs of heart failure is somewhat elevated.41 No such CVD benefits
Table 3 Present approach to diabetes management in type 2 diabetic patients. Consult endocrinologist/diabetologist for - structured education - blood glucose self monitoring (also pp glucose) - appropriate nutrition counselling - pharmacotherapy discussiong pros and cons
Insulin Metformin sulfonylureas Alpha-glucosidase-inhibitors glitazones glinides Incretin based agents
Benefits
Caveats
yes yes yes yes Yes/? ? ?
Heart? Impaired kidney function Cardiac K-channels? CHF, ?CAD rosiglitazone
408
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
have been demonstrated so far in relation to rosiglitazone.42 In fact, there have been concerns for ischaemic cardiac changes earlier on, which have not been confirmed in larger trials including the already-discussed ACCORD and VADT.19,35 The regulatory authorities have rated the situation inconclusive as yet , but certainly there is no excess mortality related to rosiglitazone treatment. Combination of metformin with basal insulin, which can be stepped up to more intensive insulin therapy as deemed necessary by adding prandial insulin, is a very well-explored option and widely recommended in various guidelines. The potential downsides are weight gain and hypoglycaemia if overdosed. Home glucose monitoring is an essential part of this type of therapy. The legacy effect of blood-glucose-lowering therapy on reduced rates for mortality and myocardial infarction in UKPDS were to 50% also associated with an initially randomly assigned basal insulin therapy.16 On the other hand, the problems encountered in ACCORD and VADT also particularly seemed to be insulin triggered, most likely in connection with hypoglycaemia, and appear to be of concern especially in patients with prior CVD.19,35 In addition, they seem to have reflections in results from DIGAMI 2, the Euro Heart Survey ‘Diabetes and the Heart’ and observations in heart failure patients.37 This issue needs urgent clarification by appropriate randomised trials. Incretin-based therapies are the latest addition to the armamentarium of blood-glucose-lowering therapy over the last 3 years. At present, there are no long-term CVD outcome results available yet. Based on theory and experimental work, they should be beneficial. The advantages include the absence of hypoglycaemic risk and weight neutrality for the dipeptidyl peptidase IV (DPP-IV) inhibitors or even significant weight loss for the glucagon-like peptide-1 (GLP-1) analogues. While DPP-IV inhibitors are available as oral agents, the latter need to be injected once or twice a day.. Both classes of drugs are usually well tolerated, apart from nausea and diarrhoea related to the administration of GLP-1 analogues by virtue of their complex mode of action. No specific home glucose monitoring is needed.
Early combination to maximise efficacy and to minimise side effects All available drug options provide a (placebo-subtracted) HbA1c decrease of around 1% (Table 4), <1% (e.g., acarbose, DPP-IV-inhibitors and nateglinide) and >1% (metformin, sulphonylureas and insulin). Due to the increasing demand for lowering HbA1c, double combinations and even triple therapies are a frequent practical necessity. As the underlying mode of actions are different for each class of drugs, so are the underlying pathogenetic abnormalities in type 2 diabetes different and multiplex; the HbA1c-lowering capacity of each class of drug is usually fully additive in combination. Since for most drug options at a medium dose already 70–80% of the maximum HbA1c lowering effect is achieved, it is advisable to begin early combination therapy instead of administering the highest dose of a single drug and thereby inducing increasing side effects. The early combination approach maximises glycaemic control and minimises side effects. Avoiding side effects, especially hypoglycaemia, perhaps also excess weight gain, seems to be a priority of present-day blood-glucose-lowering therapy. Therefore, the first step in deciding on the
Table 4 Mean efficacy of pharmacological treatment options in patients with type 2 diabetes. Drug
Mean lowering of initial HbA1c (%)
Incretin Enhancers GLP-1 Analoga Alpha-glucosidase inhibitors Biguanides Glinides Glitazones Insulin Sulfonylurea derivates CB1-Rezeptor Antagonist
0.7–1.0 w1.0 0.5–1.0 1.0–1.5 0.5–1.5 1.0–1.5 1.0–2.0 1.0–1.5 0,7
Ryden L, Standl E, Bartnik M, et al. (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Diab Stoffw Herz 16 Suppl C: C3–C74.
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
409
Table 5 Suggested policy for the selection of glucose-lowering therapy according to the glucometabolic situation. Post-prandial hyperglycaemia Fasting hyperglycaemia Insulin resistance Insulin deficiency
Alpha-glucosidase inhibitors, short-acting sulfonylureas, glinides, DPP 4 inhibitors, GLP1 analogs, short-acting regular insulin, or insulin analogs Biguanides, long-acting sulfonylureas, glitazones, long-acting insulin, or insulin analogs Biguanides, glitazones, alpha-glucosidase inhibitors Sulfonylureas, glinides, DPP 4 inhibitors, GLP1 analogs, insulin
Ryden L, Standl E, Bartnik M, et al. (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Diab Stoffw Herz 16 Suppl C: C3–C74.
pharmacotherapy of a specific patient is to exclude all drug options which are contraindicated or may be counterproductive on the individual level. Step two should explore the specific metabolic phenotype at the present situation: Are the glycaemic problems mainly due to insulin resistance or insulin deficiency? Are they mainly present in the fasting state or in the postprandial situation? This will then guide the most appropriate choice in this moment (see also Table 5). Certainly, there are also other very important factors such as patient preference and quality-of-life aspects, for example, as related to the need of injections or for frequent blood glucose monitoring. Along those lines of deliberations one can build double or triple combinations to pursue mainly reduction of insulin resistance or avoiding hypoglycaemia and weight gain or even inducing weight loss or controlling postprandial hyperglycaemia, and so on, depending on the specific individual needs. Of course, every strategy warrants confirmation by the further course, in that, every office visit of the patient should be seen as a chance to revisit the treatment concepts and modalities. The ultimate goal is always to meet and maintain the glycaemic (near normal) targets safely and gently, especially in the patient with heart disease or other significant organ damage. Perspectives There is no magic bullet in the pipeline with regard to blood-glucose-lowering therapy. Some progress is anticipated from longer-acting GLP-1-analogues, which require injection only once a week and seem to promise a fairly stronger blood-glucose-lowering effect and lesser burden of nausea and diarrhoea. The next new class of drugs reaching the market place is expected to be the sodium–glucose transporter-2 (SGLT-2) inhibitors which increase renal glucose excretion. Overall, however, the concept of differential therapy on the individual level for blood- glucose-lowering therapy, which may be particularly complex in the patient with co-existing CVD, will not change in the near future. Furthermore, it must be reiterated over and over that a shift of paradigm is urgently awaited in that the demonstration of a significant blood-glucose-lowering capacity alone is not sufficient: this capacity must translate longer term also in a significant reduction of CVD and other diabetes-related organ complications, as confirmed by adequate randomised trials. References 1. Graham I, Atar D, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). European Journal of Cardiovascular Prevention and Rehabilitation 2007; 14(Suppl. 2): S1–S113. *2. Ryden L, Standl E, Bartnik M et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Diab Stoffw Herz 2007; 16(Suppl. C): C3–C74. 3. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006; 49: 1711–1721. 4. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009; 52: 17–30. 5. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Update regarding the thiazolidinediones. Diabetologia 2008; 51: 8–11.
410
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
*6. Rodbard HW, Blonde L, Braithwaite SS et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocrine Practice 2007; 13(Suppl. 1): 1–68. *7. Standl E & Schnell O. A new look at the heart in diabetes mellitus: from ailing to failing. Diabetologia 2000; 43: 1455–1469. 8. Kahn SE, Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. New England Journal of Medicine 2006; 355: 2427–2443. 9. Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New England Journal of Medicine 2008; 358: 2560–2572. 10. Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. New England Journal of Medicine 2003; 348: 383–393. *11. Gaede P, Lund-Andersen H, Parving HH et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. New England Journal of Medicine 2008; 358: 580–591. 12. Booth GL, Kapral MK, Fung K et al. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. 13. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. New England Journal of Medicine 1998; 339: 229–234. *14. Coutinho M, Gerstein HC, Wang Y et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233–240. 15. Danaei G, Lawes CM, Vander Hoorn S et al. Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment. Lancet 2006; 368: 1651–1659. *16. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine 2008; 359: 1577–1589. 17. Effect of intensive diabetes management on macrovascular events and risk factors in the diabetes control and complications trial. American Journal of Cardiology 1995; 75: 894–903. 18. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. New England Journal of Medicine 1993; 329: 977–986. 19. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. New England Journal of Medicine 2005; 353: 2643–2653. 20. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet 1999; 354: 617–621. 21. Qiao Q, Nakagami T, Tuomilehto J et al. Comparison of the fasting and the 2-h glucose criteria for diabetes in different Asian cohorts. Diabetologia 2000; 43: 1470–1475. *22. Bartnik M, Ryden L, Ferrari R et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro heart survey on diabetes and the heart. European Heart Journal 2004; 25: 1880–1890. 23. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–412. 24. Hu FB, Stampfer MJ, Haffner SM et al. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002; 25: 1129–1134. 25. Hu DY, Pan CY & Yu JM. The relationship between coronary artery disease and abnormal glucose regulation in China: the China heart survey. European Heart Journal 2006; 27: 2573–2579. 26. Juutilainen A, Lehto S, Ronnemaa T et al. Similarity of the impact of type 1 and type 2 diabetes on cardiovascular mortality in middle-aged subjects. Diabetes Care 2008; 31: 714–719. 27. Standl E & Stiegler H. Microalbuminuria in a random cohort of recently diagnosed type 2 (non-insulin-dependent) diabetic patients living in the greater Munich area. Diabetologia 1993; 36: 1017–1020. *28. Standl E, Balletshofer B, Dahl B et al. Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich general practitioner project. Diabetologia 1996; 39: 1540–1545. 29. Stettler C, Allemann S, Juni P et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: metaanalysis of randomized trials. American Heart Journal 2006; 152: 27–38. 30. Holman RR, Paul SK, Bethel MA et al. Long-term follow-up after tight control of blood pressure in type 2 diabetes. New England Journal of Medicine 2008; 359: 1565–1576. 31. DECODA Study Group. Prevalence of the metabolic syndrome in populations of Asian origin. Comparison of the IDF definition with the NCEP definition. Diabetes Research and Clinical Practice 2007; 76: 57–67. 32. Chiasson J-L, Josse RG, Gomis R et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359: 2072–2077. 33. Otter W, Kleybrink S, Doering W et al. Hospital outcome of acute myocardial infarction in patients with and without diabetes mellitus. Diabetic Medicine 2004; 21: 183–187. *34. Anselmino M, Ohrvik J, Malmberg K et al. Glucose lowering treatment in patients with coronary artery disease is prognostically important not only in established but also in newly detected diabetes mellitus: a report from the Euro Heart Survey on Diabetes and the Heart. European Heart Journal 2008; 29: 177–184. 35. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. New England Journal of Medicine 2009; 360: 129–139. 36. Dluhy RG & McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. New England Journal of Medicine 2008; 358: 2630–2633. 37. Malmberg K, Ryden L, Wedel H et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. European Heart Journal 2005; 26: 650–661. 38. Califf RM, Boolell M, Haffner SM et al. Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial. American Heart Journal 2008; 156: 623–632.
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
411
39. Gerstein H, Yusuf S, Riddle MC et al. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). American Heart Journal 2008; 155: 26–32. 32 e21–e26. *40. Ryden L, Standl E, Bartnik M et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). European Heart Journal 2007; 28: 88–136. 41. Wilcox R, Kupfer S & Erdmann E. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone clinical trial in macro vascular events (PROactive 10). American Heart Journal 2008; 155: 712–717. 42. Nissen SE & Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine 2007; 356: 2457–2471.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem
9
The impact of glucose-lowering therapy on cardiovascular outcomes Eberhard Standl, Professor *, Martin Mu¨ller, MD, Oliver Schnell, Professor ¨dter Landstrasse 1, 85 764 Munich Neuherberg, Germany Munich Diabetes Research Institute at the Munich Helmholtz Center, Ingolsta
Keywords: diabetes blood glucose lowering HbA1c hypoglycaemia weight gain cardiovascular morbidity and mortality
Despite some controversies, especially in 2008, evidence is mounting by a number of randomised controlled trials in recent years that blood-glucose-lowering therapy (as an integral part of multifactorial therapy) reduces cardiovascular disease (CVD) for longer term, both in type 1 and type 2 diabetes. In particular, cardiovascular events are reduced by approximately 10–15% per 1% absolute reduction of HbA1c, on top of other CVD-risk-reducing therapies. With regard to mortality, the situation is less clear, as those intervention studies need at least a 10-year follow-up. In fact, some risks involved with blood-glucose-lowering therapy, for example, hypoglycaemia and weight gain, especially in patients with prior CVD, may also impact unfavourably on (cardiovascular) mortality. Therefore, blood glucose lowering is a highly individualised therapy with a target for HbA1c 7.0% or 6.5%, which takes time to tailor (poly-)pharmacotherapy gently to the patient’s needs. Drug-specific effects, both advantageous and disadvantageous, of blood-glucose-lowering therapy cannot be excluded currently and warrant further studies. Ó 2009 Elsevier Ltd. All rights reserved.
In theory, it nearly sounds like a ‘no-brainer’ that blood-glucose-lowering therapy should have a beneficial impact on the outcome of patients with diabetes and heart disease, given the overwhelming evidence of an excessive and massive risk of cardiovascular disease (CVD) associated with diabetes mellitus in human subjects. In fact, diabetes mellitus has been rated as an equivalent of coronary artery disease by several scientific associations and the corresponding guidelines.1–6 In reality, however, the linkage between heart disease and diabetes seems to be much more complex and,
* Corresponding author. Tel.: þ49 89 3187 3173; Fax: þ49 89 3081733. E-mail address: [email protected] (E. Standl). 1521-690X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.03.010
402
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
indeed, multifactorial beyond the issues of glycaemic control, such that an exclusive ‘glucocentric’ therapy may not suffice to ensure an improved cardiovascular (CV) prognosis.7 Furthermore, the results of several long-term intervention trials released recently have reminded us that potential risks associated with blood-glucose-lowering therapy, in particular, the risk of serious hypoglycaemia, may outweigh the benefits of blood-glucose-lowering therapy in certain patients and that this downside may be drug specific.8,9 In all, a highly individualised blood-glucose-lowering therapy as an integral component of multifactorial therapy appears to be key to maximise benefits in terms of an improved outcome and to avoid serious side effects.10,11 This article attempts to evaluate the present evidence of pros and cons of blood-glucose-lowering therapy and to provide some guidance for a successful approach to glycaemic control in patients with heart disease and diabetes mellitus. Hyperglycaemia and cardiovascular disease (CVD): epidemiological observations Compelling evidence has been accumulated that hyperglycaemia is closely and independently related with excessive morbidity and mortality of CVD.12,13 This involves all components of the ‘glucotriade’, that is HbA1c, fasting plasma glucose and postprandial or post-load plasma glucose.14–21 The relationship has to be seen as a continuum and starts already within the glycaemic range below the present cut-off for the definition of (ouvert) diabetes mellitus. The latter notion poses a particular challenge for early diagnosis of asymptomatic diabetes (and the related treatment) and contrasts with the findings as for the more diabetes-specific microvascular changes, for example, retinopathy and nephropathy, which rarely emerge before the manifestation of diabetes mellitus.22–25 The overall risk of CVD for people with diabetes increased two- to threefold in men, and three- to fivefold in women when compared to people without diabetes.26 Approximately 50–70%, depending on the methodology of assessment, of all people with diabetes (both type 1 and type 2), die due to CVD.26,27 As type 1 diabetes appears to be a more ‘pure’ paradigm of exclusive hyperglycaemia, it is not surprising that the relationship of hyperglycaemia not only with microangiopathy, but also with macroangiopathy seems to be stronger in type 1 diabetes compared to type 2 diabetes.26,28 Recent results from a large Finnish database showed that for every 1% increase of HbA1c, CVD mortality increased by about 50% in type 1 diabetes, whereas only by about 10% in type 2 diabetes.26 The landmark United Kingdom Prospective Diabetes Study (UKPDS) of a large cohort of newly diagnosed people with type 2 diabetes has indicated a 16% increased risk of myocardial infarction for every unit (%) increase of HbA1c.16 A global meta-analysis of all worldwide available epidemiological data for mortality from ischaemic heart disease in relation to fasting plasma glucose (FPG) has demonstrated an overall increase of 20% for every 1 mmol l1 increase of FPG above the optimum level.29 This excessive risk went up even to 40% in the age group below 60 years.29 Another analysis revealed that both men and women with diabetes develop the same rates of acute myocardial infarction at an age 20 years earlier compared to their non-diabetic gender counterparts.13 Extrapolating from these epidemiological observations, it is clear that blood-glucose-lowering therapy inducing a 1% decrease of HbA1c or a 1 mmol l1 decrease of FPG (and even this modest decrease of glycaemia seems to be a high hurdle in many randomised prospective studies) cannot achieve more than a 10–20% reduction of serious CVD events.28 In view of the high event rates of CV complications in diabetes, this may still represent a clinically meaningful outcome improvement, in terms of randomised studies; however, large patient numbers are required to detect statistically significant differences and – very crucial – a sufficiently long follow-up observation period. Based on the epidemiological evidence, one can conclude that it takes at least 8–10 years of treatment to find significant effects – if not longer.16,19,30 The recently published ‘Legacy effect’ of blood-glucoselowering therapy in preventing myocardial infarction and mortality in the UKPDS was unquestionable after a mean observation period of 18.5 years, an advantageous effect on macrovascular disease which had been heavily debated 10 years earlier.16 The time/effect relationship of improved blood glucose control on macrovascular disease seems to be similar in type 1 diabetes, as seen in the cohort of the Diabetes Control and Complication Trial (DCCT) after a mean observation period of 17 years.19 Even with the multifactorial approach, including blood-glucose-lowering-therapy as applied in the Steno 2 trial, it takes time: after 4 years in the study, only microvascular complications were reduced; it needed 7.8 years to substantiate the macrovascular benefits; and an observation time of 13 years to reveal an
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
403
impressively reduced mortality.10 This dependence on rather long-term studies poses a high challenge for randomised controlled trials to explore macrovascular outcomes. On the other hand, CVD alterations may be present, and to an abundant extent, at diagnosis of diabetes. In fact, epidemiological evaluations have indicated that up to 15 years prior to the diagnosis of diabetes the risk of macrovascular morbidity is already elevated.24 The causes for this excessive risk again seem to be complex: long-time undiagnosed diabetes, the association of type 2 diabetes with metabolic syndrome and the impact of especially impaired glucose tolerance (IGT), to name just a few. It is very clear from analysis of huge databases from many sources that the higher the 2-h post-load glucose levels, though below the threshold of ouvert diabetes, the higher the risk for macrovascular disease. This association has been found to be significantly stronger than in the event of an increasing elevation of fasting blood glucose level in relation to macrovascular disease.20,31 Of late, this notion has also sparked the debate over whether the present criteria for diagnosing diabetes should be lowered or not. Several intervention trials, therefore, have looked into whether the prevention of diabetes at the level IGT is also preventive for CVD.32 Most of the larger trials are still ongoing (see below). Finally, and astoundingly, the concentration of a single, random blood glucose measurement in the acute condition of macrovascular complications, for example, acute myocardial infarction, was found highly predictive whenever investigated, both for the short-term prognosis during hospital stay and long term over several years.33 Again, although somewhat controversial, IGT seems to carry an increased risk, especially in longer term.22,34 Results of intervention trials Presently, it is beyond doubt that lowering blood glucose is highly successful to prevent microangiopathy, for example, retinopathy, nephropathy and neuropathy, both in type 1 and type 2 diabetes. It may, however, take a longer time than expected, and there may be even some worsening early on in patients with pre-existing disease, but it clearly pays off over time in terms of preventing and reducing microvascular diabetic complications.16,19 Therefore, sufficient glycaemic control is warranted in every diabetes patient with some degree of life expectancy. Evidence suggests that maintaining glycaemic control at an HbA1c range of at least 7.5% will prevent most patients from developing serious microangiopathic sequelae. Care should be taken to avoid too rapid, overaggressive lowering of blood glucose, especially in patients with pre-existing significant retinopathy or neuropathy and/or with a tendency to encounter more severe hypoglycaemia. Recently, the results of ADVANCE have demonstrated that aiming at and attaining even lower HbA1c values in patients with type 2 diabetes, that is 6.5%, yields additional microvascular renal outcome benefits, and can be achieved safely and with very little risk of hypoglycaemia and weight gain, and certainly without any risk of excessive mortality.9 Interestingly enough, this additional benefit compared to a more conventionally treated randomised control group with an average HbA1c value of about 7.3% was fully additive to intensive blood-pressure-lowering therapy and also apparent in the subgroup on statin therapy. The number needed to treat, however, to achieve this additional benefit was not overly impressive and was approximately 50 for the 5-year observation period.9 The landmark studies to underpin the effectiveness of blood-glucose-lowering therapy to reduce not only microvascular, but also CV complications of diabetes have already been introduced: the DCCT for type 1 diabetes and UKPDS for (newly diagnosed) type 2 diabetes.16,19 The most striking long-term ‘legacy effects’ of lowering blood glucose, however, evolved in both the studies during the open poststudy observation period. On the other hand, all the available prospective randomised data sources in 2006 have been subjected to a meta-analysis and clearly showed a significant effect in both types of diabetes: some 60% reduction for any macrovascular end point in type 1 diabetes and a still significant reduction of approximately 15% in type 2 diabetes.29 Therefore, clearly, the effectiveness in type 1 diabetes can be taken as a proof of principle, whereas the effect was also detectable in type 2 diabetes, and actually within the expected range for a 1% decrease of HbA1c. It seems noteworthy that, according to this meta-analysis, the effectiveness in type 2 diabetes apparently varied across the main target areas of macrovascular complications: it was more marked for cerebrovascular and peripheral vascular disease, and only of borderline significance for CVD. In the latter context, recently published results of the Euro Heart Survey ‘Diabetes and the Heart’ seem to be more reassuring.34 Patients with established
404
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
coronary artery disease, be it acute or chronic, and newly diagnosed diabetes on this occasion showed a much better prognosis over the next year when (usually oral) blood-glucose-lowering pharmacotherapy was implemented at that time compared to the chance group of patients with identical baseline characteristics, but whose diabetes was not treated (by drugs) and only followed up.34 These results are highly suggestive that blood-glucose-lowering therapy can make a beneficial difference even rather short term in some group of patients with newly diagnosed diabetes and a high risk for further complications of CVD, although the limitations of these survey data are also clear in that they were not obtained from a randomised controlled trial with no information available about metabolic control and adherence to non-pharmacological lifestyle therapy. Therefore, undoubtedly more and longer-term randomised trials were and are urgently needed to further explore the CVD benefits of blood-glucose-lowering therapy in type 2 diabetes, whereas most scientific associations and the according ‘evidence-based guidelines’ had recently settled to recommend an overall glycaemic target range of an HbA1c value either 7.0% or 6.5% (DCCT standard), and the corresponding target ranges for blood glucose.1–6 In 2008, however, a triade of randomised studies, that is, studies with the acronyms ACCORD (Action to Control CardiOvascular Risk in Diabetes), VADT (Veterans Affairs Diabetes Trial) and ADVANCE, based on a total of about 23 000 type 2 diabetic patients and a mean follow-up between 3.5 and 6.5 years, have reported conflicting results on macrovascular outcomes, including mortality in the context of various blood-glucose-lowering regimes.9,11,19,35 ACCORD/VADT/ADVANCE: have the targets for HbA1c changed? Disturbing news have come particularly from ACCORD where the intensive treatment arm had to be stopped after a mean of 3.5 years in the study due to excessive mortality (1.4% vs. 1.1% annually in the less intensive arm, hazard ratio 1.22, confidence interval (CI) 1.01–1.46).9 Although the overall mortality was unusually low for a group of diabetes patients of this age and CVD risk, this borderline difference was of concern, as it was also reflected in an increased CV mortality.9 The intensive group had followed the intention to avoid failure of attaining glycaemic goals as in UKPDS, in which also the so-called intensive treatment arm exhibited a mean HbA1c value of approximately 8% at the end of the randomised study period.9 In fact, a perhaps overaggressive treatment algorithm was enforced in ACCORD aiming at a rather ambitious goal for HbA1c 6.0%. Indeed, the HbA1c levels fell dramatically in a short period of time from a mean of 8.1% to 6.4%. Table 1 lists the macrovascular outcomes assessed in all the three intervention trials together with the achieved hazard ratios for the primary macrovascular outcomes and for total mortality. Although non-significant for the individual study, there was a consistent trend across all the three studies for a favourable reduction of the respective composite macrovascular outcomes in
Table 1 Hazard ratios: overview VADT, ADVANCE, ACCORD.
VADT
ADVANCE
ACCORD
Definition of primary outcome
Hazard ratio for primary outcome (95% CI)
Mortality findings
Non-fatal MI, Non-fatal stroke, CVD death, hospitalization for CHF Revascularization Microvascular plus macrovascular outcomes (Non-fatal MI, Non-fatal Stroke, CVD)
0.87% (0.73 to1.04)
Hazard ratio 1.065 (0.801, 1.416)
0.9 (0.82 to 0.98) Macrovascular: 0.94 (0.84 to 1.06) 0.90 (0.78 to 1.04)
Hazard ratio 0.93 (0.83 to 1.06)
Non-fatal MI Non-fatal Stroke CVD Death
Hazard ratio 1.22 (1.01 to 1.46)
VADT: Duckworth W, Abraira C, Moritz T, et al. (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360: 129–139. ADVANCE: Patel A, MacMahon S, Chalmers J, et al. (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358: 2560–2572. ACCORD: Nathan et al. (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353: 2643–2653.
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
405
relation to more intensive blood glucose therapy and lower HbA1c levels, with a hazard ratio of about 0.9.9,19,35 In light of this uniform trend, one would like to see the result of an appropriate meta-analysis of all the three studies. At variance, however, were the observed total mortality rates, which was – as mentioned – unfavourable in ACCORD (despite the fact that CVD death was also a component of the overall beneficial trend for macrovascular outcomes there), more or less neutral in VADT and advantageous in ADVANCE.9,19,35 Table 2 compares some features of the most diverse studies, ACCORD and ADVANCE.36 As can be seen, as a consequence of the perhaps overaggressive treatment algorithm, most patients were on a quintuple therapy with intensified insulin therapy (multiple injections of short-acting and longacting insulins), a sulphonylurea, metformin and an insulin sensitiser in the intensive arm of ACCORD. In contrast, polypharmacy was much less pronounced in ADVANCE with a less ambitious HbA1c goal of 6.5%, much less insulin usage and very little use of insulin sensitisers (only 17% of patients in the intensive arm of ADVANCE vs. 92% in ACCORD). Hence, it does not seem surprising that assistance requiring hypoglycaemia amounted to an astronomically high 16.2% over the study period in the intensive arm of ACCORD (a figure which is some 2.5 times higher compared to the experience in UKPDS), and 28% of all patients gained more than 10-kg weight, whereas assistance requiring hypoglycaemia was below 1% per year in ADVANCE with no weight gain present on average.9,19 It has been stated that no single factor in ACCORD could be sorted out and made accountable for the excess CVD and total mortality, including hypoglycaemia.19 Perhaps the smallest of the three studies, VADT, might give clues to the conflicting results seen in those studies.9 Again, VADT was heavily leaning towards high usage of intensified insulin therapy in conjunction with an insulin sensitiser, a sulphonylurea and metformin; once again hypoglycaemia was a problem, and severe hypoglycaemia was tracked down as an independent predictor of both CV death and the primary macrovascular outcomes with the highest hazard ratio of all predictors.9 In addition, the VADT investigators found an interesting relationship between known diabetes duration and the hazard ratios for CVD events with intensive therapy (p < 0.0001).9 While with a short duration of diabetes at baseline, there clearly was a beneficial trend, which seemed to vanish over time, however, and reached a break-even point after 15 years of known diabetes duration at baseline, beyond which the potential downsides of intensive therapy seemed to outweigh the benefits. In a subset of patients, VADT investigators also assessed coronary calcifications and observed that at low calcium scores intensive treatment was advantageous, whereas at high calcium scores the opposite was found.9 This notion also seems to have a reflection in a subgroup analysis in ACCORD: the two-thirds of the 10 251 patients without a prior history of CV events clearly seemed to benefit from intensive therapy, in contrast to the one-third with known prior CV events.9 In addition, patients with lower HbA1c levels at baseline did seem to benefit the most, whereas patients with a higher HbA1c at start did not.9 All this combined raises the possibility that especially the ‘vulnerable’, pre-injured heart is at risk for the potential complications and downsides of Table 2 Differences between the ACCORD and ADVANCE studies. Characteristic
ACCORD
ADVANCE
Baseline N Mean age (Y) Duration of diabetes (Y) Median HbA1c at baseline History of macrovascular disease (%)
10,251 62 10 8.1 35
11,140 66 8 7.2 32
<6.0 3.4
6.5 5.0
77 95 87 92
41 vs 24 74 vs 67 94 vs 62 17 vs 11
Intervention Target HbA1c (%) Median duration (Y) Medical treatment at study completion (intensive vs standard) (%) Insulin Metformin Secretagoue (sulphonylurea or glinide) Thiazolidinedione Dluhy et al. N Engl J Med 2008; 358: 2630–3.
vs 55 vs 87 vs 74 vs 58
406
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
a too aggressive blood-glucose-lowering therapy, in particular, hypoglycaemia which seems to be mainly driven by a high-dose insulin therapy, perhaps in conjunction with an insulin-sensitising agent or a sulphonylurea. Of course, all these deliberations are only to generate hypothesis since they were made post hoc and based on subgroup analysis. They fit, however, in the context of recent results from the DIGAMI 2 Trial and the Euro Heart Survey ‘Diabetes and the Heart’.22,37 DIGAMI 2 patients with diabetes and an acute coronary syndrome have been randomly assigned to new insulin therapy. The 2-year follow-up results indicated that the patients on insulin were associated with a higher risk for non-fatal myocardial infarction and stroke and also for the composite of death and non-fatal myocardial infarction or stroke.37 The impact of in-hospital hypoglycaemia during the acute condition was also evaluated in terms of the longer-term mortality and CV events. Although there was a connection, it was thought that hypoglycaemia was mainly a surrogate of other high-risk factors for CVD and mortality and the effect, therefore, inconclusive. On the other hand, metformin-based therapy was associated with the most favourable outcomes.37 Similarly, in the Euro Heart Survey, noninsulin-based therapies were related to a more advantageous 1-year outcome compared to insulinbased therapies.22 Therefore, in summary of the discussions over the findings in ACCORD/VADT/ADVANCE, it may be stated that, although the need for further well-planned randomised trials has become even more evident, the initially conflicting results seem to follow a currently widely accepted logic. The practical implications for the present-day blood-glucose-lowering therapy may be outlined as follows: 1) In particular, in view of the prevention of microvascular complications, there is no need for a change of HbA1c targets (7% or 6.5%, respectively), but there is a need to go slow, especially in patients with pre-existing CVD and very high baseline HbA1c levels - Side effects, such as hypoglycaemia and weight gain, need to be avoided. 2) Early treatment and prevention appears to give the best results 3) Drug-specific effects, both advantageous and disadvantageous, of blood-glucose-lowering pharmacotherapy cannot be excluded currently and therefore warrant further studies 4) The beneficial effects of improved blood glucose control on CVD do emerge in longer term and there is a ‘legacy effect’ (metabolic memory) Does prevention of diabetes prevent CVD? The jury is still out whether prevention of diabetes, particularly at the level of IGT, also prevents CVD. At present, this is more a research-oriented question of high theoretical interest, and awaits further substantiation, before it could lead to a practical indication. The first study to underpin this possibility was the randomised StopNIDDM trial which sought to prevent the manifestation of type 2 diabetes by the use of acarbose and where CVD outcomes were also a pre-specified secondary objective.32 After a mean follow-up of 3 years, there was an absolute risk reduction not only for diabetes of 11%, but also for any CVD end point, especially myocardial infarction.32 Overall event numbers were low, however, and no such observation was made in other prevention trials, for example, DPP2 or DPS37,38 Interestingly enough, in 2008, the 20-year outcome results of the entirely lifestyle-based DaQuing prevention trial was made available.25 Although vanishing during the second decade, still a highly significant preventive effect of the lifestyle intervention earlier on was detectable in terms of diabetes manifestation, while in terms of prevention of CVD death a rather suggestive preventive effect emerged over the second decade which was reminiscent of the legacy effect of glucose control in UKPDS.16 Again, unfortunately, due to small overall numbers this effect failed to reach statistical significance. Therefore, the onus would be on the still-ongoing or recently started prevention trials, such as Outcome Reduction with Initial Glargine Intervention (ORIGIN), Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) or Acarbose Cardiovascular Evaluation (ACE), to prove whether prevention of type 2 diabetes – it is often said that this is only ‘masking’ diabetes by pharmacotherapy – materialises in the prevention of CVD as well.38,39
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
407
Drug-specific cardiac issues of blood-glucose-lowering therapies ‘Reach and maintain glycaemic goals safely and gently, avoid serious side effects’, must be the current policy for blood-glucose-lowering therapy. Often, this leads to a highly individualised therapy, as there is no ‘golden’ algorithm. This was also the main recommendation of the First Joint EASD/ESC Guidelines ‘Diabetes, Pre-Diabetes and Cardiovascular Diseases’.40 Depending on the conditions of the individual with regard to specific organ damage, metabolic phenotype and stage of diabetes, the appropriate mix of non-pharmacological and pharmacological options should be tailored to the particular needs (Table 3). As may be seen and already discussed in this article in detail, heart-related issues may play an important modifying role for the appropriate choice. Adequate lifestyle, self-control and empowerment are the foundation good treatment. Metformin, although not uncriticised, has been associated with the most favourable cardiac outcomes, for example, in UKPDS, Digami 2 and others.16,37 It holds the pole position in monotherapy. It may have some unpleasant gastrointestinal side effects, is contraindicated in patients with a GFR < 50 ml or high risk of severe hypoxaemia and has to be stopped 1 day prior to the exposure to contrast media. It can be re-instituted later, provided there is a stable and sufficient circulatory function. All remaining options, including insulin, are for (early) combination with metformin or an alternate option, when metformin is contraindicated or not tolerated (some 50% of all cases with type 2 diabetes). Sulphonylureas, in particular glibenclamide, are often burdened with some degree of hypoglycaemic risk (about 30% of all treated cases) and weight gain. The combination with metformin and a potential influence on cardiac K-channels and on ischaemic remodelling have been under debate. Compared to metformin, epidemiological evaluations have yielded less favourable outcomes. On the other hand, the positive effects in ADVANCE and the ‘legacy effect’ in UKPDS have been substantiated in randomised trials with sulphonylureas.9,16 Short-acting sulphonylurea analogues, that is ‘gliptins’, are also available. In theory, they should offer a lesser risk of hypoglycaemia, but appropriate randomised trials are lacking, and especially studies demonstrating a long-term CVD benefit. The alpha-glucosidase-inhibitor acarbose seems to have a rather advantageous risk/benefit ratio. The CVD benefits are opposed only by a few gastrointestinal side effects (in about 30% of all treated cases), which do afford ‘gentle’ skills when introducing or stepping up this therapy, but certainly not by serious side effects such as hypoglycaemia or weight gain.32 Insulin sensitisers (thiazolidindiones (TZDs) or glitazones) are well tolerated by patients and do not induce hypoglycaemia but are noted for inducing weight gain, which seems to be a mix of true (subcutaneous) weight gain and some fluid retention in prone patients. TZDs are contraindicated in patients with heart failure. Pioglitazone has been shown associated with significant CVD benefits in the Prospective Pioglitazone Clinical Trial in Macro Vascular Events (PROACTIVE) trial and in a large metaanalysis, though the risk to develop signs of heart failure is somewhat elevated.41 No such CVD benefits
Table 3 Present approach to diabetes management in type 2 diabetic patients. Consult endocrinologist/diabetologist for - structured education - blood glucose self monitoring (also pp glucose) - appropriate nutrition counselling - pharmacotherapy discussiong pros and cons
Insulin Metformin sulfonylureas Alpha-glucosidase-inhibitors glitazones glinides Incretin based agents
Benefits
Caveats
yes yes yes yes Yes/? ? ?
Heart? Impaired kidney function Cardiac K-channels? CHF, ?CAD rosiglitazone
408
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
have been demonstrated so far in relation to rosiglitazone.42 In fact, there have been concerns for ischaemic cardiac changes earlier on, which have not been confirmed in larger trials including the already-discussed ACCORD and VADT.19,35 The regulatory authorities have rated the situation inconclusive as yet , but certainly there is no excess mortality related to rosiglitazone treatment. Combination of metformin with basal insulin, which can be stepped up to more intensive insulin therapy as deemed necessary by adding prandial insulin, is a very well-explored option and widely recommended in various guidelines. The potential downsides are weight gain and hypoglycaemia if overdosed. Home glucose monitoring is an essential part of this type of therapy. The legacy effect of blood-glucose-lowering therapy on reduced rates for mortality and myocardial infarction in UKPDS were to 50% also associated with an initially randomly assigned basal insulin therapy.16 On the other hand, the problems encountered in ACCORD and VADT also particularly seemed to be insulin triggered, most likely in connection with hypoglycaemia, and appear to be of concern especially in patients with prior CVD.19,35 In addition, they seem to have reflections in results from DIGAMI 2, the Euro Heart Survey ‘Diabetes and the Heart’ and observations in heart failure patients.37 This issue needs urgent clarification by appropriate randomised trials. Incretin-based therapies are the latest addition to the armamentarium of blood-glucose-lowering therapy over the last 3 years. At present, there are no long-term CVD outcome results available yet. Based on theory and experimental work, they should be beneficial. The advantages include the absence of hypoglycaemic risk and weight neutrality for the dipeptidyl peptidase IV (DPP-IV) inhibitors or even significant weight loss for the glucagon-like peptide-1 (GLP-1) analogues. While DPP-IV inhibitors are available as oral agents, the latter need to be injected once or twice a day.. Both classes of drugs are usually well tolerated, apart from nausea and diarrhoea related to the administration of GLP-1 analogues by virtue of their complex mode of action. No specific home glucose monitoring is needed.
Early combination to maximise efficacy and to minimise side effects All available drug options provide a (placebo-subtracted) HbA1c decrease of around 1% (Table 4), <1% (e.g., acarbose, DPP-IV-inhibitors and nateglinide) and >1% (metformin, sulphonylureas and insulin). Due to the increasing demand for lowering HbA1c, double combinations and even triple therapies are a frequent practical necessity. As the underlying mode of actions are different for each class of drugs, so are the underlying pathogenetic abnormalities in type 2 diabetes different and multiplex; the HbA1c-lowering capacity of each class of drug is usually fully additive in combination. Since for most drug options at a medium dose already 70–80% of the maximum HbA1c lowering effect is achieved, it is advisable to begin early combination therapy instead of administering the highest dose of a single drug and thereby inducing increasing side effects. The early combination approach maximises glycaemic control and minimises side effects. Avoiding side effects, especially hypoglycaemia, perhaps also excess weight gain, seems to be a priority of present-day blood-glucose-lowering therapy. Therefore, the first step in deciding on the
Table 4 Mean efficacy of pharmacological treatment options in patients with type 2 diabetes. Drug
Mean lowering of initial HbA1c (%)
Incretin Enhancers GLP-1 Analoga Alpha-glucosidase inhibitors Biguanides Glinides Glitazones Insulin Sulfonylurea derivates CB1-Rezeptor Antagonist
0.7–1.0 w1.0 0.5–1.0 1.0–1.5 0.5–1.5 1.0–1.5 1.0–2.0 1.0–1.5 0,7
Ryden L, Standl E, Bartnik M, et al. (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Diab Stoffw Herz 16 Suppl C: C3–C74.
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
409
Table 5 Suggested policy for the selection of glucose-lowering therapy according to the glucometabolic situation. Post-prandial hyperglycaemia Fasting hyperglycaemia Insulin resistance Insulin deficiency
Alpha-glucosidase inhibitors, short-acting sulfonylureas, glinides, DPP 4 inhibitors, GLP1 analogs, short-acting regular insulin, or insulin analogs Biguanides, long-acting sulfonylureas, glitazones, long-acting insulin, or insulin analogs Biguanides, glitazones, alpha-glucosidase inhibitors Sulfonylureas, glinides, DPP 4 inhibitors, GLP1 analogs, insulin
Ryden L, Standl E, Bartnik M, et al. (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Diab Stoffw Herz 16 Suppl C: C3–C74.
pharmacotherapy of a specific patient is to exclude all drug options which are contraindicated or may be counterproductive on the individual level. Step two should explore the specific metabolic phenotype at the present situation: Are the glycaemic problems mainly due to insulin resistance or insulin deficiency? Are they mainly present in the fasting state or in the postprandial situation? This will then guide the most appropriate choice in this moment (see also Table 5). Certainly, there are also other very important factors such as patient preference and quality-of-life aspects, for example, as related to the need of injections or for frequent blood glucose monitoring. Along those lines of deliberations one can build double or triple combinations to pursue mainly reduction of insulin resistance or avoiding hypoglycaemia and weight gain or even inducing weight loss or controlling postprandial hyperglycaemia, and so on, depending on the specific individual needs. Of course, every strategy warrants confirmation by the further course, in that, every office visit of the patient should be seen as a chance to revisit the treatment concepts and modalities. The ultimate goal is always to meet and maintain the glycaemic (near normal) targets safely and gently, especially in the patient with heart disease or other significant organ damage. Perspectives There is no magic bullet in the pipeline with regard to blood-glucose-lowering therapy. Some progress is anticipated from longer-acting GLP-1-analogues, which require injection only once a week and seem to promise a fairly stronger blood-glucose-lowering effect and lesser burden of nausea and diarrhoea. The next new class of drugs reaching the market place is expected to be the sodium–glucose transporter-2 (SGLT-2) inhibitors which increase renal glucose excretion. Overall, however, the concept of differential therapy on the individual level for blood- glucose-lowering therapy, which may be particularly complex in the patient with co-existing CVD, will not change in the near future. Furthermore, it must be reiterated over and over that a shift of paradigm is urgently awaited in that the demonstration of a significant blood-glucose-lowering capacity alone is not sufficient: this capacity must translate longer term also in a significant reduction of CVD and other diabetes-related organ complications, as confirmed by adequate randomised trials. References 1. Graham I, Atar D, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). European Journal of Cardiovascular Prevention and Rehabilitation 2007; 14(Suppl. 2): S1–S113. *2. Ryden L, Standl E, Bartnik M et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Diab Stoffw Herz 2007; 16(Suppl. C): C3–C74. 3. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006; 49: 1711–1721. 4. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009; 52: 17–30. 5. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Update regarding the thiazolidinediones. Diabetologia 2008; 51: 8–11.
410
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
*6. Rodbard HW, Blonde L, Braithwaite SS et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocrine Practice 2007; 13(Suppl. 1): 1–68. *7. Standl E & Schnell O. A new look at the heart in diabetes mellitus: from ailing to failing. Diabetologia 2000; 43: 1455–1469. 8. Kahn SE, Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. New England Journal of Medicine 2006; 355: 2427–2443. 9. Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New England Journal of Medicine 2008; 358: 2560–2572. 10. Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. New England Journal of Medicine 2003; 348: 383–393. *11. Gaede P, Lund-Andersen H, Parving HH et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. New England Journal of Medicine 2008; 358: 580–591. 12. Booth GL, Kapral MK, Fung K et al. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. 13. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. New England Journal of Medicine 1998; 339: 229–234. *14. Coutinho M, Gerstein HC, Wang Y et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233–240. 15. Danaei G, Lawes CM, Vander Hoorn S et al. Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment. Lancet 2006; 368: 1651–1659. *16. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine 2008; 359: 1577–1589. 17. Effect of intensive diabetes management on macrovascular events and risk factors in the diabetes control and complications trial. American Journal of Cardiology 1995; 75: 894–903. 18. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. New England Journal of Medicine 1993; 329: 977–986. 19. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. New England Journal of Medicine 2005; 353: 2643–2653. 20. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet 1999; 354: 617–621. 21. Qiao Q, Nakagami T, Tuomilehto J et al. Comparison of the fasting and the 2-h glucose criteria for diabetes in different Asian cohorts. Diabetologia 2000; 43: 1470–1475. *22. Bartnik M, Ryden L, Ferrari R et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro heart survey on diabetes and the heart. European Heart Journal 2004; 25: 1880–1890. 23. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–412. 24. Hu FB, Stampfer MJ, Haffner SM et al. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002; 25: 1129–1134. 25. Hu DY, Pan CY & Yu JM. The relationship between coronary artery disease and abnormal glucose regulation in China: the China heart survey. European Heart Journal 2006; 27: 2573–2579. 26. Juutilainen A, Lehto S, Ronnemaa T et al. Similarity of the impact of type 1 and type 2 diabetes on cardiovascular mortality in middle-aged subjects. Diabetes Care 2008; 31: 714–719. 27. Standl E & Stiegler H. Microalbuminuria in a random cohort of recently diagnosed type 2 (non-insulin-dependent) diabetic patients living in the greater Munich area. Diabetologia 1993; 36: 1017–1020. *28. Standl E, Balletshofer B, Dahl B et al. Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich general practitioner project. Diabetologia 1996; 39: 1540–1545. 29. Stettler C, Allemann S, Juni P et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: metaanalysis of randomized trials. American Heart Journal 2006; 152: 27–38. 30. Holman RR, Paul SK, Bethel MA et al. Long-term follow-up after tight control of blood pressure in type 2 diabetes. New England Journal of Medicine 2008; 359: 1565–1576. 31. DECODA Study Group. Prevalence of the metabolic syndrome in populations of Asian origin. Comparison of the IDF definition with the NCEP definition. Diabetes Research and Clinical Practice 2007; 76: 57–67. 32. Chiasson J-L, Josse RG, Gomis R et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359: 2072–2077. 33. Otter W, Kleybrink S, Doering W et al. Hospital outcome of acute myocardial infarction in patients with and without diabetes mellitus. Diabetic Medicine 2004; 21: 183–187. *34. Anselmino M, Ohrvik J, Malmberg K et al. Glucose lowering treatment in patients with coronary artery disease is prognostically important not only in established but also in newly detected diabetes mellitus: a report from the Euro Heart Survey on Diabetes and the Heart. European Heart Journal 2008; 29: 177–184. 35. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. New England Journal of Medicine 2009; 360: 129–139. 36. Dluhy RG & McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. New England Journal of Medicine 2008; 358: 2630–2633. 37. Malmberg K, Ryden L, Wedel H et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. European Heart Journal 2005; 26: 650–661. 38. Califf RM, Boolell M, Haffner SM et al. Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial. American Heart Journal 2008; 156: 623–632.
E. Standl et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 401–411
411
39. Gerstein H, Yusuf S, Riddle MC et al. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). American Heart Journal 2008; 155: 26–32. 32 e21–e26. *40. Ryden L, Standl E, Bartnik M et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). European Heart Journal 2007; 28: 88–136. 41. Wilcox R, Kupfer S & Erdmann E. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone clinical trial in macro vascular events (PROactive 10). American Heart Journal 2008; 155: 712–717. 42. Nissen SE & Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine 2007; 356: 2457–2471.