Intensified glucose lowering in type 2 diabetes: time for a reappraisal

Obesity, urbanisation and an ageing population combine to drive a dramatic increase in the global prevalence of type 2 diabetes [1], a condition in which the morbidity and mortality from cardiovascular disease substantially outweigh the risk of microvascular complications such as renal disease [2]. Statins and antihypertensive agents lower cardiovascular risk in type 2 diabetes, but the benefits of intensified glucose-lowering remain controversial in this context—management recommendations tend to be based on extrapolation from surrogate endpoints. Recent studies have shown that intensified glycaemic control has limited impact on cardiovascular disease, but there is little indication that entrenched positions in the debate have been affected.
Intensified glucose-lowering is more difficult to achieve, and has a greater negative impact on quality of life, than lowering cholesterol or blood pressure [3]. Nonetheless, and despite questionable benefits to the individual, substantial pressure has been exerted on patients and practitioners to achieve rigorous glycaemic targets. This article examines the evidence for and against intensified glucose-lowering therapy in type 2 diabetes.
From magic bullets to risk reduction
Insulin was justifiably regarded as a near-miracle when first introduced [4], and antibiotics were equally life-saving [5]. These were true ‘magic bullets’, with a number needed to treat (NNT) of close to one. The scenario changed when drugs were given to people with no symptoms or evidence of vascular disease in order to reduce the possibility of future vascular events. Even drugs that reduce cardiovascular risk by 25%, such as the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors [6], would (assuming a 20% risk of a CVD event in 10 years), require 20 such people to be treated for 10 years to prevent one event. For any given year of treatment, 199 of 200 people would have an identical outcome with or without the drug. The benefits of such therapy are therefore more apparent at a public health level than at the level of an individual patient, a point that may be disregarded in clinical decision-making and in promotional material. Furthermore, there may be a substantial change in the risk–benefit ratio if the intervention is complex, inconvenient or associated with troublesome side effects.
Hyperglycaemia: risk marker or risk factor for cardiovascular disease?
Symptoms of type 2 diabetes are relatively easy to bring under control, and glucose-lowering treatment beyond this point is designed to reduce the risk of a variety of unwanted outcomes [2]. Let us emphasise that there are no arguments in favour of poor glucose control, since mortality increases substantially in those with HbA1c levels over 8–9%, regardless of therapy [7], and there can be no doubt that the burden of complications would be greatly reduced if all patients could maintain an HbA1c levels at around 7.5%. The point at issue relates to the benefits, costs and risks of lowering HbA1c levels from about 8%, a relatively achievable target, to about 7% or below in type 2 diabetes.
The observation that cardiovascular events are quantitatively related to a given variable does not necessarily mean that regulating the marker of risk will reduce the number of events [8]. The risk marker may be an innocent fellow-traveller, with no impact upon aetiological pathways, as has been argued for C-reactive protein and cardiovascular disease [9]. Alternatively, established damage to the vessel wall may be poorly reversible, as with blood pressure lowering in atherosclerotic vascular disease [10]. Finally, the treatment may, while lowering the level of its target risk factor, enhance cardiovascular or other risks through different mechanisms, as with clofibrate treatment for hypercholesterolaemia [11]. Risk factor interventions that completely cancel out the excess level of risk are correspondingly rare. Collins, MacMahon and co-workers compared the influence of blood pressure on coronary heart disease (CHD) risk in observational and interventional studies, and such analyses suggested that some two-thirds of the excess CHD risk conferred by elevated blood pressure is reversed by treatment in intervention trials of about 5 years (Fig. 1) [10, 12, 13].
Fig. 1 Cardiovascular risk factors and their reduction. Data from the major observational studies of the relationship between blood pressure and CHD risk have shown that an increase in usual diastolic blood pressure of 6 mmHg is associated with a 25% increased risk of CHD [12]. Overviews of randomised drug trials for the treatment of mild to moderate hypertension published before 1993 showed a reduction in CHD events of 16% [10, 13]. The reduction of diastolic blood pressure in these studies was about 6 mmHg. The usual duration of these trials was about 5 years, implying that the mean duration of treatment before the event occurred was 2–3 years. Rx, treatment
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Cardiovascular disease and glucose control
There is a clear epidemiological relationship between levels of HbA1c and the risk of cardiovascular disease in patients with type 2 diabetes. Epidemiological data from the UK Prospective Diabetes Study (UKPDS) showed a 14% decrease in risk of myocardial infarction and 12% decrease in risk of stroke for each 1% decrease in usual mean level of HbA1c [14]. The meta-analysis of Selvin et al. reported comparable reductions of 13% and 17%, respectively, per 1% change in HbA1c [15]. Questions regarding the reversibility of this risk, first raised by publication of the University Group Diabetes Program Study [16], have taken some 40 years to resolve. To take one example, the UKPDS [2] showed a borderline significant 16% reduction in risk of myocardial infarction with intensive therapy, but a non-significant 11% increase in stroke risk, implying that even a study of 3,867 individuals treated for 10 years was insufficiently powered to enable a clear conclusion.
Three further major cardiovascular outcome studies of intensive glycaemic control in patients with type 2 diabetes have appeared over the past 2 years: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [17], the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial [18] and Veterans Affairs Diabetes Trial (VADT) [19]. None found a significant reduction in cardiovascular events in intensively treated patients, and the ACCORD study actually reported a 22% increase in total deaths in this group. The availability of data on 140,278 person-years of treatment does, however, allow more precise estimates of the impact on individual endpoints.
When the studies are combined, there is consensus that non-fatal coronary episodes are reduced by intensive control, whereas stroke, cardiovascular mortality and total mortality are unaffected [20–23]. Differences between the point estimates reached by the various meta-analyses derive from study selection and the definition of endpoints—for example whether ‘unexplained or presumed cardiovascular disease’ [17] is included as a cause of death in the category of CHD [20] or myocardial infarction [23]. Using the data from the four studies explored by the Collaborators on Trials of Lowering Glucose (CONTROL) group [23], the authors estimate that intensified glycaemic control, with a mean reduction of about 0.9% in HbA1c, is associated with a significant 9.7% reduction in CHD events, and a non-significant 4% reduction in the risk of stroke (Table 1; Electronic supplementary material [ESM] Table 1). Estimates for total and cardiovascular mortality are unchanged with intensified glycaemic control (ESM Table 1). These analyses concur with observational data suggesting that the nadir of mortality in people with type 2 diabetes occurs at an HbA1c level of 7.5% [7]. They also do not allow for the possibility that therapies such as metformin might produce substantial reductions in cardiovascular events and in all-cause mortality independent of glucose lowering [24].
Table 1 The epidemiological and interventional relationships of cholesterol, blood pressure and HbA1c with cardiovascular disease
Epidemiological data are derived from overviews of published studies on cholesterol [25], blood pressure [12] and glycaemia [15]
For each variable, the data are shown for a change corresponding to the mean change of the variable in intervention studies. Interventional data for cholesterol and blood pressure are derived from published meta-analyses [26, 27] and for glycaemia from the meta-analysis of the CONTROL Group [23] and ESM Table 1
NNT are calculated by assuming a 5 year level of risk equivalent to that of the conventional treatment limb of the meta-analysis (CHD 7.4%, stroke 3.3%, see ESM Table 1), applying a factor of 5/4.4 (1.136) to derive these from the 4.4 year data
a CHD is defined as fatal and non-fatal myocardial infarction and sudden death
Cholesterol, blood pressure and hyperglycaemia, the three major continuously distributed risk factors for cardiovascular disease, were compared in terms of their epidemiological associations and their reversibility [22]. Table 1 shows the observed relationship between these three variables and the incidence of CHD and stroke in major reviews [25–27]. Table 1 also provides data on the effect of risk factor lowering, obtained from meta-analyses of interventions for cholesterol [26], blood pressure [27] and glycaemia ([23]; ESM Table 1). Since the benefits of intervention are generally dependent on the degree of risk factor reduction, the units used for comparison in each case are the approximate mean changes in the variable achieved in intervention studies. The data in the table suggest that glycaemia is a substantially weaker risk factor for CHD than cholesterol or blood pressure, and very much weaker than blood pressure when it comes to stroke. All three interventions cancelled out most of the excess risk for CHD, but this was not the case with respect to stroke, for which cholesterol and blood pressure lowering appear fully to reverse the excess risk, whereas intensive glycaemic control is without significant benefit. This suggests that the benefits of cardiovascular risk reduction with antihypertensive and lipid-lowering therapies greatly outweigh the benefits of intensive glucose-lowering, especially in older patients with type 2 diabetes whose main risk is that of macrovascular complications [2].
The clinical significance of an intervention is better expressed in terms of absolute rather than relative risk reduction, and absolute risk will depend upon the background risk of the population [28]. Table 1 shows the same data translated into NNT [22] by assuming, as an example, a 5 year risk similar to those of individuals in the conventional treatment limb of the authors’ meta-analysis of glucose lowering (7.4% CHD, 3.3% stroke). In terms of overall cardiovascular risk, the number of individuals who would require 5 years of treatment to prevent one event would be 44 with cholesterol lowering, 34 with blood pressure lowering and 119 with intensive glucose-lowering. Figure 2 uses data from this meta-analysis (ESM Table 1) of studies of intensive glycaemic control to quantify likely benefit and harm in a cohort of type 2 diabetic patients treated for 5 years, and using the event rate in the conventional treatment limb of the meta-analysis. The reduction in major cardiovascular event rates of about eight per 1,000, and of (statistically insignificant) serious microvascular events of about six per 1,000, was not accompanied by a reduction in mortality. Furthermore, the approximate 14 per 1,000 reduction in complications was accompanied by an increase of nearly 50 per 1,000 in the rate of serious hypoglycaemia. The fact that studies involving more than 140,000 person-years of follow-up were needed to demonstrate the cardiovascular benefits of glucose lowering indicates the modest degree of reduction in absolute risk that has been achieved. By contrast, the first Veterans Administration study on treatment of hypertension produced a clear result after randomisation of 143 patients for a mean follow-up of about 18 months [29]. The overall lack of effect of improved glucose control is often explained on the grounds that this is of greater benefit in early than in advanced cardiovascular disease [21, 23, 30–32]. From this point of view it can be noted that the 10-year follow-up of the UKPDS, a study performed in recently diagnosed individuals, showed an absolute risk reduction of 3.4% in the incidence of myocardial infarction and stroke [31], with a NNT of 29.4 for 10 years to prevent one event, showing an effect about twice that calculated in Table 1 (NNT of 118.5 for 5 years).

Fig. 2 The influence of intensified glycaemic control on rates of macrovascular and microvascular events, mortality and serious hypoglycaemia per 5 years, and NNT, in type 2 diabetic patients. Rates of events on conventional glycaemic control regimens are derived from those for 12,729 participants of mean age 62 years with type 2 diabetes in the meta-analysis based on data from the CONTROL Group [23] and shown in ESM Table 1. These rates are indicated in red as per cent incidence during 5 years. The effects of intensified glycaemic control on macrovascular and microvascular events and on hypoglycaemia are estimated from this meta-analysis ([23] and ESM Table 1). The calculated effects of glucose lowering are shown in blue, and absolute risk reductions/increases are shown at the top of these bars per 1,000 participants treated for 5 years. NNT for benefit or harm for 5 years is shown in green and red, respectively. *Statistically significant treatment effects (CHD p = 0.03; severe hypoglycaemia p < 0.00001)
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The benefits of intensified glucose control are typically experienced over the longer term. Older patients, or those with a reduced life expectancy, will therefore experience diminishing benefit. This point is often emphasised in current guidelines, but the practical implications have not been explored in any detail. Recent studies, which have used modelling techniques to estimate the impact of glycaemic control on life expectancy, are enlightening in this respect [33, 34]. The UKPDS outcomes model estimated that intensified glucose control would increase quality-adjusted life years (QALY) by 0.27, or about 99 days [33]. Huang et al. [35] estimated that intensive control would add 106 days of life expectancy to an otherwise healthy newly diagnosed diabetic patient aged 60–64 years, decreasing with increasing comorbidities, longer duration of disease, or advancing age to only five to eight additional days. Kahn et al. modelled the impact of cardiovascular prevention in a simulated population matching that of the US [36]. This model estimated that patients with diabetes would gain an additional 2.3 QALY with reduction of HbA1c to below 7% for up to 30 years. All three models estimated life expectancy gains by factoring out the impact of the risk marker under investigation. This approach assumes full reversibility of the impact of that variable on events, an assumption which may be less valid for stroke or cardiovascular mortality than for total coronary events when it comes to glucose control (Table 1) [22, 23]. It might even be suggested on this basis that intensified glycaemic control influences the cause of death more than its rate. An alternative actuarial approach, which makes no such assumptions about reversibility, was used (in the pre-HMG-CoA reductase inhibitor era), to calculate the benefits of lipid and blood pressure treatment [8], but has not been applied to glycaemia. This analysis found that the risk factor that had the greatest impact on life expectancy, and that was most reversible, was smoking cessation. Another study using this approach explored the theoretical impact on absolute risk only of combination therapy [37].
To summarise, four large clinical trials have shown no increase in life expectancy, or indeed quality of life [38], in response to intensified diabetes therapy. Epidemiological estimates do imply relatively modest improvements in life expectancy, but highlight the fact that these will be greatest in younger and healthier patients. No demonstrated benefit is present for those with established CHD. To put this in perspective, some 65% of people with diabetes are aged 60 years or above and 38% are over the age of 70 years [39], and 80% of 65-year-old people suffer three or more chronic conditions, regardless of diabetes status [40]. Current estimates suggest that the benefits of intensified glucose-lowering therapy with respect to life expectancy in this population can be measured in days.
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Microvascular complications in type 2 diabetes
A newly diagnosed patient aged 65 years who embarks on intensified glycaemic control is substantially more likely to succumb to a cardiovascular event than to develop serious microvascular complications, but the demonstrated benefits of improved control upon microvascular outcomes must not be ignored. Both the UKPDS [2] and the Diabetes Control and Complications Trial (DCCT) [41] showed that a 1% reduction in HbA1c reduced the risk of these complications by about 25%. These considerations are more relevant for the younger patient with type 2 diabetes, but even by the age of 53 years (the mean age of enrolment for the UKPDS) the combined 10 year incidence of myocardial infarction (17.4%) and stroke (5%) was more than five times greater than the combined risk of renal failure (0.8%) and blindness (3.5%) [2]. A calculation of NNT to prevent these serious microvascular events, quantified using a meta-analysis of data from the same four major studies [2, 17–19, 42], shows that it would be necessary to treat 272 patients with intensified glycaemic control for 5 years to prevent one person developing blindness in one eye, and 627 patients for 5 years to prevent one developing renal failure, although the effect is not statistically significant for either endpoint (Fig. 2; ESM Table 1). Both the lifetime risk of these microvascular outcomes and the added benefit of improved glucose control diminish with age. As an example, a 65-year-old with new-onset diabetes who has an HbA1c of 8.0% has an estimated 2/1,000 lifetime risk of blindness, falling to less than 1/1,000 by reducing HbA1c to 7.0% (NNT 500–1,000) [43]. The authors of this analysis argue that efforts should be focused on those with HbA1c levels greater than 8%, since many more microvascular events will be prevented by this approach. The implication of these observations is that benefits accruing over decades should be taken into account in planning treatment for younger people, but that intensive glycaemic targets should be advised with some caution in older individuals [22].
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Intensified glucose control: the costs
A comparison of the cost-effectiveness of intensified control of glucose, blood pressure and cholesterol in type 2 diabetes points strongly to the same conclusion [44]. For example, the cost-effectiveness of lowering HbA1c from about 8% to 7% for a 65-year-old new-onset patient (based on UKPDS data and expressed in 1,997 US$) is $154,376 per QALY, as against $43,331 for cholesterol lowering and –$413 for blood pressure lowering. The costs of glucose control rise to $401,883 per QALY for those aged 75-84 years, and to $2.1 million over that age; in contrast, blood pressure control is cost-saving at every age below 85 years [44].
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Intensified glucose control: the risks
Hyperglycaemia differs from cholesterol and blood pressure in another important respect, namely the complexity of glucose-lowering therapy. Management of risk factors implies medication for comparatively healthy individuals. The HMG-CoA reductase inhibitors, and to some degree the newer antihypertensive agents, provide simple regimens with drugs that are relatively free from side effects. Glucose-lowering therapies are, in contrast, associated with a wide range of unwanted consequences, for example weight gain, heart failure and osteopenic fractures for the thiazolidinediones, and weight gain and hypoglycaemia for the sulfonylureas. This side of the equation is rarely taken into consideration when intensified control is advocated. Furthermore, and in stark contrast to lipid-lowering or antihypertensive therapies, intensive glucose-lowering may require several injections each day [45], requires regular fingerprick blood testing and is associated with side effects that include hypoglycaemia and loss of consciousness, and perhaps an increased future risk of dementia [46]. Our data (Fig. 2) suggest that 1,000 patients treated for 5 years would experience 47 additional hypoglycaemic events requiring assistance from another person in order to prevent about eight major (non-fatal) cardiovascular events over the same period. A study of 701 patients with type 2 diabetes assessed for quality of life ‘utilities’, where 1 corresponds to perfect health and 0 to death, rated the utility for intensified glycaemic treatment as 0.67, or the loss of one-third of full quality of life [3]. In other words, this analysis suggests that it would be necessary to treat 119, 272 and 627 diabetic patients for 5 years for each person who benefits in terms of cardiovascular, eye or renal complications, respectively, using a treatment perceived to diminish quality of life by one-third.
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Conclusions
Hyperglycaemia is a substantially weaker risk factor for CVD than cholesterol or blood pressure, and glucose-lowering interventions are correspondingly less effective. This awareness has yet to be reflected in standard guidelines [47]. Furthermore, little attention has been paid to the unwanted effects of intensified therapy, and its low utility in those with established complications or a limited life expectancy. Treatment strategies that make sense at a population level may offer little advantage to the majority of those whose lives are affected by them, and can bring considerable inconvenience. Good glucose control does indeed offer protection against microvascular complications, cataracts and neuropathy, but the added benefits of an HbA1c of 7%, as against 8%, diminish with age and life expectancy. In such instances efforts and resources would be better directed to those with higher levels of HbA1c, who have much more to gain from attention to their glucose control. Each individual should indeed be encouraged to achieve the best possible compromise between glucose control and vascular risk, but fully informed consent should be the prelude to intensified therapy. This is not achieved when benefits are grossly overestimated, or when trials are presented in terms of relative risk reductions—‘25% fewer heart attacks’. Absolute risk reduction, the corresponding NNT, and the potential gain in life expectancy, are much more relevant in such discussions [48, 49], particularly when the recommended treatment impinges upon every aspect of a person’s life.

Diabetes and mental health; the problem of co-morbidity

Until quite recently, the psychological well-being of people with diabetes remained firmly on the periphery of diabetes care. In many ways it continues to do so, with biomedical targets for improving glycaemic control and reducing the risk of the physical complications of diabetes taking priority over the emotional state of the person attending the diabetes clinic. However, there is now increasing evidence of the importance of good mental health in relation to diabetes care, both from the perspective of the individual managing their condition as well as in terms of the implications for service provision. Recent research has shown that at least one third of people with diabetes suffer from clinically relevant depressive disorders [1–3]. Indeed, the prognosis of both diabetes and depression—in terms of disease severity, complications and mortality—as well as the costs to both the individual and society [4] have been found to be worse for either disease when they are co-morbid than when they occur separately [5,6]. Not only is depression more prevalent in people with diabetes, there are a whole range of other mental and emotional well-being issues of concern.

Recently, research has shown that individuals might experience feelings of depression or anxiety, but they may also find themselves overwhelmed with the demands of self management, sometimes referred to as diabetes-related distress or ‘burnout’ [7,8]. There is also evidence of psychological distress in families coping with a child with Type 1 diabetes [9], as well as the impact of chronic pain on mental health and quality of life [10]. As new diabetes technologies appear and guidelines for treatment change, this means that further research studies need to be conducted in order to find out whether new ways of working are appropriate. In biomedical terms, this usually involves setting up randomized controlled trials; however, when it comes to issues of a psychological or psychosocial nature this is often problematic. Indeed, most studies which have attempted to measure the prevalence of depression or other mental health problems have been naturalistic or observational. So far, few studies have been conducted on the efficacy of psychological treatments. A further challenge is to understand the specific health needs of minority ethnic groups, in particular those of South Asians living in the UK, whose risk of developing diabetes is much greater than the White indigenous population [11]. Research indicates, for example, that there may be particular difficulties with regard to the take-up of insulin therapy [12]. Research studies to improve both health services delivery and self care within minority ethnic populations may be compromised because established ways of collecting data have frequently been found to be inappropriate for these groups [13,14]. Although more innovative methods are becoming available, more needs to be done in order to ensure that service users can be involved in research, regardless of cultural background or literacy level [15].

Bringing research and clinical practice together so that one informs the other has always been a challenge. However, psychosocial research that helps practitioners understand why individuals decline treatment or experience difficulties in self managing their condition can only help improve the services that are offered and could impact on long-term prognosis as well as quality of life [16]. This research may well take the form of large-scale surveys, but equally important are the smaller-scale studies, usually of a qualitative design, where an in-depth understanding of the experiences and emotional status of individuals with diabetes can be gained. The Diabetes UK State of the Nations report (2005) stated that ‘All people with diabetes need access to psychological and emotional support… so that they can manage their condition effectively and reduce the risk of complications’ (18). A recent survey, however, showed that psychological support remained unavailable in most diabetes centres [17]. Furthermore, where it was available the service was patchy with variable skill levels found within diabetes teams. It seems that researchers and clinicians alike are faced with a lack of evidence of the type of psychological services required, as well as the most beneficial ways of treating those with psychological problems. Further research clearly needs to be conducted which can inform the clinical practice of those working with the individual with diabetes and maintain appropriate levels of self care.

One step towards this goal was made in December 2007, when a group of individuals from diverse global professional organizations came together in Geneva to commit to working to improve outcomes for patients with co-morbid diabetes and depression. At this meeting, the Dialogue on Diabetes and Depression (DDD) (http://www.diabetesanddepression.org/) was formed, with a whole range of specialists and stakeholders agreeing to work together as a collaborative community of research and care in order to understand the current state of knowledge about diabetes and depression, and to set the agenda for future research and care in diabetes and depression. Subsequently, the World Health Organization, the US National Institutes of Health and several other institutions and organizations have all expressed interest in the work of this group. Notwithstanding the challenges of working together across continents, as well as sometimes competing professional perspectives, the DDD continues to develop its agenda and push for greater recognition of this important and costly problem.

Given the available evidence, it is clear that the mental health and well-being of people with diabetes needs to be taken seriously, not just at the wider national/international level, but locally, where individuals receive care [18]. Some of that evidence, recently published in Diabetic Medicine, can be found in a special virtual issue of this journal, entitled Diabetes and Mental Health, accessed via http://www.diabeticmedicinejournal.com/vi. Research still needs to be conducted; we are far from fully understanding the nature of the relationship between diabetes and mental health. Despite an increased awareness in some parts of the world, there remain few integrated approaches to the problem in practice, few resources directed towards improving care and quality of life for people with co-morbid diabetes and depression and even fewer resources directed towards research focused on the causes and consequences. I look forward to a future time when research into this serious issue receives the funding it clearly deserves and emotional and psychological care is universally integrated into diabetes services.

Glucose-lowering therapies and cancer risk: the trials and tribulations of trials and observations

The potential role of glucose-lowering therapies in modulating the relationship between diabetes and cancer has seemingly exploded into our collective consciousness in the past year. While this relationship has been suggested for sometime [1–3], the recent surge in attention followed publication of several observational studies from European administrative registries and clinical databases [4–7]. This prompted a number of editorials and commentaries, most often critical of the observational nature of the reports, as well as critical of limitations in the analytic approach to those data [8–11]. Further, as is often the case with controversial reports from observational studies, calls were made to look to a higher level of evidence, such as data from randomised controlled trials.
To that end, a number of more recent publications have contributed data on this topic from randomised trials, including two meta-analyses of trials of long-acting insulin analogues [12, 13]. Both of these concluded there was no increased risk of cancer, although the trials included involved small numbers of patients with type 1 and type 2 diabetes and were generally of very short duration, highlighting some of the major limitations of randomised trials in answering questions regarding potential modification of cancer risk. Other contributions have been the post-hoc analysis of large randomised trials of glucose-lowering therapies, such as the paper by Home et al. in this issue of Diabetologia [14]. In that paper, the authors report on the risk of malignancies associated with the oral glucose-lowering treatments to which patients with type 2 diabetes were randomised in the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) [15] and ADOPT (A Diabetes Outcome Progression Trial) [16] trials. These two trials were larger and of longer duration, overcoming some of the limitations of the trials in the meta-analysis of the insulin analogues. Nonetheless, the paper by Home et al. shares a common characteristic with these meta-analyses, in that they were all unplanned post hoc analyses from those trials. As such, it must be remembered that, while the data arose from randomised trials, they are still, after all, just observations.
Home and colleagues are careful to recognise this point in the discussion of their observations, where they indicate that the data merely suggest that, with respect to cancer risk, rosiglitazone offers no significant advantage over metformin. However, with regard to these two agents relative to sulfonylureas, the data are interpreted as being somewhat more suggestive of a potential benefit [14]. Furthermore, the authors point out that their findings are in keeping with previous observational studies of oral glucose-lowering therapies [1–3], including the relative reduction of cancer deaths observed in the UK Prospective Diabetes Study (UKPDS) metformin study [17]. Consistency, as Hill noted, is one of the important considerations when attempting to draw inferences of causality from epidemiological associations [18]. Under the view that data from randomised controlled trials provide higher level evidence, this consistency may be taken as reassurance that the previous observational studies were not insurmountably confounded.
While Home and colleagues report on post-hoc observational studies of two randomised trials, their strengths lie in the quality of the data, collected prospectively following the protocols for the original trials. One wonders, however, to what extent the trial protocols may have introduced potential biases, not fully addressed in these post-hoc observational studies of cancer risk. In the case of RECORD [15], the protocol had two therapy-associated strata, each with two randomisation arms. Thus patients on metformin monotherapy were randomised to sulfonylurea or rosiglitazone, and patients on sulfonylurea monotherapy were randomised to metformin or rosiglitazone. Patients were followed for a mean of 5.5 years, with a primary outcome of fatal or non-fatal cardiovascular events. Importantly, the RECORD protocol included a glycaemic control target of HbA1c 7.0%, to be achieved through dosage escalation of the randomised therapies, with rescue therapy consisting of addition of a third oral glucose-lowering agent or transfer to insulin in patients not achieving a target HbA1c of 8.5%. Therein lies an important consideration that may not have been fully considered by Home and colleagues. While the analyses focused on the association between malignancies and the original randomised treatments, there is considerable evidence that the ‘rescue’ glucose-lowering therapies, added as part of the trial protocol, have known independent associations with cancer risk. It is also important to note that the initial treatments for patients coming into the RECORD trial (metformin or sulfonylurea monotherapy) were not randomly assigned. Failing to account for these additional exposures after randomisation over time and the non-randomised nature of the initial therapy may result in cancer risk changes being falsely attributed to the randomised assignments of the second therapy in the RECORD trial.
A defence against this contention would be a view that, in conventional survival analysis, allocation to treatment groups and other covariates must be determined before follow-up starts. Pocock and Smeeth [9, 10] recently argued that, given a complex array of factors, many of which are unmeasured or unknown, it is usually impossible to accurately gauge the extent and even the direction of bias due to changes in drug therapy during follow-up. Strictly speaking, the effect of a time-varying drug therapy exposure is confounded by the condition that underlies the time-dependent change of that exposure, unless the time-varying covariate is changing randomly over time. In this case, however, applying the ‘golden rule’ for conventional survival analyses could actually lead to cancer risk differences being falsely attributed to the randomised allocation of treatment.
Under the RECORD protocol, randomisation would have ensured a balance between patients of the treatment arms. Thus, any differences in use of add-on rescue therapy between the arms were presumably attributable to the degree to which the randomised therapies controlled blood glucose. Add-on rescue therapy is therefore not independent of the original randomisation. As such, the originally randomised drug that appeared to be associated with increased (or decreased) cancer risk may have had no direct effect on cancer risk. Instead, the drug may not have achieved adequate glucose control, inducing the use of add-on therapies that might independently have increased (or decreased) cancer risk. Some may see this as a classic case of ‘confounding by indication’, which is likely to occur in observational studies where the reasons for additional therapies are not measured or recorded. Fortunately, this is not the case in the protocol-driven data collection of a randomised trial such as RECORD; the protocol dictated the use of add-on therapy, which was fully measured and recorded. Furthermore, it is highly unlikely, albeit unverifiable, that the reasons for add-on therapy were related to cancer risk, making confounding by indication improbable. In this view, accounting for the addition of rescue therapies known to be independently associated with cancer risk, perhaps with exposure definitions that recognise the time-varying nature of these exposures, could provide a better estimate of the risk associated with the randomised therapies. At the least, such a secondary analysis would be helpful to assess the consistency with the primary analysis results.
In fact, if we were to look to randomised trial data to inform the debate on specific glucose-lowering therapies and cancer risk, we find a similar situation for all recent large randomised controlled trials of glucose-lowering therapies for type 2 diabetes, given the particular focus on overall glycaemic control. For example, in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROActive) Study [19], a large trial which randomised patients with type 2 diabetes to pioglitazone or placebo, differences in the rates of cancer as a secondary outcome were noted, with more cases of bladder cancer in the pioglitazone group and more breast cancer with placebo, but no difference overall in the incidence of cancer [20, 21]. More importantly, while PROActive was a randomised trial of pioglitazone versus placebo, the investigators also aimed for participants to achieve HbA1c below the recommended target, which they took to be <6.5% [18]. Therefore, substantial changes to non-randomised medications occurred, specifically to other glucose-lowering agents. By the end of the study, the placebo group was using more metformin and more insulin than the pioglitazone group, while both groups had a similar decline in the use of sulfonylureas [19]. In the end, the pioglitazone group achieved a significant and clinically important difference in HbA1c, but no difference in the main primary outcome of mortality or cardiovascular events.
In RECORD, the rosiglitazone group also achieved a significantly greater reduction in HbA1c, but no differences were observed in the main outcomes of fatal or non-fatal cardiovascular events [17]. At best, secondary analyses of these large randomised controlled trials may be limited to assessing the relationship between improved cancer risk and overall glycaemic control, through whatever combinations of specific therapies used. With this in mind, these observations suggest that cancer risk is not reduced by improving glycaemic control in type 2 diabetes [22].
In considering the entire trajectory of glucose-lowering therapy in RECORD, Home and colleagues indicate that the use of rescue therapy and addition of insulin therapy were minimal, with the majority of follow-up time on the rosiglitazone [14]. However, recent revelations suggest that this may not have been the case, with 40% of patients no longer taking the drug by the end of the study [23]. While this newly revealed information calls into question the overall integrity of the RECORD trial, it also highlights the need to adequately record and measure exposure to glucose-lowering therapies in the analysis of secondary outcomes such as cancer.
Understanding the relationship between diabetes and cancer is perhaps one of the next biggest challenges for the clinical community. Clearly this also means a better understanding of the role of glucose-lowering therapies. Home and colleagues’ observations from the RECORD and ADOPT trials affirm that a reasonably strong and consistent story is emerging as far as the association between metformin use and reduced cancer risk is concerned. Our current understanding is likely to be enhanced within the next few years, with data from ongoing randomised trials designed to answer the question of potential benefits of metformin and glitazones in the treatment or prevention of cancer [24]. Randomised controlled trials, whether in oncology or diabetes, are not the best sources of evidence of rare adverse events [25, 26]. As such, we must continue to look to observational studies to inform this debate, seeking and sharing those with the highest quality data and analytic approaches that attempt to disentangle these complex exposure and outcome relationships.

Diabetes Basics

Diabetes type 2
Getting the News: Now What?
Take a deep breath.
Preparing your mind for your journey with diabetes is one of the best first steps to take.
Being told you have diabetes, or that there is a problem with your blood sugar level can cause quite a bit of stress — and rightly so.
Diabetes is scary.
Denial, Guilt, Anger
You may have read headlines about what can go wrong or witnessed firsthand the negative effects of uncontrolled diabetes.
Maybe you have been in denial that anything is wrong. That's OK. Denial protects and buffers you from difficult or shocking information.
Do you feel guilty? Like you caused diabetes?
If so, your first assignment is to stop the blame game and get on your own side.
Anger, too, is a common reaction and is often the first sign that you acknowledge that something is wrong. It is never too late to jumpstart your diabetes self-management program.
The key is to be gentle with yourself because you are your best resource for managing your diabetes.
Diabetes is never convenient, but with some effort and help from the experts, it is manageable. It is important that you acknowledge this. How you perceive this diagnosis will greatly effect how successfully your diabetes is managed.
Learn to Laugh
As strange as it sounds, learning to laugh can help.
Your thoughts and feelings have an enormous impact on your body. Positive thoughts do have positive physical effects.
Humor is a useful tool in helping manage diabetes by adding perspective—not that there is anything funny about having diabetes. But a little humor may help you see from a different perspective. Humor can help you build the confidence to know that you can deal with diabetes. Plus, laughing lowers glucose levels!
Focus on Positives
Let's focus on something positive about your diabetes diagnosis. Feel free to repeat the following to yourself:
• "I can follow my dreams and passions."
• "Diabetes stinks, but I can manage it."
• "I am not alone. Millions of people are dealing with diabetes and thousands of health care professionals are fighting to make a difference in my life and the lives of others."
• "The feelings I have about diabetes—be it anger, depression, fear, eagerness to learn, or relief at finding out—are typical. I have the strength to do something about my diabetes."
You Are More Than Diabetes
Diabetes does not define you; it's just a small part of your complex being. When it comes to diabetes, your treatment plan starts with being mentally prepared.


What is Gestational Diabetes?
Pregnant women who have never had diabetes before but who have high blood sugar (glucose) levels during pregnancy are said to have gestational diabetes. Gestational diabetes affects about 4% of all pregnant women - about 135,000 cases of gestational diabetes in the United States each year.
We don't know what causes gestational diabetes, but we have some clues. The placenta supports the baby as it grows. Hormones from the placenta help the baby develop. But these hormones also block the action of the mother's insulin in her body. This problem is called insulin resistance. Insulin resistance makes it hard for the mother's body to use insulin. She may need up to three times as much insulin.
Gestational diabetes starts when your body is not able to make and use all the insulin it needs for pregnancy. Without enough insulin, glucose cannot leave the blood and be changed to energy. Glucose builds up in the blood to high levels. This is called hyperglycemia.
How gestational diabetes can affect your baby
Gestational diabetes affects the mother in late pregnancy, after the baby's body has been formed, but while the baby is busy growing. Because of this, gestational diabetes does not cause the kinds of birth defects sometimes seen in babies whose mothers had diabetes before pregnancy.
However, untreated or poorly controlled gestational diabetes can hurt your baby. When you have gestational diabetes, your pancreas works overtime to produce insulin, but the insulin does not lower your blood glucose levels. Although insulin does not cross the placenta, glucose and other nutrients do. So extra blood glucose goes through the placenta, giving the baby high blood glucose levels. This causes the baby's pancreas to make extra insulin to get rid of the blood glucose. Since the baby is getting more energy than it needs to grow and develop, the extra energy is stored as fat.
This can lead to macrosomia, or a "fat" baby. Babies with macrosomia face health problems of their own, including damage to their shoulders during birth. Because of the extra insulin made by the baby's pancreas, newborns may have very low blood glucose levels at birth and are also at higher risk for breathing problems. Babies with excess insulin become children who are at risk for obesity and adults who are at risk for type 2 diabetes.

Avoiding Complications Nurturing Your “Health Bank”

Most people who are diagnosed with diabetes or prediabetes are told at some point about the long-term damage diabetes can do, such as causing heart attack and stroke, blindness, kidney disease, and limb amputations. Unfortunately, too few are also told that all of these complications are largely preventable—through a combination of healthy lifestyle practices, frequent checkups and laboratory tests for screening and monitoring, and medication when necessary.
This may sound like a long list of things to do, but it may be simpler than you think—if you focus your efforts on the areas that will have the most impact for you.
Understanding and monitoring the big picture of your overall health with diabetes can be achieved by keeping tabs on five simple medical tests: HbA1c, blood pressure, blood lipids (cholesterol and triglycerides), microalbumin, and a dilated eye exam.
These tests are currently the best measures available to indicate each person’s individual health risks with regard to diabetes. Yet despite these tests being widely accessible and easy to administer, fewer than 42% of adults with diabetes have either had them or understand what the results mean, according to an April 2006 report by USA Today.
Why aren’t more people with diabetes aware of these critical tests or their own personal results? There are lots of possible reasons, ranging from not being informed, to not understanding the information or its importance, to feeling too overwhelmed by other concerns to act on the information.
“So often people with diabetes focus on the stuff they feel guilty about (usually weight or food), when that may not even be their most critical health issue. What they don’t usually do is get the hard facts on where they stand in terms of their own diabetes health risks. But this is what’s really going to improve the quality and length of their life,” says Dr. Richard Jackson, Director of Outreach at the Joslin Diabetes Center in Boston.
Dr. Jackson’s long-standing notion is that everyone with diabetes should track their lab test results just as carefully as they track their money in the bank. In our new book Know Your Numbers, Outlive Your Diabetes, Dr. Jackson and I describe how to create a simple “balance sheet” that can help people see clearly where they have the most “health dollars” in the bank and where their most urgent “health debts” lie. (For a sample sheet, click here.) By taking action where it’s most needed, readers can achieve the long, healthy, complication-free lives they want.
Collect your numbers
The first step in creating your health balance sheet is to gather your test results. Most people have had at least some of these tests conducted at some point, but they may not know exactly how long ago, what the tests measured, or what the results were. For clarity, here’s what each one does:
HbA1c. The HbA1c test (also called the glycosylated hemoglobin test or the A1C test) is a measure of the amount of glucose in your blood over the previous 2–3 months. This test complements daily blood glucose monitoring by providing a broader picture than the “snapshots” provided by your meter. Keeping your HbA1c test results in the recommended range lowers your risk of all diabetes-related complications.
Blood pressure. This test, which is usually done by placing an inflatable cuff around your upper arm, determines the force of blood flow through your blood vessels. High blood pressure raises the risk of stroke, heart problems, and kidney disease.
Lipid profile. This is a group of blood tests that measure (or enable the lab to calculate) your total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (another type of blood fat). Results are used to help determine your risk of heart attack or stroke.
Microalbumin. This urine test searches for small amounts of a protein called albumin, which leaks into the urine when the kidneys are becoming damaged. This is the test most frequently neglected in people with diabetes, yet it is by far the most sensitive test for identifying risk of future kidney problems.
Eye exam. A yearly dilated eye exam (in which the pupils are enlarged using eye drops) allows the eye doctor to see the backs of the insides of your eyes to check for diabetes-related eye problems (as well as non-diabetes-related eye problems).
If you don’t already have copies of your most recent test results, you will need to call your doctor’s office and ask for them. Remember that you have the right to obtain copies of your medical records, so don’t take no for an answer if you encounter resistance. In addition, don’t accept the answer that your test results are “OK” or “fine.” At least for HbA1c, blood pressure, cholesterol and triglyceride levels, and microalbumin, you want a numerical answer—just as you would if you went to the bank and asked for an update on your account balance.
Your eye exam results, which you may need to get from your eye doctor rather than your primary diabetes care doctor, are less straightforward, because there are no numerical results for diabetes-related eye problems, and it’s unusual for eye doctors to provide patients with written records. However, your eye doctor is required to provide you with a report if you request one, and there are some standard terms that eye doctors use to describe the most common diabetes-related eye problem, retinopathy. The doctor should be able to explain the significance of your results to you.
As you collect your results, note when the tests were last done. Anything over a year old is too old, and you should schedule new tests immediately. According to the Joslin Diabetes Center, the frequency of these tests should be as follows:
• HbA1c test: every three months
• Blood pressure: at least every six months, but you can take advantage of every doctor’s appointment to have your blood pressure checked
• Microalbumin, lipids, and eye exam: all annually, unless you have concerns that might require more frequent checks
Once you have your test results in hand, you can start thinking about how to respond to them.
Setting priorities
Knowing where to focus your efforts may be the hardest part of managing diabetes. Many people feel overwhelmed, believing they have to do everything at once. But doing everything at once is just too difficult, and it may not even make sense from a health standpoint since you may expend a lot of effort toward achieving a goal that has little impact on your health. You need to know what your real health risks are so that you can pinpoint your efforts to make the biggest impact on improving or maintaining your health.
Once your five tests are current and you’ve obtained the results, compare your results to the ideal target ranges to see where you stand and where you need to take action. The results that are furthest from the ideal target ranges are your “debts.” These are the numbers that require action first.
Keep in mind that while the target ranges shown here have been associated with a lowered risk of complications for the general population with diabetes, your personal goals should be individualized with the help of your health-care providers.
HbA1c. According to the American Association of Clinical Endocrinologists, if your test result is at or under 6.5%, you’re right on target, so there’s no need for you to take immediate action to lower it. In other words, you’ve got lots of HbA1c dollars in the bank. If your HbA1c is between 6.5% and 7.0%, you still have a pretty good balance in your health account. But if your HbA1c is in the 8.0% to 9.0% range, this is an area of concern that should be addressed as soon as you’ve taken care of any matters that are even more pressing. If your HbA1c is 9.0% or over, this signifies a serious health risk that you’ll want to address immediately.
Blood pressure. Blood pressure is reported as two numbers, such as 120/80 mm Hg. The top number is called the systolic pressure, and the bottom number the diastolic pressure. Both are vital in assessing your risk of heart disease. For example, for every 10 points you reduce your systolic pressure (the top number in your blood pressure result), you reduce your chance of heart attack and stroke by 15% to 20%. And while the current recommendation for people with diabetes is to maintain a blood pressure lower than 130/80 mm Hg, studies show that there is additional benefit to lowering the systolic blood pressure to 120 mm Hg or lower. Anything over 140 mm Hg systolic is considered high blood pressure.
According to Dr. Jackson, high blood pressure is an underappreciated diabetes risk factor. Most people realize that it’s somehow important to their health, but often neither they nor their health-care providers recognize its fundamental role in predicting cardiovascular risk for people with diabetes.
Blood lipids. The current recommendations of the National Cholesterol Education Program are to aim for an LDL cholesterol level below 100 mg/dl for people at high risk of heart disease. For people who already have heart disease or who are at very high risk, the goal is an LDL cholesterol below 70 mg/dl. However, a growing body of research suggests that lower levels may be better for more people. For this reason, Know Your Numbers, Outlive Your Diabetes sets a target of 80 mg/dl for people with Type 2 diabetes, as well as a goal of an HDL cholesterol level of more than 45 mg/dl (in the case of HDL, higher is better), and triglycerides below 150 mg/dl.
Microalbumin. A number of tests can be used to measure albumin in urine, but the preferred test measures the albumin-to-creatinine ratio. This test is preferred not least because it requires a small urine sample; in contrast, another test for microalbumin requires collecting all urine excreted over 24 hours.
A normal albumin-to-creatinine ratio is less than 30 milligrams of albumin per gram of creatinine (mg/g). A diagnosis of microalbuminuria is given when the test result is between 30 mg/g and 300 mg/g, and a diagnosis of macroalbuminuria requires a level over 300 mg/g.
Because albumin excretion is variable and may be affected by factors such as strenuous physical activity, a urinary tract or other infection, high blood glucose, or high blood pressure on the day of the urine test, the test result should be confirmed in two or preferably three separate tests done over a 3- to 6-month period before a diagnosis is made.
Eye exam. Terms that doctors commonly use to describe the presence or absence of retinopathy include the following:
• No evidence of diabetic retinopathy
• Mild, minimal, or moderate background retinopathy
• Nonproliferative retinopathy
• Preproliferative retinopathy
• Proliferative retinopathy
Obviously, the desired result of an eye exam is “no evidence of retinopathy” or any other eye disease. If you have proliferative retinopathy, laser therapy can be effective at slowing or stopping the progression of retinopathy. At the stages in between, no immediate treatment may be necessary, but you will want to know if you have progressed from one stage to the next so that you can reevaluate your overall diabetes regimen to determine whether your blood glucose and blood pressure control are at the levels recommended for preventing diabetes complications.
People are often surprised by their test results. Those who’ve spent months fretting about their HbA1c might find it at a respectable level (around 7.5%), while their blood pressure is dangerously high (over 140 mm Hg systolic, for example). What the “diabetes health account” approach does is allow you to pinpoint any results that are out of range, so you can focus on the one or two issues currently most critical for you personally. It’s essentially a do-it-yourself approach to good health. That means it’s your job (not your doctor’s) to collect those health dollars—by knowing your test results and taking the most effective actions to improve them where needed.
Active improvement

So what do you do about your health risks once you identify them? That’s an excellent question, and the answer depends on where your problem areas are and how far you are from your goal range. If you are very far from goal range, immediate and aggressive action—most likely requiring the involvement of your physician—is needed.
If you are close but not quite in goal range, there are a number of very effective strategies that you can “cycle through” to bring your test scores into target range. The idea in this case is to start with the least invasive approach, such as lifestyle changes like diet and exercise, then progress to more aggressive treatments such as medication as necessary. If the first recommendation doesn’t yield results, you can move on to the second, and so on.
The idea here is not to bypass professional medical care but rather to work together with your doctor, diabetes educator, dietitian, or other health professional at a new proactive level, taking initiative and full “ownership” of your diabetes care. Dr. Jackson advises people to think of their diabetes as a small business and their health-care team as their consultants. The objective is to go into appointments armed with information on where the “business” stands, and be prepared with clear goals and/or questions you want your consultants to advise you on. This way, rather than just passively answering questions, you can get a whole lot more meaningful input from your interactions with your health-care team.
In the case of high blood pressure, you might start by investing in a home blood pressure monitor, then talk to your doctor about taking blood-pressure-lowering drugs such as ACE inhibitors, angiotensin II receptor blockers (ARBs), or beta-blockers. Aerobic exercise can be very beneficial when done regularly, and there are many specific—but not drastic—changes you can make in your diet to help bring blood pressure levels down.
Lowering your microalbumin test result is almost always a matter of lowering your blood pressure. ACE inhibitors and ARBs also have a directly protective effect on your kidneys, separate from their effect on lowering your blood pressure. When taken together, the two types of drugs are even more helpful. So a drug from one of these two classes is almost always the first choice in treating high blood pressure—and at the same time lowering microalbumin—in people with diabetes. You can also improve your kidney health by lowering your blood pressure target and working to reduce your HbA1c if it is high.
The point is that you’re much more likely to significantly improve your health if you pinpoint your focus, then take a step-by-step approach to addressing your most critical risks.
Confidence is key

In October 2006, Forbes reported that “diabetes is dragging down America’s health (statistics).” According to new data from the U.S. Centers for Disease Control and Prevention, a good half of the estimated 21 million adult Americans with diabetes currently rate themselves as having only “fair” or “poor” health—levels that are associated with diabetes-related complications.
Not only is this frightening, but it is frustrating, since this does not need to be the case. Part of the trouble, of course, is that many people don’t have access to sufficient medical care, but the other factor is simply inertia: Too many people ignore their diabetes because they feel overwhelmed or hopeless, believing that their efforts to control their diabetes will have no real effect.
Motivation comes from believing that your actions (not just your doctor’s) matter. The “diabetes health account” approach outlined in Know Your Numbers, Outlive Your Diabetes offers a simple way to chart your own progress and see that your efforts have made a difference. This step-by-step set of strategies illustrates that if your blood pressure is high, for example, it can always be lowered into a safer range just by employing the right combination of lifestyle changes and medicines that are effective for you.
To reiterate, the most important first step to living longer with diabetes and preventing its long-term complications is finding out where you stand with this condition. Taking control also means finding a way to manage your diabetes every day without going crazy and without letting it rule your life.
The concept of “knowing your numbers” is really quite simple. As HealthiNation video producers (www.healthination.com) note, “Most people can rattle off their important numbers with ease. They know their date of birth, Social Security number, and even their credit scores. But if you ask people if they know their cholesterol, blood pressure, and blood glucose levels—they have no clue. Knowing the RIGHT numbers can make the difference between life and death.”
The human mind has an enormous capacity for retaining information, but there’s really no need to memorize your diabetes health numbers. What’s important is simply to get the tests and log the results regularly. And of course, you need to feel empowered to take action on anything that’s out of range.
An ounce of prevention

One thing you can be sure of: If everyone tracked and acted on these values regularly, their outlook for a long and healthy life would be a lot rosier. Keep in mind that diabetes does its damage slowly, over
the long term, so feeling fine today does not mean that you are fine. Only your test results can tell you where you stand, and only by keeping tabs on them can you ensure good health going forward.
Try thinking of keeping your test results in target range as your own personal seatbelt law. It’s something everyone is required to do for their own protection. Some people will be lucky enough to avoid accidents, so the fact that they were foolish enough not to wear a seatbelt may not harm them. But that’s largely up to chance. No one can predict whose luck might turn for the worse. By keeping your HbA1c and other health factors in range you can ensure a healthier future. Even if you discover complications starting to set in, the damage is much more likely to be treatable or even
reversible if it’s caught early.
Of course, the thought of caring for your diabetes for the rest of your life can seem daunting. But thinking about it in terms of your diabetes health account may help remove some of the dread. It’s just another practical area—like your financial security—that you want to manage as well as you possibly can to ensure a brighter future.

Children and adolescents on intensive insulin therapy maintain postprandial glycaemic control without precise carbohydrate counting

The study has demonstrated that, in free-living children who are adjusting insulin dose for carbohydrate intake, an individually calculated insulin dose covers 10-g variations in carbohydrate amount in a meal, with no differences in area under the postprandial glucose curves and in postprandial BGLs for 2.5 h. Even at 2.5–3.0 h, although there was a small difference in BGLs for the 70-g meal, the postprandial BGLs remained well within current internationally defined targets for optimal glycaemic control of 5–10 mmol/l [11]. Tight glycaemic control was achieved for all test meals (Fig. 2), with no statistical difference in AUC for any meal.
This study has shown for the first time that a mealtime insulin dose can cover a range of carbohydrate quantities in children and adolescents on intensive insulin therapy. It has been suggested that precise carbohydrate counting in grams is preferable to estimations of 10-g CHO portions or 15-g CHO exchanges to achieve optimal postprandial glycaemic control [1,10]. However, there are no studies to support this and the findings of the current study indicate that this degree of accuracy in carbohydrate quantification may be unnecessary to maintain glycaemic control in daily life. Studies are required to examine the impact of more widely variable carbohydrate amounts, such as 15-g CHO exchanges, on postprandial control.
The current study found no difference between postprandial glucose levels for children on CSII vs. MDI when insulin dose was matched to carbohydrate amount. These findings are supported by another study that compared daily glycaemic patterns in children on CSII with matched subjects on MDI [14]. However, in other studies, CSII has been reported to be associated with small improvements in postprandial control [15,16]. Larger studies are needed to determine if there is an association between insulin treatment modality and postprandial glycaemic control.
Several studies in adults have demonstrated that the pre-meal insulin requirement is proportional to the carbohydrate content of the meal [17–19]. Our findings may also be applicable to adults on intensive insulin therapy and do not conflict with these studies, but suggest a particular amount of insulin will cover a range in carbohydrate quantity. In addition, although the glucose response curve may have differed for a meal of a different glycemic index, our findings should be applicable to meals of varying carbohydrate types.
A potential limitation of our study may have been sample size. However, we had sufficient power to detect a difference in glucose excursions of 2.2 mmol/l at 2 h between carbohydrate loads. Education programmes, such as DAFNE [3], cite a rise in BGLs of 2–3 mmol/l as the potential impact of one 10-g CHO portion, although there have been no studies to demonstrate this. A further limitation of our study is that only the effect of a 10-g variation in carbohydrate amount for a 3-h postprandial period was examined. Further studies are needed into the frequency and amount by which children under- or overestimate carbohydrate quantity in meals in their daily lives and the impact this has on glycaemic control.
In clinical practice, precise carbohydrate counting often involves the inclusion of foods that were not counted in the portion or exchange systems [20]. Acquiring such a detailed knowledge of the carbohydrate content of all foods on a meal-to-meal basis increases the burden of management already placed on a child with diabetes and this additional complexity may affect adherence [8]. Furthermore, it may increase fat consumption from packaged foods that have the precise carbohydrate amount specified on the label. This is a concern as children with diabetes higher than recommended fat intakes in a number of studies [21,22].
Education programmes for children and adults that teach adjustments in insulin dose for carbohydrate intake without using precise grams, have demonstrated improved quality of life [23] and glycaemic outcomes [3,24,25]. There is limited evidence regarding the ability of adults and children to count carbohydrate, although some research suggests estimations in grams are often inaccurate [26] and teaching in precise grams fails to improve accuracy compared with portion or exchange estimations [27].
This study demonstrates that an individually calculated insulin dose for meals with ±10-g variations in carbohydrate amount results in maintenance of postprandial BGLs. We conclude that small errors in carbohydrate quantification of less than 10 g are unlikely to make a significant difference to postprandial glycaemic control for meals of approximately 60 g of carbohydrate. Precise carbohydrate counting in gram increments appears unnecessary to maintain postprandial blood glucose control in children and adolescents using intensive insulin therapy.

The Kingdom of Cockaigne

In a society accustomed to famine, people dream of food. In the Middle Ages, people dreamed of a fantasy world known to the English as the Kingdom of Cockaigne and to the Dutch as Luilekkerland (Fig. 1); there were similar legends in other European countries [1]. Physical work is unnecessary in Cockaigne, because food simply falls into your mouth. No medieval fabulist could possibly have dreamed that his descendants would one day actually come to live in the Kingdom of Cockaigne, otherwise known as the consumer society. Nor could our fabulist have imagined that these descendants might attempt to combat an excess of food by cutting out parts of their stomachs and intestines, and consider this a rational solution.

Simple obesity is a cultural and behavioural problem, strongly linked with the early environment [2] and social deprivation [3]. It is associated with social discrimination, emotional taboos and low self-esteem, while its psychological reverberations may affect life in all its aspects [4]. Last but not least, it is a prime example of allostasis, with forward-feeding behavioural and metabolic consequences that are notoriously intractable to therapy in the great majority of cases. How indeed do you treat the compulsion to put too much food into your own mouth, or those of your children?
Therapeutic failure leads to therapeutic mania, nowhere better exemplified than in the attempted treatment of obesity. Overweight people have always been willing to subject themselves to desperate remedies, and there has been no shortage of therapists, scrupulous or otherwise, willing to cater for this demand. Remedies have included an endless array of useless fad diets, enforced starvation in expensive sanatoria, wiring the jaws, surgical removal of fat, and selling the tapeworm scolex as a ‘natural’ remedy to be taken by mouth. Food consumption is one of our primal drives, and attempts to overcome this with pharmacotherapy have been a catalogue of failure, as witnessed by the recent withdrawal of rimonabant and sibutramine from the European market. Worse still, the pharmacology of obesity has been littered with therapeutic disasters, most notoriously Fen-Phen—a combination of fenfluramine and phentermine—which induced valvular lesions of the heart and fatal pulmonary hypertension [5, 6].
It has been said that there are no heroic surgeons, only heroic patients, and the history of bariatric surgery has had more than its share of these. Early attempts to shorten the small intestine were limited by severe malabsorption and associated complications; the 50% morbidity rate and approximate 10% mortality following jejunoileal bypass were ‘considered sufficient reasons to abandon it as an appropriate operation for the morbidly obese’ [7]. The modern era of bariatric surgery was heralded by the Roux-en-Y gastric bypass, first introduced in 1967 [8]. Even so, the stigma of obesity was so pervasive, and the complication rate so high, that surgery for obesity was considered faintly disreputable.
A few brave pioneers did persevere, however, and improved gastric restriction and bypass procedures coupled with minimally invasive surgery transformed the reputation of bariatric surgery. One result has been a free-for-all for surgical procedures with uncertain long-term consequences for health and well-being. Little seems to have changed since MacDonald concluded: ‘Despite accumulated knowledge from experience, no general agreement as to the optimal procedure has been reached, if one, indeed, does exist for any given morbidly obese patient. Analysis of results of surgical alternatives has always been hindered by a lack of comprehensive data collection, poor long-term patient follow-up, and lack of standardisation of the technical aspects of the procedures and of reporting of results.’ [7].

Benefits and motivation
The benefits of surgery are nonetheless compelling, and its recipients are among the most grateful patients you will encounter, so is there really cause for concern? Weight-reducing surgery does more than reduce weight. It offers psychological benefits [9] and reduces blood pressure, lipids and blood glucose [10, 11], and the need for these to be treated. Deaths from cardiovascular disease and cancer are reduced [12], and many of the secondary consequences of obesity, such as fatty liver [13], musculoskeletal disorders [14], intracranial hypertension [15], sleep apnoea [16] and infertility [17] are ameliorated. Not surprisingly, long-term health costs are also likely to fall [18], including those associated with diabetes [19, 20].
Nonetheless, there are concerns. To begin with, a mechanical remedy is hardly ideal for a condition whose root causes are genetic, social and psychological [21]. One author has vivid memories of a small celebratory meal offered to the first set of patients to undergo gastric banding at his own clinic, a meal during which one patient after another slipped away from the table to throw up in the toilet before coming back for more. There can also be a mismatch between the reasons why some people seek bariatric surgery and the reasons for which it is offered. A retrospective analysis found that candidates fell into two relatively distinct groups: those who claimed to seek gastric banding mainly for medical reasons (52%) and those who said they sought it for reasons primarily related to physical appearance or social embarrassment (32%) [22]. There were no men in the latter group. Similar opinions were expressed by patients seeking gastric bypasses or duodenal switches [23], suggesting that medical concerns predominate in stated motivation for bariatric surgery. These analyses have obvious limitations, not least sex and selection bias, their retrospective nature, and cultural taboos that might prompt men to deny concerns about their own appearance. Human motivation is complex, and we lack well-performed and adequately powered studies into why people seek and undergo surgery; studies conducted by investigators who are independent of the surgical teams involved. Some prospective candidates clearly do seek psychological and social benefit—one wanted to avoid the humiliation of having to call for an extension seatbelt whenever she got on a plane. This is a perfectly understandable motive with which we may all sympathise, but it seems profoundly irrational for her suitability for the procedure to be approved on the grounds of diabetes and hypertension, which caused her little concern. Rules governing access to bariatric surgery vary from one healthcare system to another, but bogus transactions such as this between doctor and patient do not form the basis of good medical care.
A further concern is the trend towards more invasive interventions, which may hold an irresistible appeal for overweight people desperate for a solution, and for surgical teams seeking to improve their outcome measures. Bias towards more invasive treatments exists even within well-regulated surgical settings. At the other end of the scale (and all too often ignored in the literature) are those who perform surgery for personal profit within a largely unregulated environment.
The American Diabetes Association and the National Institute for Health and Clinical Excellence have greeted bariatric surgery with evidence-based caution [24, 25]. Each concluded that it may be a useful treatment option for patients with type 2 diabetes and a BMI of ≥35 kg/m2 who remain in poor control despite adequate lifestyle change and pharmacological treatment, and both highlight the need for lifelong monitoring and for well-designed long-term controlled trials comparing bariatric surgery with non-surgical treatment. Neither saw a role for bariatric surgery in the treatment of diabetes in patients with a BMI of <35>30 kg/m2, a category so broad as to include some 50% of the total diabetic population [26]. Gastric bypass was considered the probable best option, despite the absence of controlled trial data or adequate consideration of the long-term metabolic consequences of this procedure in this group of patients. The extension of surgery beyond its evidence base, otherwise known as ‘indication creep’, thus seems to offer a temptation that many are unable to resist.

Surgery and diabetes
Although psychosocial or cosmetic considerations may loom large in the thinking of those who seek surgery, health concerns generally provide the final stimulus for the patient and the formal justification for the surgeon. Let us therefore consider the risks and benefits of surgery in relation to diabetes. Food consumption in excess of energy requirements underlies the current pandemic [27], and enforced starvation in time of war produced a dramatic reduction in the incidence and mortality of diabetes [28, 29]. Calorie deprivation, whether voluntary or enforced, forms the basis of effective diet regimens and almost every other form of successful weight-reducing therapy. No surprise, therefore, that surgically induced starvation by malabsorption or gastric restriction has proved highly effective in lowering blood glucose and reducing the need for other therapies.
A recent meta-analysis from Buchwald et al. suggests that 78% of patients with type 2 diabetes achieve biochemical ‘remission’ following bariatric surgery [30], but the accompanying commentary emphasised the retrospective and uncontrolled nature of virtually all these data and the heterogeneity between the procedures analysed, some of which would now be considered obsolescent. Ascertainment and follow-up was unsatisfactory in most studies, and a mere 1.6% of the material evaluated qualified as grade 1 evidence [31]. Patient selection also favoured a positive outcome, as many of the patients were young (the mean age was just 40 years), fit and female and were thus unrepresentative of the diabetic population as a whole.
It is remarkable that only one properly designed prospective randomised controlled study of bariatric surgery has ever been conducted with a specific focus on people with diabetes [32]. This reported short-term outcomes with laparoscopic gastric banding vs standard medical treatment in a group of patients with recent-onset type 2 diabetes and an average BMI of 38 kg/m2. After 2 years, 73% of those in the surgical group and 13% of those in the medically treated group were in treatment-free glycaemic remission. Gastric banding also enhanced short-term quality of life as compared with conventional medical treatment for type 2 diabetes [33]. No other relevant controlled trials have been published.

Which is the better operation?
While it remains a matter of opinion which operation is better, some observations can be made. Gastric and intestinal bypass procedures rapidly enhance insulin secretion, probably through short-term effects on gut peptide hormones [34], whereas metabolic improvements after gastric banding are less immediate and may depend more directly on weight loss. Although various authorities have long debated the relative merits of one procedure or another, long-term outcomes have yet to be compared for those with diabetes. As surgeons tend to compete in terms of short-term weight reduction and other surrogate measures, gastric bypass surgery is often the preferred option, despite evidence that gastric banding—a safer and potentially reversible procedure—produces similar weight loss beyond 2 years [35] and may be almost as good at controlling diabetes [32, 36]. Weight loss may indeed be an unreliable surrogate for improved glucose control in diabetes [36], as rapid weight loss also results in a proportionately greater loss of lean tissue [37].
In principle it may seem obvious that safer, reversible procedures should be preferred to more complex irreversible procedures with a wider range of complications, except where the latter have very clear advantages. As many different types of surgical intervention are now on offer, such comparisons are urgently needed. These should be based on longer-term medical outcomes and quality of life, rather than kilograms shed, and the rate and proportion of patients for whom glucose-lowering therapy can be stopped. Short-term withdrawal of hypoglycaemic medication is a naive and inadequate endpoint for surgical studies.
A further concern is that little has been done to establish the most appropriate type of intervention for patients in different age groups and at different stages of diabetes. It is far from clear, for example, that the restoration of euglycaemia by bariatric surgery will benefit older individuals following years of exposure to poor glucose control. Conversely, when bariatric surgery is offered to young people with decades of life in front of them, its longer-term metabolic and nutritional consequences surely demand more active consideration. Uncertainties such as these persist because we lack rigorous, controlled studies. Observational reports of experimental procedures in lean people with diabetes [38] have done little to advance our understanding, other than to suggest that this approach has little to offer.
Bariatric surgery does not ‘cure’ diabetes. A relevant comparison might be with gestational diabetes, in which the escalating insulin demands of pregnancy exceed the capacity of the pancreatic islets to respond, yet normoglycaemia is restored following delivery—a ‘remission’ that, as we know, is often transient. This is consistent with the observation that hyperglycaemia is most effectively controlled by surgery in those with disease of a shorter duration, whereas those with a longer duration of diabetes or higher treatment requirements derive less benefit [32, 39]. In agreement with this, a recent retrospective report highlights the extent to which long-term glycaemic control may eventually deteriorate after gastric bypass [40]. Surgery may be a useful way of buying time, but it should not be regarded as a permanent cure for hyperglycaemia.
Even those in whom diabetes treatment can be reduced or withdrawn still require long-term surveillance of glucose, lipids and blood pressure, not to mention the potential adverse consequences of surgery. The Swedish Obese Subjects (SOS) study included 34 patients who had undergone gastric bypass in the 10 year analysis, and in these systolic blood pressure was reduced by 4.7%, diastolic blood pressure by 10.4% and cholesterol by 12.6% [11]. The 10 year incidences of hypertension and hypercholesterolaemia were unaffected by bariatric surgery [11]. Blood-pressure lowering therapies [41] and statins [42] still provide the largest and best-documented reduction in cardiovascular risk in those with diabetes.

Potential problems of bariatric surgery
Bariatric surgery has come a very long way, and is far safer than in previous years. It is not, however, free from surgical risk (see text box: Potential complications of bariatric surgery). The short-term operative mortality for low-risk patients attending centres with experienced surgical teams is around 1/200 after gastric bypass, as against 1/2,000 for laparoscopic gastric banding [35]. One meta-analysis revealed a 30 day mortality of 0.1% after gastric banding, 0.5% after gastric bypass and 1.1% after biliopancreatic diversion [43]. The authors commented that these risks compare favourably with other forms of surgery, but the question here is whether such risks are justified in the treatment of diabetes. The main short-term causes of death after bariatric surgery are venous thromboembolism and cardiorespiratory disease [44]. Venous thromboembolism affected 0.3% of banding patients and 0.4% of laparoscopic gastric bypass patients in the Longitudinal Assessment of Bariatric Surgery (LABS) [45]. All these risks are increased in older people [46] and in those with diabetes or hypertension [44]. Varela et al. found that hospital mortality rose to 4.7% in a subset of patients aged over 60 with pre-existing cardiac disease [47]. Gastric bypass not only carries a greater risk of death than banding, but is also associated with a greater risk of early postoperative complications and re-admission to hospital [45]. One study reported a 20.6% rate of early re-admission or emergency visit following this form of surgery [48]. Revisional surgery is probably required in at least 5% of patients [49].

The fact that modern bariatric surgery is frequently carried out laparoscopically does nothing to eliminate potentially serious long-term nutritional, medical and psychological consequences (see text box: Long-term nutritional, medical and psychological complications of bariatric surgery). The upper part of the intestine fulfils an essential nutritional function, and gastric and intestinal bypass procedures result in micronutrient depletion [50–52] that requires scrupulous monitoring and lifelong replacement [53]. Here again, systematic data are lacking and the scale of the problem is likely to have been underestimated. The most common concern is anaemia resulting from dietary inadequacy, malabsorption of iron, folic acid, vitamin B12 and vitamin C, and sometimes blood loss from surgical complications. Deficiencies of vitamin D and calcium are also common, with a substantial early decline in bone mineral density [54]; the long-term implications of this are uncertain. Less commonly, peripheral neuropathy and occasional central nervous system damage result from deficiencies of vitamin B12, thiamin or copper or from Guillain–Barré syndrome. A systematic review identified 104 reports of Wernicke’s encephalopathy after bariatric surgery, suggesting that thiamin deficiency is not rare [55]. More unusually, malabsorptive bariatric surgery has been associated with depletion of vitamin A, vitamin K, niacin, zinc and selenium [53], while drug malabsorption is another potential concern [56]. Furthermore, while bariatric surgery generally improves fertility and pregnancy outcomes, intrauterine growth retardation, fetal brain haemorrhage and neural tube defects have been described [57, 58]. Most of these nutritional deficiencies are indeed avoidable, but the limiting factors in their prevention and treatment are human rather than medical, and relate to treatment non-adherence or inadequate specialist follow-up.