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http://dvr.sagepub.com/content/early/2013/05/26/1479164113490765The online version of this article can be found at:

 DOI: 10.1177/1479164113490765

published online 27 May 2013Diabetes and Vascular Disease ResearchGlobal Partnership for Effective Diabetes Management

Clifford J Bailey, Pablo Aschner, Stefano Del Prato, James LaSalle, Linong Ji, Stephan Matthaei and on behalf of theIndividualized glycaemic targets and pharmacotherapy in type 2 diabetes

  

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Introduction

The Global Partnership for Effective Diabetes Management,* established to provide practical guidance to improve patient outcomes in diabetes, has previously developed 10 key rec-ommended steps to assist health-care professionals to ensure that patients achieve glycaemic targets (Table 1).1 Following the initial proposal of the 10 steps to improve glycaemic control, results of large intervention trials have been published. Whereas trials have consistently reported a

reduction in microvascular complications with intensive glycaemic control,2–6 a reduction in macrovascular compli-cations with this approach remains the subject of debate.7

A main outcome of such a discussion is the appreciation that a ‘one-size-fits-all’ strategy for managing type 2 diabe-tes will not provide a great deal of treatment success. Such an approach does not take into consideration the heteroge-neity of the patient population (i.e. phenotype, genotype, age, disease duration, complications status, susceptibility to medication adverse effects, education etc.), requiring that individualized management should be employed along with full consideration of cardiovascular (CV) risk factors in the context of multifactorial interventions.7 Moreover, in the past decade, new pharmacological options have been made available for the treatment of type 2 diabetes after metformin failure, and more options are advanced in

Individualized glycaemic targets and pharmacotherapy in type 2 diabetes

Clifford J Bailey1, Pablo Aschner2, Stefano Del Prato3, James LaSalle4, Linong Ji5 and Stephan Matthaei6 on behalf of the Global Partnership for Effective Diabetes Management

AbstractThe Global Partnership for Effective Diabetes Management, established to provide practical guidance to improve patient outcomes in diabetes, has developed and modified recommendations to improve glycaemic control in type 2 diabetes. The Global Partnership advocates an individualized therapeutic approach and, as part of the process to customize therapy, has previously identified specific type 2 diabetes patient subgroups that require special consideration. This article builds on earlier publications, expanding the scope of practical guidance to include newly diagnosed individuals with complications and women with diabetes in pregnancy. Good glycaemic control remains the cornerstone of managing type 2 diabetes, and plays a vital role in preventing or delaying the onset and progression of diabetic complications. Individualizing therapeutic goals and treatments to meet glycaemic targets safely and without delay remains paramount, in addition to a wider programme of care to reduce cardiovascular risk factors and improve patient outcomes.

KeywordsGlycaemic targets, HbA1c, type 2 diabetes, individualized therapy, Global Partnership

1 Diabetes Research, School of Life & Health Sciences, Aston University, Birmingham, UK

2 Endocrinology Unit, Javeriana University School of Medicine, Bogota, Colombia

3School of Medicine, University of Pisa, Pisa, Italy4Medical Arts Research Collaborative, Excelsior Springs, MO, USA5Peking University People’s Hospital, Beijing, People’s Republic of China6Diabetes-Zentrum Quakenbrück, Quakenbrück, Germany

Corresponding author:Clifford J Bailey, Diabetes Research, School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK. Email: c.j.bailey@aston.ac.uk

490765 DVR0010.1177/1479164113490765Diabetes & Vascular Disease ResearchBailey et al.2013

Review Article

*Global Partnership for Effective Diabetes Management Members: Pablo Aschner, Javeriana University School of Medicine, Bogota, Colombia; Clifford Bailey, Aston University, Birmingham, UK; Lawrence Blonde, Ochsner Medical Center, New Orleans, LA, USA; Stefano Del Prato, University of Pisa, Pisa, Italy (Chair); Anne-Marie Felton, Federation of European Nurses in Diabetes, London, UK; Ramon Gomis, Hospital Clinic, Barcelona, Spain; Edward Horton, Joslin Diabetes Center, Boston, MA, USA; Linong Ji, Peking University Peoples Hospital, Beijing, China; James LaSalle, Medical Arts Research Collaborative, Excelsior Springs, MO, USA; Lawrence A. Leiter, Keenan Research Center in the Li Ka Shing Knowledge Institute, St Michael’s Hospital, and Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada; Stephan Matthaei, Diabetes Centre Quakenbrück, Quakenbrück, Germany; Marg McGill, Diabetes Centre, Royal Prince Alfred Hospital, Sydney, Australia; Neil Munro, Beta Cell Diabetes Centre, Chelsea and Westminster Hospital, London, UK; Richard Nesto, Lahey Clinic, Burlington, MA, USA; Jay Skyler, University of Miami, FL, USA; Paul Zimmet, Baker IDI Heart and Diabetes Institute, Caulfield, Australia.

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2 Diabetes & Vascular Disease Research 0(0)

development such as sodium glucose co-transporter 2 (SGLT2) inhibitors.

Added on top of metformin, the different pharmacologi-cal options are associated with a similar level of efficacy,3 although they differentiate with respect to other features (effect on body weight, risk of hypoglycaemia, potential CV safety/protection etc. [Table 2]). Given these new options, the Global Partnership already advocated the need for an individualized therapeutic approach, and in an attempt to facilitate customized treatment, we identified specific type 2 diabetes patient subgroups that require special consideration and proposed practical advice for setting glycaemic targets for these groups.7 A patient-centred approach has also been recommended by several organizations, such as the Canadian Diabetes Association and the American Association of Clinical Endocrinologists, and more recently, this approach was included in the updated joint position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).8 Herein, we review the recent evidence to refine our recommendations on individualization of therapy in terms of glycaemic targets and choice of treatment.

Defining glycaemic targets: the evidence

Hyperglycaemia defines diabetes, and glycaemic control is fundamental to management of the disease.9 The UK Prospective Diabetes Study (UKPDS) established that early intensive glycaemic control in newly diagnosed type 2 dia-betic patients is associated with significantly decreased rates of microvascular complications (retinopathy, neurop-athy and nephropathy).10 For macrovascular complications, a trend towards a reduced rate of myocardial infarctions (MIs) was observed in patients treated with intensive ther-apy, although this was not statistically significant.10 Ten-year follow-up of patients in the UKPDS, during which glycaemic control was similar between groups, demon-strated that the benefit of intensive therapy (i.e. reduction in microvascular complications)10 was maintained over the long term.11 Analysis of the long-term UKPDS data also showed that those patients treated intensively to achieve

glycaemic control received a benefit in terms of cardiovas-cular disease (CVD) and total mortality reduction.11 These findings from the long-term follow-up led to the concept of a ‘legacy effect’ for both micro- and macrovascular compli-cations resulting from early and intensive glycaemic con-trol,11 and highlight the importance of optimizing metabolic control as early as possible.12

Other intervention studies (Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron Magnetic Resonance Controlled Evaluation [ADVANCE] and Veterans’ Administration Diabetes Trial [VADT]) that included patients with known CVD or multiple CV risk fac-tors who had type 2 diabetes for a longer period than those enrolled in the UKPDS confirmed the benefits of intensive glycaemic control to reduce microvascular complications, predominantly nephropathy.13–15 However, results from these individual trials did not demonstrate a reduction in macrovas-cular complications with an intensive therapy regimen and, in fact, treating to a HbA1c target of <6% (<42 mmol/mol) (and achieving <6.5% [<48 mmol/mol]) in the ACCORD study was associated with an increase in mortality of 22%.13

Given the neutral or negative outcomes on macrovascu-lar complications in these studies despite the benefits on microvascular disease, the temptation to relax measures that reduce hyperglycaemia would seem understandable. It is vital, therefore, that these results are viewed in context,16 and new analyses are considered that not only reinforce the need to reduce glycaemia effectively (in order to manage the risk of microvascular complications) but also clarify the benefit of early and intensive control of hyperglycaemia on macrovascular disease.

In ACCORD, ADVANCE and VADT, the overall CV mortality rate was actually substantially lower than origi-nally expected, although this most likely reflects general improvements in type 2 diabetes management such as multi-factorial therapeutic strategies.7 The study duration of these trials (3.5–5.6 years) may have been too short for any signifi-cant benefits of tight glycaemic control on CV outcomes to become apparent (as opposed to the 10-year follow-up in the UKPDS).16 Furthermore, the patients enrolled in the short-term studies had a history of poorly controlled long-standing

Table 1. Ten steps to get more type 2 diabetes patients to goal.16

1. Aim for an appropriate individualized glycaemic target, for example, HbA1c 6.5%–7% (48–53 mmol/mol) (fasting/preprandial plasma glucose 110–130 mg/dL [6.0–7.2 mmol/L] where assessment of HbA1c is not possible) when safe and appropriate.

2. Monitor HbA1c every 3 months in addition to appropriate glucose self-monitoring.3. Appropriately manage all cardiovascular risk factors.4. Refer all newly diagnosed patients to a unit specializing in diabetes care where possible.5. Address the underlying pathophysiology of diabetes, including the treatment of β-cell dysfunction and insulin resistance.6. Treat to achieve appropriate target HbA1c within 6 months of diagnosis.7. After 3 months, if patients are not at the desired target HbA1c, consider combination therapy.8. Consider initiating combination therapy or insulin for patients with HbA1c ≥ 9% (≥75 mmol/mol).9. Use combinations of anti-hyperglycaemic agents with complementary mechanisms of action.

10. Implement a multidisciplinary team approach that encourages patient self-management, education and self-care, with shared responsibilities to achieve goals.

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Bailey et al. 3T

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4 Diabetes & Vascular Disease Research 0(0)

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Bailey et al. 5

diabetes together with either micro- or macrovascular com-plications,13–15 and were therefore at higher risk of negative outcomes than their counterparts in the UKPDS (newly diag-nosed patients with no prior CV events).7

A meta-analysis of the UKPDS, Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), ADVANCE, ACCORD and VADT studies found that intensive therapy achieving a modest 0.9% (10 mmol/mol) reduction in HbA1c was associated with a 17% reduction in non-fatal MI and a 15% reduction in coronary heart dis-ease (CHD) compared with conventional therapy.17 Further meta-analyses have also evaluated the effectiveness of good glycaemic control in preventing or delaying the onset of macrovascular complications and provide potential explanations for the lack of apparent benefits seen in land-mark trials.18–20 A Cochrane review of intensive glycaemic control in type 2 diabetes (including 20 trials and ~30,000 patients) reported a significant 14% reduction in non-fatal MI with intensive glycaemic control, although no differ-ences in all-cause or CV mortality were reported.18 In this analysis, patients who had poor glycaemic control at base-line (higher fasting blood glucose or HbA1c) were less likely to benefit from intensive control in terms of all-cause mor-tality.18 Pooled analyses have also suggested that the pres-ence of CVD,20 a higher degree of obesity and longer duration of diabetes19 are factors associated with poorer out-comes in patients receiving intensive glycaemic control.

Retrospective analysis of ACCORD data suggested that episodes of severe hypoglycaemia may be associated with a high mortality rate,21 possibly reflecting the intensive escalation of therapy in those patients failing to achieve the low HbA1c target of <6% (<42 mmol/mol).16 However, the higher mortality rate in the intensive therapy arm was not related to the incidence of hypoglycaemia,21 and a post hoc analysis later showed that the excess mortality actually occurred in patients who did not achieve their HbA1c target (or who had displayed substantial hyperglycaemia).22 That is, intensive therapy in individuals with poorly controlled diabetes may, in fact, carry a higher risk of mortality than in patients with better controlled disease.

The ADVANCE investigators also pointed out that hypo-glycaemia rather than being a trigger for CV events may rep-resent a marker for vulnerability.14 A post hoc analysis of data from ADVANCE reported that reducing HbA1c to less than 7% (53 mmol/mol) was not associated with an added benefit in terms of CV risk reduction but also showed that lowering HbA1c levels even further did not appear to be harmful. Moreover, the analysis found no evidence of interaction between severe hypoglycaemia, the assigned glucose-lower-ing treatment and mortality,23 although the relationship between hypoglycaemia and MI remains unresolved.

As outlined here, new interpretations of data from large-scale clinical trials and assessment of meta-analyses and retro-spective studies have provided the Global Partnership with the opportunity to further update and revise suggestions for the

management of type 2 diabetes. In the following sections, we re-examine and expand upon the original sub-categories of type 2 diabetes patients for whom specific recommendations are necessary, with the aim of defining more closely the gly-caemic targets and choice of treatments to achieve these goals.

Tailoring treatment to type 2 diabetes patients: glycaemic targets and individualized therapy

Definitions for patient types have been described in an ear-lier publication by the Global Partnership.7 We stated that early and effective intervention is likely to confer the great-est benefits,7 particularly bearing in mind the ‘legacy effect’ of early glycaemic control demonstrated in the UKPDS11 and outcomes reported in meta-analyses.18–20 As part of management, lifestyle adjustment and a defined target HbA1c are required, with rapid treatment assessment should targets fail to be met – primarily to avoid periods of inade-quately controlled hyperglycaemia.1,7 Table 3 contains an at-a-glance summary of treatment recommendations for the patient subtypes discussed in more detail below.

Newly diagnosed individuals with type 2 diabetes but no complications

Newly diagnosed overweight or obese adults

In overweight and obese individuals with type 2 diabetes, diet and exercise are essential components of therapy, as are agents that address the underlying pathophysiology of dia-betes, including treatments directed at β-cell dysfunction24 (owing to impaired β-cell function at diagnosis that declines thereafter)24 and insulin resistance.7 An additional consid-eration in this patient population is the impact of pharmaco-logical therapies on weight, with sulphonylureas (SUs), thiazolidinediones (TZDs) and insulin associated with weight gain,8 whereas weight neutral agents or those associ-ated with weight loss8 would appear more preferable.24

Practical guidance for newly diagnosed overweight or obese individuals

• Implement a multifactorial management plan, including diet and lifestyle intervention to achieve a healthy weight, and appropriate treatment to combat CV risk factors such as dyslipidaemia and hypertension.

• Individuals with newly diagnosed type 2 diabetes and without CVD should aim for an HbA1c that is as near to normal as possible (<6.5% [<48 mmol/mol]), without causing hypoglycaemia or marked weight gain (met-formin, glucagon-like peptide-1 [GLP-1] receptor ago-nists and dipeptidyl peptidase-4 [DPP-4] inhibitors).

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6 Diabetes & Vascular Disease Research 0(0)

Table 3. Treatment recommendations for subtypes of type 2 diabetes patients.

Patient subtype definition HbA1c target/range Recommendations for therapy/treatmenta

Newly diagnosed overweight or obese adults with no complications

<6.5% (<48 mmol/mol) Metformin; GLP-1 receptor agonists; DPP-4 inhibitors; combination therapies (e.g. metformin plus DPP-4 inhibitor) if target not met (or HbA1c ≥ 9% [≥75 mmol/mol]) with a single agent; temporary use of insulin in patients with HbA1c > 9% (>75 mmol/mol; also possible use of GLP-1 receptor agonist in these patients); in individuals on a diet rich in complex carbohydrates, an α-glucosidase inhibitor may offer benefit and to avoid weight gain or facilitate weight loss, the upcoming SGLT2 inhibitors may also be useful.

Newly diagnosed lean adult with no complications

6.5%–7% (48–53 mmol/mol) DPP-4 inhibitors; GLP-1 receptor agonists; metformin; SUs and meglitinides may be considered in suitable patients and combination therapies or temporary use of insulin in patients with HbA1c > 9% (>75 mmol/mol)

Newly diagnosed children and adolescents with no complications

6.5%–7% (48–53 mmol/mol) DPP-4 inhibitors; GLP-1 receptor agonists and metformin and accepting that clinical classification of diabetes is difficult in overweight or obese young people, insulin can be considered as a first-line treatment.

Newly diagnosed individuals with micro- or macrovascular complications

<7% (<53 mmol/mol) Combination therapies may be required early to maintain HbA1c (in those patients in whom this can be achieved safely and without delay) and choice of medication is dependent on the nature and severity of complications and response of the patient to initial therapy and a less strict target of 7%–7.5% (53–58 mmol/mol) (or even up to 8.5% [69 mmol/mol]) in non-responsive patients may be accepted

Individuals with a history of inadequate glycaemic control (lean or obese) and no complications

6.5%–7% (48–53 mmol/mol) DPP-4 inhibitors; GLP-1 receptor agonists; metformin; combination therapies or temporary use of insulin can be considered to achieve control in those patients in whom this can be achieved safely and without delay and choice of medication is dependent on the response of the patient to initial therapy

Individuals with a history of inadequate glycaemic control (lean or obese) and a history of CVD

7%–7.5% (53–58 mmol/mol) DPP-4 inhibitors; GLP-1 receptor agonists; metformin; treatment changes should be based on the patient’s response to initial therapy and comprehensive CV risk factor management plan

Individuals with a history of inadequate glycaemic control (lean or obese) and a history of microvascular complications

6.5%–7% (48–53 mmol/mol) Individualized therapy is of paramount importance in this patient group; several medications are contraindicated (Table 2) and the potential for drug interactions requires vigilance

Individuals at risk of hypoglycaemia

7%–7.5% (53–58 mmol/mol) Agents not associated with an increased risk of hypoglycaemia are preferable, as are those not contraindicated in renal insufficiency or liver dysfunction (Table 2) and mixed formulations of insulin can be used if regular eating patterns are adhered to

Women with pre-existing diabetes during pregnancy

6.5%–7% (48–53 mmol/mol)b Insulin is recommended for glycaemic control during pregnancy; however, oral agents such as metformin may be considered on an individual basis and folic acid and multivitamin supplementation is advised

Women with gestational diabetes

6.5%–7% (48–53 mmol/mol)b Insulin is recommended for glycaemic control during pregnancy; however, oral agents such as metformin may be considered on an individual basis and folic acid and multivitamin supplementation is advised

GLP-1: glucagon-like peptide-1; DPP-4: dipeptidyl peptidase-4; SGLT2: sodium glucose cotransporter-2; SUs: sulphonylureas; CVD: cardiovascular disease; CV: cardiovascular; FPG: fasting plasma glucose.aIn addition to lifestyle measures (exercise, diet).bOr FPG < 7 mmol/L.

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Bailey et al. 7

• HbA1c should be monitored on a 3-month basis, and a combination of glucose-lowering therapies should be considered if glycaemic targets are not met with one agent.

• Among patients with mild-to-moderate hyperglycaemia (HbA1c <7.5% [<58 mmol/mol]), opt for agents that are not associated with hypoglycaemia (metformin) and address the underlying pathophysiology of diabetes (GLP-1 receptor agonists and DPP-4 inhibitors). In indi-viduals on a diet rich in complex carbohydrates, an α-glucosidase inhibitor may offer benefit. To avoid weight gain or facilitate weight loss, the SGLT2 inhibitors may also be useful when available.

• For patients with an HbA1c between 7.5% (58 mmol/mol) and 8.9% (74 mmol/mol), provide more intensive use of the agents in the category above, possibly con-sidering combination therapy for patients in the upper end of the range but avoiding the risk of hypoglycaemia for patients in the lower end.

• In patients with HbA1c approximately 9% (75 mmol/mol) or above, consider initiating combination therapy (e.g. metformin plus DPP-4 inhibitor), or temporarily insulin to reduce glucose toxicity, together with an increase in glucose monitoring. Use of a GLP-1 recep-tor agonist could also be an option, although experi-ence is limited at the current time.

Newly diagnosed lean adults

In lean patients, the degree of β-cell dysfunction requires major consideration and may be more marked than in obese/overweight individuals.7,25 Insulin resistance in lean patients is generally comparatively lower,25 risk factors for CVD are often less obvious and the risk of developing macrovascular complications may not be as great compared with their obese/overweight counter-parts.7,26 It may be appropriate to measure antibodies, for example, for glutamic acid decarboxylase (GAD), in an effort to exclude or confirm latent autoimmune diabetes in adults (LADA).

Practical guidance for newly diagnosed lean adults

• Individuals with newly diagnosed type 2 diabetes and no complications should aim for an HbA1c of 6.5%–7% (48–53 mmol/mol) (even in patients with mild hyper-glycaemia) while avoiding hypoglycaemia or marked weight gain.

• Agents that are not associated with hypoglycaemia or weight gain are preferable (DPP-4 inhibitors, GLP-1 receptor agonists and metformin), although SUs and meglitinides may be considered in suitable patients.

• Where possible, choose anti-hyperglycaemic agents that support β-cell function (DPP-4 inhibitors and GLP-1 receptor agonists).

• In patients with HbA1c > 9% (>75 mmol/mol), con-sider initiating combination therapy of oral agents or temporarily, insulin to reduce glucose toxicity, together with an increase in glucose monitoring to reduce the risk of hypoglycaemia.

• Tailor the wider management plan to account for the less marked CV risk profile compared with their obese/overweight counterparts.

• Reinforce the need for a healthy lifestyle.

Children and adolescents

The onset of type 2 diabetes at an early age points to a glycaemic legacy if the disease is uncontrolled for long periods of time.7 Many of these patients are overweight at diagnosis and also have co-morbidities at a relatively early age (such as hypertension, dyslipidaemia and microalbu-minuria).27 Although lifestyle interventions do not appear as effective as in adults, an education programme involv-ing family and friends can assist in improving glycaemic control.7 An HbA1c target in the near-normal range of <7.0% (<53 mmol/mol) is appropriate in these patients.27

Choice of pharmacotherapy should aim to preserve β-cell function and improve insulin sensitivity. At present, met-formin is the only oral anti-hyperglycaemic agent approved for use in children and adolescents.27 However, recent data from the Treatment Options for Type 2 Diabetes and Adolescents and Youth (TODAY) study showed that 50% of children and adolescents failed to maintain durable glycae-mic control with metformin monotherapy and combination therapy or insulin was often necessary within a few years of diagnosis.28

Practical guidance for newly diagnosed children/adolescents

• Measure antibodies to GAD to exclude or confirm type 1 diabetes.

• Implement a multidisciplinary approach to optimize care among young people with type 2 diabetes, empha-sizing education of family and friends on the impor-tance of lifestyle choices.

• Agents that address insulin resistance (metformin) and potentially help to preserve β-cell function (DPP-4 inhibitors and GLP-1 receptor agonists) may be pref-erable given the disease will progress over many decades.

• Accepting that clinical classification of diabetes is dif-ficult in overweight or obese young people, consider insulin as a first-line treatment.

• Long-term safety is of paramount importance in children and adolescents with type 2 diabetes – an HbA1c target as near to normal as possible, while minimizing the risk of hypoglycaemia is appropri-ate (HbA1c 6.5%–7% [48–53 mmol/mol]).

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Newly diagnosed individuals with complications (micro- or macrovascular)

Type 2 diabetes can remain undiagnosed until an advanced stage of the disease, and micro- and macrovascular complica-tions are often already present when a new patient is diag-nosed. Indeed, up to 40% of adults with either diagnosed or undiagnosed type 2 diabetes have a degree of chronic kidney disease.29 Moreover, the risk of CVD increases proportionally as glomerular filtration rate declines in this patient group.29

Treatment choice should be based on the types of com-plications identified, with some medications contraindi-cated in specific patient groups. Metformin, for example, is contraindicated in patients with renal insufficiency (esti-mated glomerular filtration rate [eGFR] <50 mL/min) and heart failure. However, because of the accepted CV benefit of metformin, both National Institute for Health and Clinical Excellence (NICE)30 and the ADA/EASD8 posi-tion statements suggest that metformin should be avoided for eGFR < 30 mL/min, while dosage should be reduced for eGFR of 30–45 mL/min. TZDs should not be used in patients with moderate-to-severe heart failure, and risk of fracture should be taken into consideration.3 In patients with renal insufficiency, medications that are eliminated by the kidneys, such as many SUs, increase the risk of hypo-glycaemia and should be used with caution.29 Dose of DPP-4 inhibitors should be reduced for eGFR < 60 mL/min with the exception of linagliptin, which has less than 5% renal elimination. More caution should be used for GLP-1 receptor agonists in cases of moderate renal failure. Careful control of blood pressure is recommended in patients with diabetic nephropathy and retinopathy.

Practical guidelines for newly diagnosed individuals with micro- or macrovascular complications

• An HbA1c target of <7% (<53 mmol/mol) is recom-mended in those patients in whom the reduction in blood glucose can be achieved safely and without delay.

• Multiple therapies may be required at an early stage to maintain control of HbA1c and reduce the risk of com-plication progression, and caution should be exercised with respect to drug interactions.

• Less stringent glycaemic targets of HbA1c 7%–7.5% (53–58 mmol/mol) (or even up to 8.5% [69 mmol/mol]) may be indicated where co-morbidities impede use of, or full titration of, some therapies.

• Ensure regular glucose monitoring owing to the risk of hypoglycaemia with some medications.

• Remember that neuropathy and nephropathy are risk factors for severe hypoglycaemia.

• Choice of medication is dependent on the nature and severity of complications, with several therapies

contraindicated in renal insufficiency, hepatic impair-ment or CVD.31

Individuals with a history of inadequate glycaemic control (lean or obese)

A key component of eliminating poor glycaemic control is determining the factors behind insufficient management, such as poor adherence with medications, delayed use of combination therapy or insulin to provide suitable control and failure to adequately assess β-cell function.1,7

No complications

In patients with a history of inadequate glycaemic control, the risk of a legacy effect on development of complications emphasizes the need to establish HbA1c levels to near normal (HbA1c 6.5%–7% [48–53 mmol/mol]) while also ensuring patient safety.7 Long disease duration moderates the effects of rapid glycaemic control in this patient group,19 and efforts to reduce blood glucose should not be delayed.

Practical guidelines for individuals with a history of inadequate glycaemic control but no complications

• Address the underlying causes for poor glycaemic con-trol, including adherence, inadequate therapy and fail-ure to manage the underlying pathophysiology.

• Aim for a target HbA1c near to normal levels (HbA1c 6.5%–7% [48–53 mmol/mol]) in those patients in whom the reduction in blood glucose can be achieved safely and without delay. Avoid hypoglycaemia and marked weight gain.

• Do not delay the therapeutic decision and explain to the patient the potential risk of long-term unacceptable hyperglycaemia.

• Consider a change of therapy (including insulin) or combination of medications to achieve control based on the patient’s response to initial treatment.

• Implement additional education programmes to assist patients in taking a more active role in the management of their disease.

Individuals with a history of CVD

Results from the ADVANCE, ACCORD and VADT studies suggested that very intensive glycaemic control regimens may be inappropriate for some patients with more advanced diabetes who also have macrovascular complications.13–15 As discussed in more detail earlier, several potential expla-nations have been proposed to account for the outcomes observed in these studies,18–20 and meta-analyses have

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also suggested that intensive glycaemic regimens have positive effects if targeted at specific patient types.17,18 Improved glycaemic control may still have microvascu-lar benefits in these patients if achieved safely, that is, without hypoglycaemia.

Avoiding hypoglycaemia in this group of patients is par-ticularly important, and less strict glycaemic targets (HbA1c 7%–7.5% [53–58 mmol/mol] or even up to 8.5% [69 mmol/mol]) with a gradual decrease in HbA1c levels may be more appropriate, or, indeed, imposed by limitations in the choice of therapies.24 In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study, a regimen based on insulin sensitization (e.g. with metformin) had a similar effect on survival and incidence of major CV events as an insulin provision regimen.32 However, the frequency of severe hypoglycaemic episodes in these type 2 diabetes patients with CHD was decreased in those patients receiv-ing insulin-sensitizing agents.32 In addition, insulin sensiti-zation was associated with less weight gain, higher high-density lipoprotein cholesterol levels and improved glycaemic control.32

Practical guidelines for individuals with a history of inadequate glycaemic control and CVD

• A target of <7% (<53 mmol/mol) is desirable in those patients in whom the reduction in blood glucose can be achieved safely but less strict HbA1c targets (HbA1c 7–7.5% [53–58 mmol/mol] or even up to 8.5% [69 mmol/mol]) are recommended where safety is a concern.

• Aim to avoid hypoglycaemic episodes (increased moni-toring of glucose is also advised), marked weight gain and the burden of extra therapies with limited efficacy (treatment changes should be based on the patient’s response to initial therapy).

• Insulin-sensitizing agents (e.g. metformin) should be employed where appropriate unless complications con-traindicate their use or drug interactions are an issue (owing to the high frequency of multiple therapies in this patient group).

• Implement an intensified comprehensive CV risk factor (dyslipidaemia, hypertension) management plan.

• Safety and potential cardioprotective properties of incretin-based therapy are currently under assessment in large intervention trials.

Individuals with a history of microvascular complications

Intensive glycaemic control regimens have been shown to reduce the risk of microvascular disease development in peo-ple with type 2 diabetes.2–6 Strict glycaemic control is war-ranted in the presence of microalbuminuria without elevated serum creatinine levels or in patients with early stage retinopa-thy, to reduce the rate of disease progression.33

As noted for people with a history of CVD, however, the risk of hypoglycaemia in patients with a history of micro-vascular complications has to be balanced against the ben-efits in terms of delaying progression of microvascular complications.24 Moreover, type 2 diabetes patients with autonomic neuropathy are predisposed to hypoglycaemia unawareness (in addition to increased cardiac mortality), and therapy must therefore be implemented with appropri-ate care.33 Options for managing inadequate glycaemic control in this patient group are further limited by contrain-dications, with several medications not suitable in patients with renal impairment or renal insufficiency.3,29

Practical guidance for individuals with a history of inadequate glycaemic control and microvascular complications

• Individualized glycaemic targets and therapy are of paramount importance in this patient group.

• Set initial glycaemic targets as close to normal as possible (HbA1c 6.5%–7% [48–53 mmol/mol]) with-out causing hypoglycaemia in those patients whose microvascular complications are at an early stage.

• Be aware of contraindications, especially in individuals with late-stage microvascular complications, and be vigilant for drug interactions in patients receiving mul-tiple medications.

• Consider less stringent control where the risk of hypogly-caemia or the limited therapeutic choices are problematic.

Individuals at risk of hypoglycaemia

As discussed in an earlier publication, individuals with an increased susceptibility to hypoglycaemia have usually experienced a hypoglycaemic episode on previous occa-sions, have a wide fluctuation in their daily glucose levels and may already have impaired creatinine clearance.7 In type 2 diabetes, the risk for hypoglycaemia is further enhanced with microvascular complications, such as auto-nomic neuropathy33 and renal impairment,29 and occurs more frequently in patients receiving therapy to achieve intensive glycaemic control.10,13–15

Hypoglycaemia can also exacerbate CVD risk among individuals who already have CV risk factors through increas-ing or fluctuating heart rate and rhythm, raising systolic blood pressure and increasing myocardial contractility.34 This increase in cardiac stress has the potential to contribute to destabilization of existing atherosclerotic plaques in older patients with type 2 diabetes who have CHD.35,36

Practical guidance for individuals at risk of hypoglycaemia

• Identify patients at risk of severe hypoglycaemia. Risks include older age, diabetic neuropathy, impaired kidney

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function, lower body weight, long duration of diabetes and prior episodes of severe hypoglycaemia.

• Individualize glycaemic targets according to the level of hypoglycaemia risk and potential implications for that patient, for example, less stringent targets (HbA1c 7%–7.5% [53–58 mmol/mol] or even up to 8.5% [69 mmol/mol]) for patients at higher risk (increased glu-cose monitoring is also advised), or those who live alone or are elderly.

• Agents that are not associated with an increased risk of hypoglycaemia are preferable, for example, agents that reduce insulin resistance or potentiate (but not initiate) glucose-dependent insulin release, or agents that are not contraindicated in significant renal insufficiency or liver dysfunction.

• Educate patients on the symptoms of hypoglycaemia and the associated risks, in order to increase awareness and responsiveness to these symptoms.

• If conventional insulin therapy (mixed formulations) is used, encourage regular eating patterns to lessen the risk of hypoglycaemia.

• Counsel patients on regular self-monitoring of blood glucose where appropriate.

Type 2 diabetes and pregnancy

Women with pre-existing diabetes during pregnancy

Pre-existing diabetes is associated with numerous adverse out-comes for mother and child during and following pregnancy,37 including a higher frequency of Caesarean section, hyperten-sion, fetal congenital anomaly, pre-term birth and spontaneous abortion.37 Pregnancy can also exacerbate the effects of diabe-tes on renal function and retinopathy,38,39 and has the potential to accelerate the development of these complications.37 The occurrence of these adverse outcomes is related to the level of glycaemic control achieved during pregnancy.37

Women planning or continuing pregnancy are recom-mended to substitute their oral anti-diabetic agent(s) with insulin, although oral anti-diabetic agents can still be con-sidered on an individual basis.35 Metformin may be an appropriate agent for women who refuse insulin therapy or who require an additional therapeutic agent.35

Practical guidance for women with pre-existing diabetes during pregnancy

• In pre-conception and antenatal care, management of maternal glucose concentrations should remain a priority.

• Prior to conception, women with diabetes should receive multidisciplinary care, including an assessment of dia-betes complications and advice/education on glycaemic control, diet (including folic acid and multivitamin

supplementation), maternal diabetes complications and fetal risks.

• Aim for normal glycaemia (HbA1c 6.5%–7% [48–53 mmol/mol], or fasting plasma glucose [FPG] <7 mmol/L) to minimize the risk of perinatal complica-tions (use of fructosamine to assess glycaemic control may be helpful in pregnancy).

• Insulin is recommended for glycaemic control during pregnancy; however, oral agents (e.g. metformin) may be considered on an individual basis.

Women with gestational diabetes

Gestational diabetes is associated with a number of compli-cations and an increased long-term risk of type 2 diabetes and CVD in both mother and infant.37 Balancing the bene-fits of therapy with potential adverse effects is essential: lifestyle intervention and insulin have been demonstrated to improve perinatal outcomes (although insulin is associated with hypoglycaemia and weight gain),40 and metformin can be an option in those women who prefer not to use insulin.40

Practical guidance for women with gestational diabetes

• Women with gestational diabetes should receive multi-disciplinary care, including advice/education on gly-caemic control, diet (including folic acid and multivitamin supplementation), maternal diabetes com-plications and fetal risks.

• Aim for normal glycaemia (HbA1c 6.5%–7% [48–53 mmol/mol], or FPG <7 mmol/L) to minimize the risk of perinatal complications.

• Insulin is recommended for glycaemic control during pregnancy; however, oral agents such as metformin may be considered on an individual basis.

Additional considerations affecting glycaemic control

Setting and achieving glycaemic targets also relies on a number of additional patient characteristics or factors.31 These include age and life expectancy, patient preference, degree of social support, adherence to therapy and ethnic-ity.31 Frequently, poor adherence to medications is a signifi-cant cause of inadequate glycaemic control in type 2 diabetes.31 Non-adherence can result from a series of contributing factors, including lack of confidence in effectiveness of therapy and fear of side effects such as hypoglycaemia or weight gain.

In addition, the absence of apparent symptoms in type 2 diabetes may have an impact on patient perception with respect to the seriousness of their condition and the need to

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Bailey et al. 11

take medication.31 Complex dosing regimens, polyphar-macy, difficulties with language and socio-economic issues may also impact adherence.6,31 Measures to maximize adherence through enhanced communication and education of patients on the benefits of treatment are vital. As part of this approach, physicians should aim to minimize the num-ber of medications and doses per week, including the use of fixed-dose combinations where appropriate.31

Conclusion

Good glycaemic control remains the cornerstone of manag-ing type 2 diabetes and plays a vital role in preventing or delaying the onset and progression of diabetic complications. Treating a heterogeneous population of patients as a homog-enous group is impractical and does not take into account the variety of factors that affect patients with type 2 diabetes. As such, the ‘10 steps to get more type 2 diabetes patients to goal’, developed by the Global Partnership, continue to offer a valuable way of ensuring patients achieve and main-tain their glycaemic targets. This article builds on earlier publications, expanding the scope of practical guidance to account for newly diagnosed individuals with complications and for women with diabetes in pregnancy. Individualizing therapeutic goals and treatments to meet those goals remains paramount, as is the recognition that early and intensive gly-caemic control to achieve near-normal HbA1c targets, while essential in some patient subgroups, is not applicable to every patient with type 2 diabetes.

Key messages

• Good glycaemic control achieved safely and without delay remains the cornerstone of managing type 2 diabetes.

• An individualized therapeutic approach rather than a ‘one-size-fits-all’ strategy is essential to ensure maxi-mum success.

• It is important to recognize that early and intensive gly-caemic control to achieve near-normal HbA1c targets is not applicable to every patient with type 2 diabetes.

Acknowledgements

The authors acknowledge the editorial assistance of Dr Sheelagh Farrow, Dr Paola Accalai and Duncan Pennington, International Medical Press, in the development of this article.

Conflict of interest statement

Pablo Aschner is a member of the Global Partnership for Effective Diabetes Management and has received honoraria from GlaxoSmithKline for his participation in board meetings and other related scientific activities. He has also participated in advi-sory panels and provided ad hoc consultancy to AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme, Novartis and Sanofi-Aventis.

Clifford Bailey has received research support from AstraZeneca, Sanofi-Aventis and has received presentation sup-port from, has participated in advisory panels and provided ad hoc consultancy to, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Novo Nordisk and Takeda.

Larry Blonde has received research support from Eli Lilly and Company, Novo Nordisk and Sanofi and has received speaker/consultant honoraria from Amylin Pharmaceuticals, Johnson & Johnson – Janssen, Johnson & Johnson Diabetes Institute, Merck & Co; Inc, Pfizer Inc, Novo Nordisk, Sanofi and Santarus. Dr Blonde’s late spouse’s estate contains shares of Pfizer.

Stefano Del Prato has received research support from Boehringer Ingelheim Pharmaceuticals, Merck Sharp & Dohme, Sanofi-Aventis, and has acted as a consultant for Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Sanofi-Aventis, Takeda and Eli Lilly.

Anne-Marie Felton has participated in Bayer and GlaxoSmith- Kline advisory boards and symposia sponsored by Bayer, Novo Nordisk and Abbott.

Ramon Gomis has received fees for serving as a speaker, a consultant and an advisory board member for GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Sanofi-Aventis.

Ed Horton has received fees for consulting and advisory boards from Abbott, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Medtronic, Merck, Metabasis, Novartis, Roche, Sanofi-Aventis, Takeda and Tethys Bioscience, and is on the speakers bureau for Merck and has received research support from Amylin Pharmaceuticals and Eli Lilly.

Linong Ji has received fees for lectures and consulting from Abbott, AstraZeneca, Bristol-Myers Squibb, Merck, Metabasis, Novartis, Eli Lilly, Roche, Sanofi-Aventis and Takeda.

James LaSalle has received fees as an advisor and speaker from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Eli Lilly and Novo Nordisk, and received research support from AstraZeneca, Bristol-Myers Squibb and Novo Nordisk.

Lawrence Leiter has received research funding and has acted as a consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Roche, Sanofi-Aventis, Servier and Takeda.

Stephan Matthaei has received research support from Sanofi-Aventis and Novo Nordisk, and honoraria for advisory boards and/or speaker engagements from AstraZeneca, Bayer, Bristol-Myers Squibb, Disetronic, Eli Lilly, GlaxoSmithKline, LifeScan, Merck, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis and Takeda.

Marg McGill has acted as a consultant for GlaxoSmithKline.Neil Munro has received fees for serving as a speaker, a con-

sultant or an advisory board member for Eli Lilly, Novo Nordisk, GlaxoSmithKline, Takeda, Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme, LifeScan, Medtronic, Novartis, Pfizer, Servier, Daiichi-Sankyo and Roche.

Richard Nesto is on the speakers bureau of, and is a consultant to, GlaxoSmithKline and Sanofi-Aventis.

Jay Skyler has received research funding from Bayhill Therapeutics, Halozyme Therapeutics, Osiris Therapeutics and Mesoblast; is on the Board of Directors of DexCom Corporation, Moerae Matrix and Paean Therapeutics and has received fees for serving as a consultant or an advisory board member from BD Technologies, Cebix, Gilead, Ideal Life, Merck, Sanofi Diabetes, Takeda, and Valeritas.

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12 Diabetes & Vascular Disease Research 0(0)

Paul Zimmet is currently involved in advisory work with Novartis, NovoNordisk and OM Pharma.

Funding

The Global Partnership for Effective Diabetes Management, including the development of this article, is supported by an unrestricted educational grant from Bristol-Myers Squibb and AstraZeneca LP, and also Novartis Pharma AG.

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