Alas, a Patient-Centred Guidelines on the Glycemic Management in People with Type 2 Diabetes Mellitus

Abstract

Diabetes is one of the most common noncommunicable diseases in the world, and its prevalence and burden continue to rise at an alarming rate. The latest projection by the International Diabetes Federation is a 51% increase between 2011 and 2030, from an estimated 366 million to 552 million people globally (1International Diabetes Federation. IDF Diabetes Atlas. 2012. Fifth edition. (available online at http://www.idf.org/diabetesatlas/5e/the-global-burden).Google Scholar). About half of the people with diabetes are undiagnosed, 80% of them live in low- and middle-income countries, and the number of people with diabetes is increasing in every country (1International Diabetes Federation. IDF Diabetes Atlas. 2012. Fifth edition. (available online at http://www.idf.org/diabetesatlas/5e/the-global-burden).Google Scholar)! In Canada, over 2 million adults are living with diabetes and more than half of them are of working age between 25 and 64 years old (2Public Health Agency of CanadaDiabetes in Canada: facts and firgures from a public health perspective. Public Health Agency of Canada, Ottawa2011Google Scholar). Nearly 40% of Canadian adults with diabetes have 2 or more chronic conditions such as hypertension, heart disease and mood disorders. The health and economic burdens of diabetes are enormous. For example, people with diabetes are over 3 times more likely to be hospitalized with cardiovascular disease (CVD) than individuals without diabetes. Diabetes was the primary cause of new cases of end-stage renal disease requiring dialysis or transplantation in 2009 (2Public Health Agency of CanadaDiabetes in Canada: facts and firgures from a public health perspective. Public Health Agency of Canada, Ottawa2011Google Scholar). Diabetes is a serious disease associated with many acute and chronic long-term complications that are major causes of disability and premature deaths. Since the discovery of insulin by Banting and colleagues 91 years ago, we have learned a great deal about the pathogenesis, the pathophysiology, the underlying genetic factors, and management of both type 1 and type 2 diabetes mellitus. Regardless of etiology and pathogenesis hyperglycemia is a common feature of both types of diabetes. The first definitive proof of the glucose hypothesis was the publication of the results of the Diabetes Control and Complications Trial (DCCT) in people with newly diagnosed type 1 diabetes (3The Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.New Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (22702) Google Scholar). Intensive glucose therapy over a mean of 6.5 years reduced glycated hemoglobin (A1C) from 9.1% (control) to 7.4%, and led to a 60% to 75% delay in the onset or progression of microvascular complications (retinopathy, nephropathy and neuropathy). However, the beneficial effects of intensive therapy on CVD, a 57% relative risk reduction in composite end-points, did not become evident until after a mean follow-up of 17 years (4Nathan D.M. Cleary P.A. Backlund J.Y. et al.Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.New Engl J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (4135) Google Scholar). After 30 years of diabetes, the cumulative incidences of retinopathy, nephropathy and CVD were significantly lower with intensive glucose therapy when compared with conventional treatment (5Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research GroupModern-day clinical course of type 1 diabetes mellitus after 30 years' duration.Arch Intern Med. 2009; 169: 1307-1316Crossref PubMed Scopus (515) Google Scholar). The United Kingdom Prospective Diabetes Study (UKPDS) data on intensive glucose-lowering in people with newly diagnosed type 2 diabetes yielded similar results on microvascular complications (6UK Prospective Diabetes Study (UKPDS) GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar). Over a median follow-up of 10 years, a difference in A1C of 0.9% (7% in the intensive therapy group vs. 7.9% in the conventional group) led to a 25% reduction in microvascular end-points although not affecting macrovascular disease. The compelling DCCT and UKPDS data led to the generalized statement that each 1% lowering in A1C resulted in a 25% to 30% reduction in microvascular disease. These seminal findings on the role of hyperglycemia in the genesis of vascular complications have led to the development of standards of care and clinical practice guidelines (CPGs) espousing the concept of glycemic targets on the management of hyperglycemia in people with diabetes. Goal targets for fasting and postprandial glucose levels, as well as A1C levels, were established by different diabetes societies and federations across the world as a top priority to optimize diabetes management. In general, an A1C level of <7% was chosen as the goal target for most adults with diabetes. The greater vigilance toward the management of hyperglycemia, regular screening, surveillance and treatment of complications are largely responsible for the improvement in glycemic control in the United States over the past several decades (7Hoerger T.J. Segel J.E. Gregg E.W. Saaddine J.B. Is glycemic control improving in U.S. adults?.Diabetes Care. 2008; 31: 81-86Crossref PubMed Scopus (413) Google Scholar). Consequently people with diabetes in high income countries are living longer, suffer less frequent vascular complications and enjoy a better quality of life. Standards of care and CPGs on the management of diabetes continue to evolve to incorporate emerging scientific and clinical data, and to provide guidance on the use of existing and newer classes of glucose-lowering drugs. In August 2006, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a joint consensus algorithm for the initiation and adjustment of therapy in the management of hyperglycemia in type 2 diabetes (8Nathan D.M. Buse J.B. Davidson M.B. et al.Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.Diabetes Care. 2006; 29: 1963-1972Crossref PubMed Scopus (1091) Google Scholar) in an attempt to simplify the guidance on the selection of glucose-lowering therapies for healthcare practitioners. The authors advocated a 2-step approach, starting with lifestyle modification and metformin, followed by additional therapy with a basal insulin, or sulfonylureas, or thiazolidinediones. An ADA/EASD update was published in 2008 that addressed the CVD safety issues regarding the thiazolidinediones (9Nathan D.M. Buse J.B. Davidson M.B. et al.Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.Diabetes Care. 2008; 31: 173-175Crossref PubMed Scopus (246) Google Scholar). In 2008, 3 large-scale, multicentre, randomized clinical trials reported their findings on whether strict glycemic control (A1C <6% or 6.5%) would reduce the incidence of CVD outcomes in people with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) (10The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) (11The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar), and Veterans Affairs Diabetes Trial (VADT) (12Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3866) Google Scholar) were conducted in older patients (60 to 66 years of age with 8 to 11.5 years of diabetes). All 3 trials failed to demonstrate benefits of intensive glucose control on composite macrovascular outcomes while exerting positive effects on microvascular outcomes. The intensive glucose lowering arm of the ACCORD trial was terminated prematurely at 3.5 years because of increased all-cause and CVD-related mortality (hazard ratio [HR] 1.22) with no reduction in the primary composite CVD outcome. The ADVANCE trial and VADT did not report an increase in mortality but the overall results were negative. Intensive glucose lowering resulted in weight gain and a significant increase in hypoglycemic episodes, and especially severe hypoglycemia requiring third-party intervention (10The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar, 11The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar, 12Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3866) Google Scholar). A meta-analysis of these pooled trial data, along with those of the UKPDS, concluded that intensive glycemic control significantly reduced myocardial infarctions by 15% and major macrovascular events by 9%, whereas CV and total mortality were unaffected (13Turnbull F. Abraira C. Anderson R. et al.Intensive glucose control and macrovascular outcomes in type 2 diabetes.Diabetologia. 2009; 52: 2288-2298Crossref PubMed Scopus (966) Google Scholar). These findings raised concerns among many experts and healthcare practitioners on the role of intensive glucose control in retarding and preventing vascular complications, on how to balance benefits and risks in an individual patient, and importantly, how to decide on the appropriate glycemic targets for their patients. The ADA/EASD consensus panel updated their recommendations in 2009 to incorporate new interventions and clinical trial evidence (14Nathan D.M. Buse J.B. Davidson M.B. et al.Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.Diabetes Care. 2009; 32: 193-203Crossref PubMed Scopus (1909) Google Scholar). They continued to favour a 2-tiered approach, initially with lifestyle modification and metformin monotherapy, followed by the addition of basal insulin or a sulfonylurea if glycemic goals were not met. All other glucose-lowering therapies were considered less well-validated and accorded as tier 2 (14Nathan D.M. Buse J.B. Davidson M.B. et al.Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.Diabetes Care. 2009; 32: 193-203Crossref PubMed Scopus (1909) Google Scholar). The overarching principle in selecting glucose-lowering therapies was based on the efficacy of the agents, followed by nonglycemic effects on CVD risk factors such as hypertension and dyslipidemia. The ADA/EASD algorithm was challenged by many experts and diabetes associations, including the Canadian Diabetes Association (CDA), as opinion rather than evidence-based, which failed to take into consideration the multifactorial pathophysiology of type 2 diabetes, the advantages and disadvantages of different classes of glucose-lowering therapies, or the need for individualized therapy (15Woo V. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.Diabetes Care. 2009; 32: e34Crossref PubMed Scopus (4) Google Scholar, 16Schernthaner G. Barnett A.H. Betteridge D.J. et al.Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis.Diabetologia. 2010; 53: 1258-1269Crossref PubMed Scopus (99) Google Scholar, 17Smith R.J. Nathan D.M. Arslanian S.A. et al.Individualizing therapies in type 2 diabetes mellitus based on patient characteristics: what we know and what we need to know.J Clin Endocrinol Metab. 2010; 95: 1566-1574Crossref PubMed Scopus (89) Google Scholar). Many scholarly organizations have also produced recommendations on the management of type 2 diabetes, recognizing that effective management of hyperglycemia in type 2 diabetes is complex and should target its pathophysiology using existing and new classes of glucose-lowering agents, and simultaneously taking into consideration each patient's clinical characteristics, such as patient's age, gender, ethnicity and history of diabetes. Choice of pharmacotherapy should also be predicated by its efficacy, safety, tolerability and cost. How does a health practitioner navigate through and assess the quality of this maze of diabetes CPGs? The Institute of Medicine (IOM) released a detailed report last year, entitled “Clinical Practice Guidelines We Can Trust” that proposed standards for creating CPGs. The IOM defined CPGs as “statements that include recommendations intended to optimize patient care that are informed by a systematic review of the evidence and an assessment of the benefits and harms of alternative care options” (18Institute of MedicineClinical practice guidelines we can trust. Institute of Medicine, Washington, DC2011Google Scholar). More recently a systematic review evaluated the published guideline recommendations on oral medications for type 2 diabetes (19Bennett W.L. Odelola O.A. Wilson L.M. et al.Evaluation of guideline recommendations on oral medications for type 2 diabetes mellitus: a systematic review.Ann Intern Med. 2012; 156: 27-36Crossref PubMed Scopus (90) Google Scholar). Only 2 sets of evidence-based guidelines on diabetes management scored close to 100% on both the rigor of development and editorial independence: the Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada (20Canadian Diabetes AssociationCanadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada.Can J Diabetes. 2008; 32 (S1–201)Google Scholar), and the UK National Institute for Health and Clinical Excellence (NICE) updated recommendations based on systematic reviews of the best available evidence (21National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes. NICE clinical guideline 87. National Institute for Health and Clinical Excellence; 2009.Google Scholar). Both sets of CPGs were published at about the same time as the ADA/EASD consensus algorithm; with the latter scoring only approximately 30% on rigor of development and approximately 80% on editorial independence (19Bennett W.L. Odelola O.A. Wilson L.M. et al.Evaluation of guideline recommendations on oral medications for type 2 diabetes mellitus: a systematic review.Ann Intern Med. 2012; 156: 27-36Crossref PubMed Scopus (90) Google Scholar). The professional members of the CDA published the first comprehensive, evidence-based CPGs in North America on the management of diabetes in 1998 (22Meltzer S. Leiter L. Daneman D. et al.1998 clinical practice guidelines for the management of diabetes in Canada.Can Med Assoc J. 1998; 159 (S1–29)Google Scholar). The guidelines contained a total of 93 recommendations, which covered all aspects of ambulatory diabetes care, ranging from organization, responsibilities, diagnosis, glycemic and metabolic management, to screening, prevention and treatment of long-term complications. The CPGs were updated by a large committee of expert volunteers every 5 years, in 2003 (23Canadian Diabetes AssociationCanadian Diabetes Association 2003 clinical practice guidelines for the prevention and management of diabetes in Canada.Can J Diabetes. 2003; 27 (S1–152)Google Scholar) and in 2008 (20Canadian Diabetes AssociationCanadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada.Can J Diabetes. 2008; 32 (S1–201)Google Scholar). The CPGs became more comprehensive and expanded from 29 pages in 1998 to 152 pages in 2003, and to 201 pages in 2008 to take into consideration the new advances in diagnosis, treatment and prevention of diabetes and its attendant complications. Screening, identification and management of micro- and macrovascular disease, and the concept of vascular protection, became major emphases in the 2008 CPG update. The CDA CPGs followed the AGREE (Appraisal of Guidelines for Research and Evaluation) instrument (24The AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.Qual Saf Health Care. 2003; 12: 18-23Crossref PubMed Google Scholar) and have a standardized evidence-based approach to all recommendations, with over 90 authors and a steering committee of 18 experts for the 2008 updates, and all recommendations required 100% approval by the steering committee and the chapter authors. This process attempted to remove as much inherent bias as possible, in contrast to the ADA/EASD consensus algorithm, which emphasized collective knowledge and clinical experience, and taking into account the benefits and risks. The CDA evidence-based approach gives more flexibility, whereas the consensus approach is more directive- and opinion-based (15Woo V. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.Diabetes Care. 2009; 32: e34Crossref PubMed Scopus (4) Google Scholar). Both the CDA and NICE CPGs offer a comprehensive evidence-based approach to the management of diabetes and glycemic management and targets for therapy were only a part of the overall recommendations. Both guidelines are meant to aid in decision making but they also emphasized patient-centred care and reminded healthcare professionals about the need to incorporate patient values and preferences in their clinical practice (24The AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.Qual Saf Health Care. 2003; 12: 18-23Crossref PubMed Google Scholar). The NICE guidelines also offered much more detailed information resembling care map for primary care practitioners (25Home P. Mant J. Diaz J. Turner C. Management of type 2 diabetes: summary of updated NICE guidance.BMJ. 2008; 336: 1306-1308Crossref PubMed Scopus (72) Google Scholar). Over the past 2 years, new data emerging from the ACCORD, ADVANCE and VADT and other studies have provided greater insights into the safety of glucose-lowering therapies, and notably hypoglycemia. The lessons on hypoglycemia in type 2 diabetes from these trials have fostered more research and advances in our knowledge. Hypoglycemia is more prevalent than previously reported, and severe hypoglycemia is 2- to 3-fold higher with intensive glucose therapy. Studies using continuous glucose monitoring devices revealed that patients with type 2 diabetes suffer from unrecognized daytime and nocturnal hypoglycemia (26Harman-Boehm I. Continuous glucose monitoring in type 2 diabetes.Diabetes Res Clin Pract. 2008; 82: S118-S121Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Importantly the ACCORD and ADVANCE trials both reported higher mortality rates in participants with one or more episodes of severe hypoglycemia even though no direct causal relationship was established (10The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar, 11The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar). Experts are now raising concerns that the CPGs lack details and specific guidance to help healthcare professionals make decisions on glycemic targets to balance the benefits vs. risks of intensifying glycemic control in an individual patient. Several publications have appeared in the past 2 years calling for individualizing glycemic targets based on patient characteristics (16Schernthaner G. Barnett A.H. Betteridge D.J. et al.Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis.Diabetologia. 2010; 53: 1258-1269Crossref PubMed Scopus (99) Google Scholar, 17Smith R.J. Nathan D.M. Arslanian S.A. et al.Individualizing therapies in type 2 diabetes mellitus based on patient characteristics: what we know and what we need to know.J Clin Endocrinol Metab. 2010; 95: 1566-1574Crossref PubMed Scopus (89) Google Scholar, 27Ismail-Beigi F. Moghissi E. Tiktin M. et al.Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials.Ann Intern Med. 2011; 154: 554-559Crossref PubMed Scopus (296) Google Scholar). The presence of comorbid conditions, macrovascular disease, the patient's age, ethnicity, duration of diabetes, history of hypoglycemia, economic considerations, quality of life issues, patient's values and preferences are factors that can influence the health professional's decision on setting individualized glycemic target goals (27Ismail-Beigi F. Moghissi E. Tiktin M. et al.Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials.Ann Intern Med. 2011; 154: 554-559Crossref PubMed Scopus (296) Google Scholar). Last month the ADA/EASD released a position statement on the management of hyperglycemia in type 2 diabetes that, in response to criticisms on the previous algorithms, emphasized a patient-centred approach (28Inzucchi S.E. Bergenstal R.M. Buse J.B. et al.Management of hyperglycemia in type 2 diabetes: a patient-centered approach.Diabetes Care. 2012; 35: 1364-1379Crossref PubMed Scopus (2969) Google Scholar). This document was the work of a joint task force convened by both organizations, and produced recommendations that “incorporated the best available evidence,” and are “less prescriptive than and not as algorithmic as prior guidelines” (28Inzucchi S.E. Bergenstal R.M. Buse J.B. et al.Management of hyperglycemia in type 2 diabetes: a patient-centered approach.Diabetes Care. 2012; 35: 1364-1379Crossref PubMed Scopus (2969) Google Scholar). The position statement emphasizes that glycemic targets and glucose lowering therapies must be individualized, and all treatment decisions should be made in conjunction with the patient focusing on the individual's values, preferences and needs. It reinforces that diet, exercise and education are the cornerstone of type 2 diabetes management. Metformin is still the first line drug but no longer recommended as concomitant therapy with lifestyle modification, as stated in previous ADA/EASD algorithms. After metformin, combination therapy with one or more oral or injectable glucose-lowering agents is recommended but aiming to minimize adverse side-effects where possible. Finally the position statement also stressed the importance of comprehensive CV risk reduction as a major focus of therapy. By abandoning the outdated “one-size fits all cookie-cutter approach,” the ADA/EASD position statement has certainly raised the bar on the management of hyperglycemia in people with type 2 diabetes. It recognizes that type 2 diabetes is a heterogeneous disorder with respect to its susceptibility, the development of a prediabetic state and progression from subclinical to overt disease. The phenotypic and genotypic heterogeneity of type 2 diabetes can greatly influence the clinical course of the disease and the development and progression of micro- and macrovascular complications. Finally the interaction between environmental and genetic determinants can also modulate the natural history and disease course. The CDA will publish their latest CPG update in early 2013. Work for the 2013 update had already begun some 2 years ago. The CPG update is an arduous process that requires the effort of a large panel of experts volunteering their time and effort to produce a guidance for the health practitioners on best practice and care for people with diabetes. While we eagerly await the CPG update, the ADA/EASD position statement serves as a useful template for best practice in managing patients with type 2 diabetes, and one that the CDA should emulate.