Diabetes Pro

ORIGIN TRIAL PROVES SAFETY OF INSULIN, LACK OF EFFICACY FOR N-3 FATTY ACIDS

Gilles Dagenais, MD, Laval University Heart and Lung Institute, Quebec City, Quebec, Canada, and Ambady Ramachandran, MD, India Diabetes Research Foundation, Chennai, India, presented an overview of the Outcome Reduction With an Initial Glargine Intervention Trial [ORIGIN; NCT00069784].

ORIGIN was a large, international, randomized, controlled trial that lasted >6 years in people with new or recently diagnosed diabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and additional cardiovascular (CV) risk factors.

ORIGIN is the longest investigation of the effect of insulin treatment on CV outcomes and cancer incidence in this population to date. The relationship between long-term supplementation with n-3 fatty acids and the rate of CV events was also studied [Gerstein H et al. N Engl J Med 2012].

ORIGIN TRIAL DESIGN 

ORIGIN was a double-blind study with a 2-by-2 factorial design. It was designed to test the effect of titrated basal insulin glargine versus standard care, and it also investigated n-3 fatty acid supplements versus placebo on CV outcomes [Gerstein H et al. Am Heart J2008].

A total of 12,537 participants (mean age, 63.5 years; 35% women) were enrolled from 573 clinical sites in 40 countries. Patients were randomly assigned by region. The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7 years). At the conclusion of the study, the primary outcome status was known for 99% of participants.

Coprimary outcomes in the glargine trial were the first occurrence of nonfatal myocardial infarction (MI) or nonfatal stroke or CV and the first occurrence of nonfatal MI or nonfatal stroke or CV death or hospitalization for heart failure or revascularization. Other outcomes and measures included new or recurrent cancers, angina, ischemia-related amputation, hypoglycemia, and CV and other hospitalizations.

n-3 FATTY ACID TRIAL RESULTS 

Jacqueline Bosch, MSc, McMaster University, Hamilton, Ontario, Canada, presented results from the n-3 fatty acid portion of the ORIGIN trial.

Baseline intake of n-3 fatty acids was 210 mg/day versus 209 mg/day for placebo. At the end of the study, it was 257 mg/day versus 253 mg/day for placebo. The primary outcome of the trial was CV death. Secondary outcomes were MI, stroke or CV death, all-cause mortality, presumed arrhythmic death, or cardiac arrest.

Patients were randomized to receive a daily supplement of n-3 fatty acid (1g per day) or placebo. The primary outcome of the trial was CV death. Secondary outcomes were MI, stroke or CV death, all cause mortality, presumed arrhythmic death, or cardiac arrest.

Omega-3 fatty acids did not reduce the rate of CV events in high-risk patients with diabetes or prediabetes. The rate of CV death was 9.1% in patients who were treated with placebo and 9.3% in patients who were treated with omega-3 fatty acids. Supplementation with n-3 fatty acids did not have a significant effect on major vascular events (16.5% versus 16.3%) or all-cause death (15.1% versus 15.4%), nor did it make a difference in fatal or nonfatal MI, fatal or nonfatal stroke, heart failure hospitalization, revascularization, limb or digit amputation, or hospitalization for any CV cause.

Except for a significant decrease of 14.5 mg/dL (0.16 mmol/L; p<0.001) in triglycerides in the group that took fish oil supplements, there was minimal difference in blood pressure, heart rate, and cholesterol.

Kaplan-Meier curves were virtually indistinguishable between arms for death from CV cause (HR, 0.98; 95% CI, 0.87 to 1.10; p=0.72); MI, stroke, or CV death (HR, 1.01; 95% CI, 0.93 to 1.10; p=0.81); all-cause death (HR, 0.98; 95% CI, 0.89 to 1.07; p=0.63); or death from arrhythmia (HR, 1.10; 95% CI, 0.93 to 1.30; p=0.26).

Previous randomized, double-blind, placebo-controlled trials have reported conflicting results on the efficacy of n-3 fatty acid supplements in the secondary prevention of CV disease.

Aldo P. Maggioni, MD, ANMCO Research Center, Florence, Italy, explained that these differences may be due to differences in background clinical conditions, risks, or therapies. In patients with dysglycemia and additional CV risk factors, 1 g of n-3 fatty acids daily over a period of 6 years does not reduce CV deaths or other CV outcomes.

The different risks of these patients and optimized background therapies may explain the neutral results of ORIGIN versus those of other trials that have been conducted in higher-risk populations. Additional large trials will provide important information that is related to n-3 fatty acids at various stages of CV disease. These include ASCEND [NCT00135226], the Rischio and Prevenzione study, and VITAL [NCT01169259].

INSULIN GLARGINE MAIN TRIAL RESULTS

Hertzel C. Gerstein, MD, MSc, McMaster University, Hamilton, Ontario, Canada, presented the main results from the insulin glargine trial.

The intervention (added to lifestyle change) for the insulin glargine group used the same approach for subjects with or without type 2 diabetes: add evening glargine to 0 or 1 oral agent; self-titrate at 1 to 2 units twice a week to target capillary fasting plasma glucose (FPG) ≤95 mg/dL (5.3 mmol/L); and add metformin if needed to mitigate hypoglycemia. The nondiabetes standard care group was screened for type 2 diabetes annually. Those with the disease received treatment, based on guidelines and physician’s judgment.

During the study, insulin use in the glargine group dropped from 100% to 83% at Year 6, while it rose from 0% to 10% in the standard care group (Figure 1). At the end of the study, median FPG in the glargine group was 95 mg/dL (5.3 mmol/L) versus 123 mg/dL (6.8 mmol/L) in the standard care group. At 6 years, median HbA1C levels were 6.2% for glargine and 6.5% for standard care.

Figure 1. Insulin Use.

Rates of incident CV outcomes were similar in the glargine and the standard care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (MI, stroke, or CV death; HR, 1.02; 95% CI, 0.94 to 1.11; p=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (MI, stroke, CV death, revascularization, heart failure; HR, 1.04; 95% CI, 0.97 to 1.11; p=0.27). Differences in the incidence of any cancer were not significant (HR, 1.00; 95% CI, 0.88 to 1.13; p=0.97).

Dr. Gerstein concluded that basal insulin glargine that is titrated to a normal FPG has a neutral effect on CV outcomes and on cancer compared with standard care.

DIABETES PREVENTION 

Jeffrey L. Probstfield, MD, University of Washington School of Medicine, Seattle, Washington, USA, discussed diabetes prevention, asking the question: "Could insulin prevent diabetes?"

The predefined outcome of new diabetes that developed from the time of randomization up to and including an oral glucose tolerance test (OGTT) that was done approximately 1 month after all glucose-lowering therapies were stopped occurred in 24.7% versus 31.2% of 1456 participants without baseline diabetes (OR, 0.72; 95% CI, 0.58 to 0.91; p=0.006). A consistent but attenuated effect size was noted when the results of a second OGTT (done 3 months later in people without diabetes, based on the first OGTT) were included (OR, 0.80; 95% CI, 0.64 to 1.00; p=0.05) [Gerstein H et al. N Engl J Med 2012].

Dr. Probstfield concluded that although the durability of the effect is unclear, in people who are at risk for future diabetes, approximately 6 years of basal insulin glargine that is titrated to a normal FPG reduces the incidence of diabetes compared with standard care.

SAFETY: HYPOGLYCEMIA AND WEIGHT 

Lars E. Rydén, MD, PhD, Karolinska University Hospital, Stockholm, Sweden, noted that insulin therapy has been known to cause hypoglycemia for 90 years and that it is also linked to CV outcomes. Whether or not the relationship is causal is controversial. To estimate benefits and risks of insulin glargine, ORIGIN sites collected information about severe and nonsevere episodes of clinical hypoglycemia at each visit.

Severe hypoglycemia was defined as: a) signs and/or symptoms of hypoglycemia; b) required assistance (unable to help self); and c) spontaneous recovery with carbohydrate/glucagon or any measured glucose ≤36 mg/dL (2 mmol/L). Nonsevere hypoglycemia was defined as signs and/or symptoms of hypoglycemia.

According to Dr. Rydén, there were significant differences between the two groups in all categories of hypoglycemia. Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years (p<0.001). Median weight increased by 1.6 kg (95% CI, 2.0 to 5.5; p<0.001) in the glargine group and decreased by 0.5 kg (95% CI, 4.3 to 3.2; p<0.001) in the standard care group during 6.2 years.

IMPLICATIONS FOR INSULIN THERAPY 

Compared with standard glycemic care of people with early diabetes, IGT, and/or IFG, using once-daily basal insulin glargine to an FPG ≤95 mg/dL (5.3 mmol/L) for a median of 6.2 years maintains near-normal glycemic control; has a neutral effect on CV outcomes and on cancers; slows the progression of dysglycemia; and modestly increases hypoglycemia and weight.

The implications of these findings are that supplementing endogenous insulin with basal insulin injections slows progression of dysglycemia. Although later benefits or harms can not be ruled out, exogenous basal insulin’s main effect over 6 to 7 years is to flexibly lower glucose.

Despite lower glucose levels, routine early use of basal insulin glargine is not better than guideline-based standard care in limiting important health outcomes. Basal insulin glargine is now the best-studied glucose-lowering drug that is available, and no new safety concerns limit its early use when needed.

CLOSED-LOOP INSULIN THERAPY IN YOUNG CHILDREN

Glycemic control is difficult to maintain in children with diabetes aged <7 years for several reasons. Children of this age are at increased risk of hypoglycemia (particularly at night), and there is the potential for hypoglycemia-related neurocognitive outcomes. In addition, at this age, children often have unpredictable eating patterns and variable levels of activity. Closed-loop insulin delivery is a recent medical innovation that aims to achieve tight glucose control while reducing the risk of hypoglycemia, but it has not been tested in young children. Andrew Dauber, MD, Boston Children’s Hospital, Boston, Massachusetts, USA, presented data from the Closed-Loop Insulin Delivery in Children <7 years of Age Study that showed how closed-loop therapy (CLT) has the potential to improve diabetes care in young children [NCT01421225].

CLT combines glucose-sensing and insulin-delivery components with real-time glucose-responsive insulin administration. A disposable sensor measures interstitial glucose levels, which are fed automatically into an algorithm that is used to control the delivery of a rapid-acting insulin analog into the subcutaneous tissue by an insulin pump. This was a randomized crossover trial that compared CLT with standard (open-loop) pump therapy (SPT) in children aged <7 years who were diagnosed with type 1 diabetes for more than 6 months and had been treated with insulin pump therapy for more than 6 weeks. Study participants (n=10) had a mean age of 5.1 years (range 2.0 to 6.8 years) with a mean duration of diabetes of 2.1 years (range 0.5 to 4.7 years). Mean HbA1C was 8.1% (range 7.1% to 8.9%), and the average daily insulin dose was 0.72 units/kg (range 0.61 to 1.0 units/kg). All subjects had fasting c-peptide levels <0.1 ng/mL.

In this study, glucose values were transmitted from 2 Freestyle Navigator^® sensors (one placed in each thigh) to a bedside receiver. The values were retrieved from the receiver and entered manually into a control algorithm to calculate insulin recommendations. The control algorithm was a physiological insulin delivery algorithm, developed by one of the investigators, that utilized proportional-integral-derivative terms that were modified by insulin feedback. All recommendations generated by the algorithm were approved by the physician and then entered into the Animus OneTouch^® Ping^® insulin pump remote, which transmitted the insulin order to the insulin pump attached to the patient. There were 2 periods of control: overnight (10:00 PM to 8:00 AM) when basal rates were adjusted every 20 minutes based on sensor readings, and daytime (8:00 AM to noon), when mini-boluses of insulin in increments of 0.05 units were given up to every minute, based on sensor readings. Target blood sugars were 150 mg/dL during the night and 120 mg/dL during the day.

Subjects were admitted to the clinic for 48 hours. Meals and snacks were provided on a regular schedule. Participants were free to choose from a standardized menu but received the identical meals/snacks on Days 1 and 2. All meals were weighed pre- and post-consumption. The Freestyle sensors were placed on the morning of admission. That afternoon patients were switched to the study insulin pump. An intravenous line was also placed to allow for frequent blood sampling. The study period began at 10:00 PM and ran until noon the following day. During that time, subjects were randomized to receive either CLT or SPT. From noon until 10:00 PM, subjects received their standard therapy. At 10:00 PM on the second evening, subjects were randomized to the opposite therapy from the prior night.

Time at overnight target was increased with CLT but was not significantly different from SPT; however, time in extreme hyperglycemia was significantly reduced as was the total glycemic excursion overnight. There was no difference in the number of interventions for hypoglycemia or in daytime peak postprandial glucose (despite the absence of a pre-meal bolus), while the pre-lunch was significantly decreased (Table 1).

Table 1. Outcomes.

CLT maintained tight glucose control without increasing the incidence of hypoglycemia and improved pre-lunch blood sugars, leading the investigators to conclude that it has the potential to improve diabetes care for very young children.

ABATACEPT IN PATIENTS WITH NEW-ONSET TYPE 1 DIABETES: ONE-YEAR FOLLOW-UP

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that is driven by activated T-lymphocytes. To be fully active, immune T-cells need a costimulatory signal in addition to the main antigen-driven signal. A previous study showed that abatacept, a costimulation modulator that prevents full T-cell activation, slowed reduction in b-cell function over 2 years in individuals with recent-onset T1DM [Orban T et al. Lancet2011]. Tihamer Orban, MD, Joslin Diabetes Center, Boston, Massachusetts, USA, presented 1-year follow-up data from the previous 2-year study [NCT00505375].

The primary study was a multicenter, double-blind, randomized, controlled trial in which subjects (n=112) aged 6 to 45 years (mean 14 years) who were recently diagnosed with T1DM were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on Days 1, 14, and 28 and monthly thereafter for a total of 27 infusions over 2 years. Dr. Orban reported on the effects of discontinuing costimulation modulation with abatacept on preservation of β-cell function in patients from this study who were followed for 1 year after infusions were stopped.

The follow-up analysis included 93 subjects (64 from the abatacept group and 29 from the placebo group). C-peptide 2-hour AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.215 (95% CI, 0.168 to 0.265) and 0.135 (95% CI, 0.0692 to 0.205) nmol/L for the abatacept and the placebo groups, respectively (p=0.033). This difference was similar to the difference observed during the treatment phase of the trial. The C-peptide decline from baseline remained parallel with an estimated 9.5-month delay with abatacept. HbA1C was lower in abatacept-treated patients (p<0.001), with no difference in insulin use. A treatment effect was observed only for race and CDR3 status.

Data from this follow-up study indicate that costimulation modulation with abatacept slows the decline in β-cell function in recent-onset T1DM beyond drug administration and leads to lower HbA1C levels. These results suggest that abatacept may be useful in prevention studies in individuals who are at high risk of T1DM and/or as a component in studies that use a combination of different treatment strategies. Further trials are needed to test whether or not a shorter course of abatacept treatment would be sufficient to achieve similar beneficial effects.

EXPLAINING THE UKPDS LEGACY EFFECT

Ten years of follow-up observations from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated virtually identical HbA1C levels in subjects who were randomly assigned to 2 different glucose control strategies (intensive or conventional). However, subjects who received intensive glucose control remained at a significantly lower risk of diabetic complications. This continuing benefit of earlier improved glucose control has been termed the type 2 diabetes legacy effect [Chalmers J, Cooper ME. N Engl J Med 2008], an influence that is similar to the metabolic memory that has been described for type 1 diabetes [Stumvoll M et al. N Engl J Med 1995]. Marcus Lind, MD, University of Gothenburg, Gothenburg, Sweden, presented data that examined the degree to which historical HbA1C values contribute to later reductions in the risks of myocardial infarction (MI) and all-cause mortality. An additional aim was to elucidate the time-dependent impact of earlier HbA1C values on a year-by-year basis.

Continuous hazard functions for death and MI from diagnosis of type 2 diabetes in relation to age, sex, HbA1C, and original treatment assignment (intensive/conventional) were estimated in 3849 individuals from UKPDS. These data were then evaluated for different HbA1C levels during a preceding time interval to determine the degree to which they might explain the death and MI legacy effects.

Older age, male sex, and HbA1C, but not treatment group, were all found to be significantly (all p<0.001) related to MI and death. The model was used to estimate the impact of a 1% reduction in HbA1C from each of 2 time periods (at diagnosis and 10 years after diagnosis) on the risk of death and MI. For all-cause mortality, the results indicate the reduction in risk from the legacy effect is almost 3 times stronger when the HbA1C reduction is achieved early (at diagnosis) compared with later (after 10 years), and this effect is mostly because of the lower HbA1C levels at the earlier time points. The pattern is similar, but the effects of early reduction are somewhat less potent for MI.

The model was used to predict the relative reduction in the probability of death for a 50-year-old man with newly diagnosed type 2 diabetes and an HbA1C of 8% in 2 different scenarios: immediate (at diagnosis) reduction of HbA1C by 1% and waiting 10 years for the same HbA1C reduction. Reducing the HbA1C by 1% (to 7%) at diagnosis will result in an 18.6% risk reduction for death compared with only a 6.6% risk reduction if the HbA1C reduction is delayed for 10 years. Similar relationships in risk reduction and timing of the HbA1C reduction were seen when the model was applied to MI and to women.

Statistical modeling of UKPDS data confirmed that earlier HbA1C levels continue to contribute to the risk of diabetic complications, as seen in the Diabetes Control and Complications Trial [The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993]. The long-term impact of achieved HbA1C levels explains to a large extent the sustained reductions in the risk of death and MI that were seen in the UKPDS post-trial monitoring period. Thus, early intensive, optimal, glycemic control is essential to minimize the long-term risk of diabetic complications.

CHINA DA QING STUDY: LIFESTYLE CHANGE IN WOMEN WITH IGT EXTENDS LIFE

Twenty-three years of follow-up data from the China Da Qing Diabetes Prevention Study (CDQPDS) show that lifestyle intervention to prevent diabetes can reduce all-cause and cardiovascular (CV) mortality among women with impaired glucose tolerance (IGT) but not among men. Findings from the study were reported by Guangwei Li, MD, Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China.

In 1986, 577 adults with IGT from 33 clinics in Da Qing, China, were randomly assigned to a control group or 1 of 3 lifestyle intervention groups (diet, exercise, or diet plus exercise). Active intervention was carried out from 1986 to 1992. Participants who were assigned to the exercise group or diet-plus-exercise group were encouraged to increase the amount of their physical activity by at least 1 unit per day (as defined in Table 1) and by 2 units per day, if possible, for participants aged <50 years with no evidence of CV disease (Table 1) [Pan XR et al. Diabetes Care1997].

Table 1. Activities Required for Increasing Activity by One Unit of Exercise.

A 20-year follow-up study showed that group-based combined lifestyle interventions over 6 years in people with IGT can prevent or delay diabetes for up to 14 years after the active intervention [Li G et al. Lancet 2008]. Lifestyle intervention for 6 years in IGT was also associated with a 47% decline in the incidence of severe, vision-threatening retinopathy over 20 years [Gong Q et al. Diabetologia2011].

The aim of the current trial was to examine all-cause and CV mortality among those who participated in the 6-year lifestyle intervention that was implemented in the Da Qing Diabetes Prevention Study. In 2009, 23 years after randomization, participants were traced to determine the long-term impact of the interventions on mortality; 47 women and 127 men had died.

Mortality rates were compared between the control groups and the combined intervention groups (diet, exercise, and diet plus exercise). All-cause mortality was defined as death from any cause. CV mortality was defined as death from coronary heart disease, stroke, and sudden death.

In women, combined lifestyle intervention (diet, exercise, and diet plus exercise) reduced all-cause mortality by 53% (hazard rate ratio [HRR], 0.47; 95% CI, 0.25 to 0.86), with cumulative all-cause mortality of 16.2% (95% CI, 11.2 to 21.2) in the intervention group versus 29.3% (95% CI, 17.5 to 48.0) in the control group (p=0.02). Among men, there was no significant difference in cumulative all-cause mortality (p=0.41) between the combined intervention and control groups (41.1% versus 46.7%).

The reduction in all-cause mortality in women was mainly because of differences in CV mortality (heart disease and stroke; HRR, 0.30; 95% CI, 0.12 to 0.68), with 23-year cumulative mortality of 6.8% in the intervention group (95% CI, 3.4 to 10.2) versus 18.8% (95% CI, 8.8 to 28.8) in the control group (p=0.006). In men, there was also no significant difference in cumulative CV mortality (p=0.47) in the combined intervention and control groups (26.4%; 95% CI, 21.1 to 31.6 versus 27.4; 95% CI, 18.6 to 32.2).

Data from the intervention groups (diet, exercise, and diet plus exercise) suggest that combined lifestyle intervention significantly lowers all-cause and CV mortality among women with IGT but not among men. Reasons may include a large difference in baseline smoking rates between men and women.

Apart from diabetes, measures of risk factors for death (and CV disease) at baseline and during the trial were limited. In turn, the investigators were unable to identify or exclude possible confounding factors for the differences in outcomes between women and men. The reasons remain unclear.

Participants in the intervention group were, on average, 2 years younger than those in the control group, but there were no differences in baseline body mass index (BMI) in controls, 26.2±0.2 kg/m² versus BMI in the combined intervention group, 25.7±0.2 kg/m². The changes in body weight during the active-intervention period (1986 to 1992) and the entire follow-up period (1986 to 2006) did not differ significantly by group [Guangwei L et al. Lancet2008].

NEW ADA/EASD POSITION STATEMENT ENDORSES A PATIENT-CENTERED APPROACH

Overview

Glycemic management in type 2 diabetes mellitus (T2DM) has become increasingly complex and, to some extent, controversial. A widening array of pharmacological agents [Nyenwe EA et al. Metabolism 2011; Blonde L. Am J Med 2010; Bergenstal RM et al. Am J Med 2010] has raised concerns about their potential adverse effects, as well as new uncertainties about the effects of intensive glycemic control on macrovascular complications [Yudkin JS et al. Lancet 2011]. Many clinicians are, therefore, perplexed as to the optimal treatment strategies for their patients [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

Silvio E. Inzucchi, MD, Yale University School of Medicine, New Haven, Connecticut, USA, reviewed key points from the new Position Statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

The statement covers the growing variety and number of antihyperglycemic agents, new data on the benefits versus risks of tight glycemic control, increasing concerns about drug safety, and growing discourse about personalized medicine and patient-centered care. Dr. Inzucchi pointed out that prior guidelines were consensus documents that did not undergo formal Association review to become official position statements.

Main Pathological Defects in T2DM

Any rise in glycemia is the net result of glucose influx exceeding glucose outflow from the plasma compartment [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia2012]. In the fasting state, hyperglycemia is directly related to increased hepatic glucose production. In the postprandial state, further glucose excursions result from the combination of insufficient suppression of this glucose output and defective insulin stimulation of glucose disposal in target tissues, mainly skeletal muscle.

Abnormal islet cell function that progresses over time is a key and requisite feature of T2DM and the main quantitative determinant of hyperglycemia [Ferrannini E et al. J Clin Endocrinol Metab2005] (Figure 1). However, islet dysfunction is not necessarily irreversible. It responds to increased insulin action that relieves b-cell secretory burden and any intervention that improves glycemia, from energy restriction to bariatric surgery [Ferrannini E. Cell Metab 2010]. More recently, abnormalities in the incretin system have also been identified [Nauck MA. Am J Med 2009].

Figure 1. Main Pathophysiological Defects in T2DM.

Reproduced with permission from SE Inzucchi, MD.

Antihyperglycemic agents are directed at one or more of the pathophysiological defects of T2DM, or they modify physiological processes related to appetite or to nutrient absorption or excretion. Ultimately, T2DM is a disease that is heterogeneous in both its pathogenesis and clinical manifestation. This point must be considered when determining the optimal therapeutic strategy for individual patients [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

Patient-Centered Approach

According to Dr. Inzucchi, patient-centered care is defined as an approach to providing treatment that is respectful of and responsive to an individual patient’s preferences, needs, and values, and it ensures that a patient’s values guide all clinical decisions [Committee on Quality of Health Care in America: Institute of Medicine. The National Academies Press 2001]. He noted that this should be the organizing principle underlying health care for individuals with any chronic disease, but it is especially pertinent in T2DM, with the uncertainties of choice as well as the sequence of therapy [Inzucchi et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

In a shared decision-making approach, the clinician and the patient act as partners, mutually exchanging information and deliberating on options to reach a consensus on the therapeutic course of action [Tsapas A, Matthews DR. Diabetologia 2008]. Ultimately, the patient makes the final decisions regarding lifestyle choices and, to some degree, the pharmaceutical interventions used [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

A patient’s involvement in medical decision-making constitutes one of the core principles of evidence-based medicine, which mandates the synthesis of best available evidence from the literature with the clinician’s expertise and the patient’s inclination [Guyatt GH et al. JAMA 2000]. The implementation of the plan occurs in the context of a patient’s real life and his consumption of public and private resources [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

For many people with complex, chronic comorbidities, the burden of treatment reduces their capacity to collaborate in their care. Therefore, clinicians must establish the weight of burden, encourage coordination in clinical practice, acknowledge comorbidity in clinical evidence, and prioritize from the patient’s perspective [May C et al. BMJ 2009].

Position Statement

The document refers to glycemic control pursued within a multifactorial risk-reduction framework. Such a framework is necessary because patients with T2DM are at increased risk of cardiovascular (CV) morbidity and mortality. Aggressive management of CV risk factors (blood pressure and lipid therapy, antiplatelet treatment, and smoking cessation) is likely to have even greater benefits among these patients [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

The key points of the ADA/EASD Position Statement: Management of Hyperglycemia in Type 2 Diabetes are: 1) glycemic target blood-glucose lowering therapies must be individualized; 2) diet, exercise, and education are the foundation of any T2DM therapy program; 3) unless contraindicated, metformin is the optimal first-line drug; 4) after metformin, data are limited; combination therapy with one or two other oral/injectable agents that minimize side effects is reasonable; 5) ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain blood glucose control; 6) all treatment decisions should be made in conjunction with the patient (focus on preferences, needs, and values); and 7) comprehensive CV risk reduction is a major focus of therapy [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].

Compared with the 2008 ADA/EASD Treatment Algorithm, the 2012 statement is not as prescriptive/algorithmic. It calibrates treatment targets to patients’ needs and acknowledges the role of lifestyle change prior to metformin in selected patients. It individualizes treatment options and harmonizes 5 dual-therapy options after metformin. It recognizes the role of initial combination therapy (HbA1C >9%), and endorses triple therapy, when required. It also includes insulin options beyond basal and basal-bolus (Figure 2).

Figure 2. The ADA/EASD Position Statement on Management of Hyperglycemia in T2DM.

Reproduced with permission from SE Inzucchi, MD.

The position statement clearly argues for less stringent HbA1C goals in patients who are predisposed to hyperglycemia and have limited life expectancy, advanced complications, extensive comorbidities, or a glycemic target that is difficult to control despite intensive education, counseling, and effective doses of glucose-lowering agents.

The statement was developed over a period of approximately 2 years by an international writing group, chaired by Dr. Inzucchi and Professor David Matthews from Oxford University and underwent dozens of revisions with additional input from 25 experts around the world. It highlights a proposed patient-centered approach that provides not only the most comprehensive management strategy to date, but also the most vetted and thoroughly reviewed statement ever published [Cefalu CT. Diabetes Care 2012].

It is an expansive approach that suggests recommendations considered within the context of the needs, preferences, and tolerances of each patient. At the same time, the recommendations clearly state that the informed judgment and expertise of experienced clinicians will always be necessary [Cefalu CT. Diabetes Care 2012].

This new ADA/EASD Position Statement will generate a wide range of opinions and emotions. However, no one will disagree with the fact that the initiative was conducted with due diligence deserving of a document that will likely have major impact for millions of patients throughout the world [Cefalu CT. Diabetes Care 2012].

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