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Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1 –5 ), mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications (6 –9 ). Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations (10 ) and by other societies and federations (2 ,11 –15 ). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16 ,17 ), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18 ,19 ).
This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular risk factors (blood pressure and lipid therapy, antiplatelet treatment, and smoking cessation) is likely to have even greater benefits.
These recommendations should be considered within the context of the needs, preferences, and tolerances of each patient; individualization of treatment is the cornerstone of success. Our recommendations are less prescriptive than and not as algorithmic as prior guidelines. This follows from the general lack of comparative-effectiveness research in this area. Our intent is therefore to encourage an appreciation of the variable and progressive nature of type 2 diabetes, the specific role of each drug, the patient and disease factors that drive clinical decision making (20 –23 ), and the constraints imposed by age and comorbidity (4 ,6 ). The implementation of these guidelines will require thoughtful clinicians to integrate current evidence with other constraints and imperatives in the context of patient-specific factors.
Evidence-based advice depends on the existence of primary source evidence. This emerges only from clinical trial results in highly selected patients, using limited strategies. It does not address the range of choices available, or the order of use of additional therapies. Even if such evidence were available, the data would show median responses and not address the vital question of who responded to which therapy and why (24 ). Patient-centered care is defined as an approach to “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions” (25 ). This should be the organizing principle underlying health care for individuals with any chronic disease, but given our uncertainties in terms of choice or sequence of therapy, it is particularly appropriate in type 2 diabetes. Ultimately, it is patients who make the final decisions regarding their lifestyle choices and, to some degree, the pharmaceutical interventions they use; their implementation occurs in the context of the patients’ real lives and relies on the consumption of resources (both public and private).
Patient involvement in the 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 patient's own inclinations (26 ). During the clinical encounter, the patient's preferred level of involvement should be gauged and therapeutic choices explored, potentially with the utilization of decision aids (21 ). In a shared decision-making approach, clinician and patient act as partners, mutually exchanging information and deliberating on options, in order to reach a consensus on the therapeutic course of action (27 ). There is good evidence supporting the effectiveness of this approach (28 ). Importantly, engaging patients in health care decisions may enhance adherence to therapy.
Epidemiology and health care impact
Both the prevalence and incidence of type 2 diabetes are increasing worldwide, particularly in developing countries, in conjunction with increased obesity rates and westernization of lifestyle. The attendant economic burden for health care systems is skyrocketing, owing to the costs associated with treatment and diabetes complications. Type 2 diabetes remains a leading cause of cardiovascular disorders, blindness, end-stage renal failure, amputations, and hospitalizations. It is also associated with increased risk of cancer, serious psychiatric illness, cognitive decline, chronic liver disease, accelerated arthritis, and other disabling or deadly conditions. Effective management strategies are of obvious importance.
Relationship of glycemic control to outcomes
It is well established that the risk of microvascular and macrovascular complications is related to glycemia, as measured by HbA1c ; this remains a major focus of therapy (29 ). Prospective randomized trials have documented reduced rates of microvascular complications in type 2 diabetic patients treated to lower glycemic targets. In the UK Prospective Diabetes Study (UKPDS) (30 ,31 ), patients with newly diagnosed type 2 diabetes were randomized to two treatment policies. In the standard group, lifestyle intervention was the mainstay with pharmacological therapy used only if hyperglycemia became severe. In the more intensive treatment arm, patients were randomly assigned to either a sulfonylurea or insulin, with a subset of overweight patients randomized to metformin. The overall HbA1c achieved was 0.9% lower in the intensive policy group compared with the conventional policy arm (7.0% vs. 7.9%). Associated with this difference in glycemic control was a reduction in the risk of microvascular complications (retinopathy, nephropathy, neuropathy) with intensive therapy. A trend toward reduced rates of myocardial infarction in this group did not reach statistical significance (30 ). By contrast, substantially fewer metformin-treated patients experienced myocardial infarction, diabetes-related and all-cause mortality (32 ), despite a mean HbA1c only 0.6% lower than the conventional policy group. The UKPDS 10-year follow-up demonstrated that the relative benefit of having been in the
intensive management policy group was maintained over a decade, resulting in the emergence of statistically significant benefits on cardiovascular disease (CVD) end points and total mortality in those initially assigned to sulfonylurea/insulin, and persistence of CVD benefits with metformin (33 ), in spite of the fact that the mean HbA1c levels between the groups converged soon after the randomized component of the trial had concluded.
In 2008, three shorter-term studies [Action to Control Cardiovascular Risk in Diabetes (ACCORD) (34 ), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) (35 ), Veterans Affairs Diabetes Trial (VADT) (36 )] reported the effects of two levels of glycemic control on cardiovascular end points in middle-aged and older individuals with well-established type 2 diabetes at high risk for cardiovascular events. ACCORD and VADT aimed for an HbA1c <6.0% using complex combinations of oral agents and insulin. ADVANCE aimed for an HbA1c ≤6.5% using a less intensive approach based on the sulfonylurea gliclazide. None of the trials demonstrated a statistically significant reduction in the primary combined cardiovascular end points. Indeed, in ACCORD, a 22% increase in total mortality with intensive therapy was observed, mainly driven by cardiovascular mortality. An explanation for this finding has remained elusive, although rates of hypoglycemia were threefold higher with intensive treatment. It remains unclear, however, if hypoglycemia was responsible for the adverse outcomes, or if other factors, such as more weight gain, or simply the greater complexity of therapy, contributed. There were suggestions in these trials that patients without overt CVD, with shorter duration of disease, and lower baseline HbA1c. benefited from the more intensive strategies. Modest improvements in some microvascular end points in the studies were likewise demonstrated. Finally, a meta-analysis of cardiovascular outcomes in these trials suggested that every HbA1c reduction of ∼1% may be associated with a 15% relative risk reduction in nonfatal myocardial infarction, but without benefits on stroke or all-cause mortality (36 ).
Overview of the pathogenesis of type 2 diabetes
Any rise in glycemia is the net result of glucose influx exceeding glucose outflow from the plasma compartment. 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. Once the renal tubular transport maximum for glucose is exceeded, glycosuria curbs, though does not prevent, further hyperglycemia.
Abnormal islet cell function is a key and requisite feature of type 2 diabetes. In early disease stages, insulin production is normal or increased in absolute terms, but disproportionately low for the degree of insulin sensitivity, which is typically reduced. However, insulin kinetics, such as the ability of the pancreatic β-cell to release adequate hormone in phase with rising glycemia, are profoundly compromised. This functional islet incompetence is the main quantitative determinant of hyperglycemia (37 ) and progresses over time. In addition, in type 2 diabetes, pancreatic α-cells hypersecrete glucagon, further promoting hepatic glucose production (38 ). Importantly, islet dysfunction is not necessarily irreversible. Enhancing insulin action relieves β-cell secretory burden, and any intervention that improves glycemia—from energy restriction to, most strikingly, bariatric surgery—can ameliorate β-cell dysfunction to an extent (39 ). More recently recognized abnormalities in the incretin system (represented by the gut hormones, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic peptide [GIP]) are also found in type 2 diabetes, but it remains unclear whether these constitute primary or secondary defects (40 ). In most patients with type 2 diabetes, especially the obese, insulin resistance in target tissues (liver, muscle, adipose tissue, myocardium) is a prominent feature. This results in both glucose overproduction and underutilization. Moreover, an increased delivery of fatty acids to the liver favors their oxidation, which contributes to increased gluconeogenesis, whereas the absolute overabundance of lipids promotes hepatosteatosis (41 ).
Antihyperglycemic agents are directed at one or more of the pathophysiological defects of type 2 diabetes, or modify physiological processes relating to appetite or to nutrient absorption or excretion. Ultimately, type 2 diabetes is a disease that is heterogeneous in both pathogenesis and in clinical manifestation—a point to be considered when determining the optimal therapeutic strategy for individual patients.
The ADA's “Standards of Medical Care in Diabetes” recommends lowering HbA1c to <7.0% in most patients to reduce the incidence of microvascular disease (42 ). This can be achieved with a mean plasma glucose of ∼8.3–8.9 mmol/L (∼150–160 mg/dL); ideally, fasting and premeal glucose should be maintained at <7.2 mmol/L (<130 mg/dL) and the postprandial glucose at <10 mmol/L (<180 mg/dL). More stringent HbA1c targets (e.g. 6.0–6.5%) might be considered in selected patients (with short disease duration, long life expectancy, no significant CVD) if this can be achieved without significant hypoglycemia or other adverse effects of treatment (20 ,43 ). Conversely, less stringent HbA1c goals—e.g. 7.5–8.0% or even slightly higher—are appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbid conditions and those in whom the target is difficult to attain despite intensive self-management education, repeated counseling, and effective doses of multiple glucose-lowering agents, including insulin (20 ,44 ).
The accumulated results from the aforementioned type 2 diabetes cardiovascular trials suggest that not everyone benefits from aggressive glucose management. It follows that it is important to individualize treatment targets (5 ,34 –36 ). The elements that may guide the clinician in choosing an HbA1c target for a specific patient are shown in Fig. 1. As mentioned earlier, the desires and values of the patient should also be considered, since the achievement of any degree of glucose control requires active participation and commitment (19 ,23 ,45 ,46 ). Indeed, any target could reflect an agreement between patient and clinician. An important related concept is that the ease with which more intensive targets are reached influences treatment decisions; logically, lower targets are attractive if they can be achieved with less complex regimens and no or minimal adverse effects. Importantly, utilizing the percentage of diabetic patients who are achieving an HbA1c <7.0% as a quality indicator, as promulgated by various health care organizations, is inconsistent with the emphasis on individualization of treatment goals.