Application of clinical judgment and guidelines to achieving glycemic goals in type 2 diabetes: focus on pharmacologic therapy.

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Application of Clinical Judgment and Guidelines to Achieving Glycemic Goals in Type 2 Diabetes: Focus on Pharmacologic Therapy Tamer G. Yacoub MD, FACE

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Clinical Endocrinologist, Prima-Care Medical Center, Fall River, MA Published online: 28 May 2015.

Click for updates To cite this article: Tamer G. Yacoub MD, FACE (2014) Application of Clinical Judgment and Guidelines to Achieving Glycemic Goals in Type 2 Diabetes: Focus on Pharmacologic Therapy, Postgraduate Medicine, 126:3, 95-106 To link to this article: http://dx.doi.org/10.3810/pgm.2014.05.2759

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C L I N I C A L F O C U S : D I A B E T E S A N D C O N C O M I TA N T D I S O R D E R S

Application of Clinical Judgment and Guidelines to Achieving Glycemic Goals in Type 2 Diabetes: Focus on Pharmacologic Therapy

Downloaded by [Emory University] at 15:47 12 August 2015

DOI: 10.3810/pgm.2014.05.2759

Tamer G. Yacoub, MD, FACE Clinical Endocrinologist, Prima-Care Medical Center, Fall River, MA

Abstract: Successful management of patients with type 2 diabetes mellitus requires attention to 4 pillars of care: diet, exercise, blood glucose monitoring, and pharmacologic therapy. For pharmacologic therapy, the availability of multiple drugs in different classes can make choices regarding initiation and intensification of treatment challenging. This article, focusing on clinical practice, reviews and provides guidance on assessing recommendations made by the latest diabetes guidelines for pharmacotherapy published by the American Diabetes Association and the American Academy of Clinical Endocrinologists. The article discusses how diabetes guidelines evolved, their move toward personalization of therapy, and their effective use in clinical practice. An appraisal of various pharmacologic strategies is integrated with the author’s approach to achieving glycemic goals with a minimum of weight gain or hypoglycemic episodes. Using patients’ baseline glycated hemoglobin levels and the degree to which their fasting and postprandial plasma levels contribute to their hyperglycemia is explained as a strategy by which drugs can be chosen that act on these parameters. Lifestyle interventions such as diet and exercise should continue to form the foundation of the therapeutic alliance between the clinician and patient as pharmacologic therapy is initiated or intensified. Keywords: type 2 diabetes mellitus; guidelines; antihyperglycemic drugs; hemoglobin A1c goals; American Diabetes Association; American Academy of Clinical Endocrinologists

Introduction

Correspondence: Tamer G. Yacoub, MD, FACE, Prima-Care Medical Center, 277 Pleasant St, Suite 302, Fall River, MA 02720. Tel: 508-646-7710 Fax: 508-646-7714 E-mail: [email protected]

The goals of successful management of patients with type 2 diabetes mellitus (T2DM) are to achieve glycemic control; avoid the micro- and macrovascular complications of hyperglycemia;1 and manage blood pressure, dyslipidemia, and comorbid conditions— all of which require a multimodal approach, representing overall standards of care (SOC).2,3 These goals involve 4 pillars of T2DM management—diet, exercise, blood glucose monitoring, and pharmacologic therapy—as a comprehensive way to achieve glycemic goals. This approach has been recognized by a variety of professional organizations, such as the American Association of Clinical Endocrinologists (AACE), the American College of Endocrinologists (ACE), the American Diabetes Association (ADA), and the European Association for the Study of Diabetes (EASD).2–5 The availability of multiple drug classes and combinations makes it important for a clinician to not only assess the evidence for and against any specific drug or combination, but to do so in the context of an individual patient’s comorbidities, age, glycated hemoglobin (HbA1c) levels, history of treatment, and individual preferences and treatment goals.2,4,6,7

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Tamer G.Yacoub

Diet and exercise (discussed in a companion article in this issue) form the foundation of SOC, with pharmacologic therapy to be added and maintained as needed. In addition, diabetes self-management education and support is an important part of successful management of patients with T2DM. A meta-analysis of 11 studies showed a significant change in HbA1c levels of −0.55% from baseline to 1 year with group-based education,8 and diabetes self-management education and support are advocated by the ADA 2014 SOC as an integral component of care for the management of patients with diabetes and as effective in both individual and group settings.2 This article provides a clinically oriented approach to management strategies by describing considerations for initiating and intensifying pharmacologic therapy in patients with T2DM based on the latest ADA and AACE/ACE guidelines and the author’s experience with over 2000 patients with T2DM, integrated with a critical review of the literature.

Evolution and Implementation of Guidelines for T2DM in Clinical Practice Background

Selection of a pharmacologic agent for treating T2DM is complex. Only insulin and sulfonylureas (SUs) were available before 1995 in the United States;9 now there are > 10 different classes of agents available (even more, if we count the different types of insulin), and in some cases multiple drugs within a class.5 Compounding this wealth of choices is the prospect of more drugs in the near future, given that many novel compounds are being pursued (nearly 1000 compounds have been described as of 2012 for the possible treatment of T2DM, and about 180 are already in clinical studies in the United States).10 This creates a potential challenge for health care practitioners who treat patients with T2DM, but at the same time provides patients with more options. Because many of the drugs across classes work through different mechanisms of action and address different pathophysiologic defects involved in T2DM, there are many opportunities for combination therapy and potential synergies among the drug classes.11 However, making these choices is not always easy because of the many patient-specific factors involved in treatment decisions (such as age, duration of T2DM, and comorbidities) and the variety of responses to drugs shown by patients with T2DM.7 One tool that may be helpful to clinicians is guidelines developed by experts in the field, which offer different approaches to solve this clinical challenge. Some guidelines, 96

such as the AACE/ACE 2013 comprehensive diabetes management algorithm,4 offer algorithmic approaches, whereas others, such as the ADA 2014 SOC guidelines (as with the ADA/EASD 2012 position statement on pharmacologic therapy),2,5 offer a less prescriptive and more patientcentered approach. The ACE/AACE roadmap was an early guideline for pharmacotherapy for T2DM management.12 Previous guidelines, such as the ADA/EASD 2006 consensus statement13 and the AACE/ACE 2009 consensus algorithm,14 focused on algorithms. The 2009 ADA/EASD guidelines included a 2-tiered approach consisting of lifestyle changes and metformin as the first step of the first tier, followed by addition of basal insulin or an SU in the second step (wellvalidated therapies); the second tier consisted of addition of what at the time was considered by these guidelines as therapies that were less well validated, namely pioglitazone or glucagon-like peptide-1 (GLP-1) receptor agonists.15 The ADA 2014 SOC suggests that if initial monotherapy with metformin does not achieve goals in about 3 months, then thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists, SUs, or insulin could be added to metformin.2 Particularly with the ADA/EASD 2012 position statement on pharmacologic therapy, recommendations were individualized and patient-centric.5 The guidelines are intended for use in conjunction with clinical judgment.2,16

Considerations for the Use of Guidelines in Clinical Practice

Clinical practice guidelines are often developed by expert consensus and by review of population-based studies, with the purpose of providing clinicians a means to interpret and apply to clinical practice the large body of medical evidence.17 How this gets translated into clinical practice for specialists and primary care physicians, however, is not always straightforward, with varying degrees of adherence to guidelines existing among health care practitioners.18 In terms of treatment individualization and avoiding a one-sizefits-all approach, the reliance on expert consensus guidelines versus evidence-based grading of the literature could theoretically offer benefits for clinical practice.19 As discussed in the companion article on overall SOC, guidelines for the management of diabetes rely not only on evidence-based grading of the literature2,3 but also on expert consensus and clinical experience,2 all of which offer distinct benefits.

Pathophysiologic Heterogeneity of T2DM

Type 2 diabetes mellitus is a progressive disease that, despite long-term drug therapy, involves a progressive loss of β-cell

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Pharmacologic Therapy for T2DM

function as well as a host of other pathophysiologic defects that contribute to insulin resistance or deficiency. Both insulin resistance and β-cell dysfunction are usually present very early in the course of T2DM and account for the defects that lead to hyperglycemia.20,21 Many drugs (such as metformin and SUs) do not affect the underlying pathophysiology of T2DM in terms of preventing the loss of beta-cell function.11 By understanding the pathophysiologic defects in T2DM, therapy can be targeted using drugs that act on those defects.11 Type 2 diabetes mellitus is a heterogeneous disease in terms of its pathogenesis and clinical presentation (eg, the variety of comorbidities)5 and thus not all patients respond similarly to any given drug. Many of the large clinical trials comparing different drugs, in seeking to minimize confounding variables and variability that could affect drug response, may fail to capture individual variation in responses.22 Landmark diabetes trials, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Veterans Affairs Diabetes Trial (VADT), the UK Prospective Diabetes Study (UKPDS), and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) demonstrated the importance of varying glycemic goals based on individual patient characteristics and understanding how the heterogeneity of T2DM could affect response to therapy.7 Metabolic memory has been described as the prolonged beneficial effects of a period of good glycemic control, but also as the prolonged harm produced by poor glycemic control.23 The long-term benefits of early, intensive antihyperglycemic therapy may thus provide a rationale for the need to individualize treatment based on the duration of therapy. The pathophysiologic heterogeneity that underlies T2DM makes it difficult to predict a patient’s response to any given therapy and highlights the importance of an individualized approach.22

Personalized medicine can play an important role for select patients because in cases where there is large-scale evidence for several drugs, any one of which might be indicated for the patient (such as add-on therapy to metformin), singlesubject (ie, N = 1), randomized, crossover studies in which the patient serves as his or her own control can establish which drug might be more efficacious in a particular patient.24 In the future, genotyping and testing patients for metabolomic markers could help predict patients’ responses to T2DM drugs.7 Table 1 shows some of the considerations I keep in mind when approaching individualization of drug therapy for a patient.

Considerations for Initial Pharmacologic Therapy for T2DM

Although the latest ADA and AACE/ACE guidelines on pharmacotherapy suggest initiating therapy with a single drug,2,4 considerations for combination therapy stem from the need to achieve greater reductions in HbA1c levels than with monotherapy alone, as well as the goal of addressing the different pathophysiologic defects in T2DM based on the different mechanisms of action of the drugs.11 In the long term, because of the progressive nature of T2DM, many patients cannot achieve glycemic control with metformin, SU, or TZD monotherapy, as shown, for example, by A Diabetes Outcome Progression Trial (ADOPT).25 Many of the major drugs for

Table 1. Some Considerations Recommended by the Author in Individualizing Therapy for Patients With T2DM Drug Considerationa

Examples of why it is important

Precautions for use

a) TZDs b) Metformin c) GLP-1 receptor agonists d) Bromocriptine

Personalized Approaches

The move of the recent guidelines toward personalized care underscores the value of this approach, which can involve knowing the contributors to HbA1c (fasting plasma glucose [FPG] and postprandial plasma glucose [PPG]), and how to tailor treatment accordingly.3 Despite recommending that HbA1c levels be lowered to a specific target, the latest guidelines for diabetes, although still providing such cutoffs, also emphasize personalized care and the importance of individualizing HbA1c levels based on patient-specific factors such as age, comorbidities, cardiovascular complications, the possibility of achieving HbA1c goals without hypoglycemia, duration of T2DM, life expectancy, and patient preferences.2,4

Adverse effects, such as hypoglycemia and weight gain

Fasting/postprandial blood glucose effects

Relevance to which patients (examples)

a) Concomitant CHF55 b) Renal insufficiency5 c) Gastroparesis56,b d) Orthostatic hypotension, syncopal migraine57 Insulin/SUs/meglitinides Obese or overweight may cause fear of patients; patients with hypoglycemia, which can other comorbidities lead to defensive eating (hypertension and and further weight gain hyperlipidemia) Strategic selection of All patients therapy

Contraindications of the drugs can be found in the drugs’ prescribing information. Based on a case report of its occurrence in a 44-year-old woman with T1DM, and, because GLP-1 receptor agonists delay gastric emptying, in patients with gastroparesis this effect could be accentuated, predisposing patients to bezoars, with the risk of other complications (eg, obstruction, pancreatitis, and intestinal perforation).56 Abbreviations: CHF, congestive heart failure; GLP-1, glucagon-like peptide 1; SUs, sulfonylureas; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.

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Tamer G.Yacoub

T2DM have been found in large randomized controlled studies to reduce HbA1c levels to a similar degree;26 consequently, choosing the right drug or combination depends in part on its adverse event profile, effects on weight and hypoglycemia risk, and targeting of FPG or PPG.6 In clinical practice, the author’s approach is based in part on the AACE 2011 comprehensive care plan recommendations3 to initiate monotherapy/combination therapy that works specifically on FPG or PPG, and is personalized depending on the patient’s baseline HbA1c, FPG, and PPG levels.


Setting an HbA1c Goal

Initial pharmacologic treatment starts with an evaluation of the most appropriate HbA1c goal for a patient. Although both the latest ADA and AACE/ACE guidelines recommend that the HbA1c goal be individualized, they also suggest different targets depending on a number of factors.2,4 The AACE/ ACE 2013 algorithm lists a goal of # 6.5% for patients who are relatively healthy, have no concurrent illness, and are at low risk for hypoglycemia, and . 6.5% for patients with concurrent illness and at risk for hypoglycemia.4 The target HbA1c level of the ADA 2014 SOC, on the other hand, is , 7.0% for many nonpregnant adults; more stringent goals (such as , 6.5%) are listed for selected individual patients if they can be achieved without significant hypoglycemia or other adverse effects of treatment; and less stringent goals (such as , 8%) for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and for those for whom achieving treatment goals has proven difficult to attain.2 Whether an HbA1c goal of , 6.5% or , 7.0% for most patients represents satisfactory glycemic control depends on a number of clinical factors, including the intensity of the pharmacologic regimen and risk for hypoglycemic events, as well as the patient’s age, body mass index, risk of complications, and other factors.27 Such considerations have been enshrined in methods for individualizing HbA1c goals, such as the ABCD approach, which individualizes the HbA1c goal on the basis of a patient’s age, body weight, complications, and duration of disease.28

Use of Metformin and Treatment Considerations Based on Contraindications and Drug Interactions

Because many oral antihyperglycemic drugs affect cytochrome P-450 enzyme activity or have other pharmacologic actions, dose adjustments may be required for either the antihyperglycemic drug or any drug used to treat concomitant 98

conditions, or both.29 Given the central place of metformin in many of the diabetes guidelines, evaluating the role of contraindications and combination therapy is important, particularly for metformin, given its widespread use. The ADA 2014 SOC recommends metformin as the initial preferred drug to use if tolerated and not contraindicated.2 This approach is also advocated by the American College of Physicians guidelines, which, in evaluating comparative effectiveness studies, found that when used as monotherapy or in combination, metformin in most cases is more effective in reducing HbA1c levels compared with other drugs or combinations.26 Metformin is included in the AACE/ACE 2013 treatment algorithm, which recommends that for starting patients on monotherapy, if entry HbA1c levels are , 7.5%, then metformin, a GLP-1 receptor agonist, a DPP-4 inhibitor, or an alpha-glucosidase inhibitor (AGI) be used (in that order of preference).4 However, metformin is not always the best choice for all patients because some patients cannot tolerate its gastrointestinal side effects. In addition, metformin is contraindicated in patients with impaired kidney function, decreased tissue perfusion or hemodynamic instability, liver disease, alcohol abuse, heart failure, and any condition that might lead to lactic acidosis (black-box warning for lactic acidosis).5,26 Compared with metformin monotherapy, the combination of metformin with either an SU or meglitinide has been shown to result in an increase in hypoglycemia.26 A meta-analysis of randomized controlled trials found no evidence of benefits of metformin in terms of all-cause or cardiovascular mortality and all diabetes macrovascular complications, concluding that metformin may not be the best comparator for evaluating new antihyperglycemic drugs.30 This is because the authors found that the number and quality of available studies were insufficient to evaluate the benefit/risk ratio of metformin, while at the same time pointing out that it is not clear which antihyperglycemic drug has the most favorable benefit/risk ratio to serve as the comparator.

Importance of Baseline HbA1c, Fasting Plasma Glucose, and Postprandial Plasma Glucose

Baseline HbA1c levels influence the response to treatment and thus can be a guide to the selection of pharmacologic agents. For example, a meta-analysis that assessed the relationship between baseline HbA1c levels and perceived efficacy of treatment suggested that baseline differences in HbA1c levels may account for apparent differences in responses to sitagliptin, rosiglitazone, and pioglitazone.31 Lower baseline




HbA1c levels were the best predictor of achieving HbA1c levels # 7.0% for systematically titrated insulin glargine added to oral drugs.32 A positive relationship has also been found between baseline HbA1c levels and the magnitude of HbA1c change across 10 categories of glucose-lowering therapies.33 The HbA1c levels reflect contributions from both FPG and PPG34; PPG accounts for approximately 70% of the overall glycemic exposure above normal levels in patients in the lowest range of HbA1c (, 7.3%), with the contribution from FPG increasing with higher HbA1c levels.35 In the highest HbA1c range (. 10.2%), the contributions are reversed; PPG contributes 30% and FPG 70%.35 Basal fasting glucose levels, which are markedly reduced when treatment is intensified with basal insulin, still account for about one third of hyperglycemic exposure.34 If FPG is decreased, PPG has to fall as well because the starting point is lowered. Overcorrecting FPG in an attempt to lower PPG can therefore result in significant risk of hypoglycemia. Because of the differential contribution of FPG and PPG to HbA1c levels, targeting either or both of these sources of hyperglycemia with drugs that reduce FPG or PPG may be of clinical benefit.34

Decision Making Using Fasting and Postprandial Glucose Levels

The AACE 2011 comprehensive care plan guidelines emphasize decision making using FPG and PPG levels.3 They recommend that when PPG is elevated, glinides or AGIs, short- or rapid-acting insulin, and metformin should be considered.3 The DPP-4 inhibitors and GLP-1 receptor agonists, especially short-acting GLP-1 receptor agonists, also target PPG in a glucose-dependent manner, which reduces the risks of hypoglycemia.3 Although the ADA/EASD 2012 position statement on pharmacologic therapy does not distinguish between FPG and PPG levels as a guide to which drug(s) to use,5 the ADA 2014 SOC acknowledges that PPG contributes to elevated HbA1c levels, with its relative contribution being higher at HbA1c levels closer to 7%.2 They also point out that outcome studies have clearly shown HbA1c to be the primary predictor of complications, with major clinical trials overwhelmingly relying on preprandial self-monitoring of blood glucose.2 They explain that even if preprandial glucose goals are met, if HbA1c goals are not being met, then PPG may be targeted.2 Treating PPG has been shown to improve HbA1c levels and reduce cardiovascular complications.36 My approach is to choose agents that work on either FPG or PPG, depending on the patient’s HbA1c levels (Table 2).

Patient comorbidities and avoidance of agents associated with weight gain or hypoglycemia are also factors to consider. Figure 1 shows a schematic of my approach for individualizing therapy on the basis of HbA1c levels, using drugs that do not cause hypoglycemia or weight gain. If HbA1c levels , 7.0% or 7.5%, PPG is the main driver of HbA1c,35 making a single drug for monotherapy that works on reducing PPG levels a good choice to try initially, except SUs because of their high risk of hypoglycemia. When HbA1c is between 7.5% and 9%, about 50% of hyperglycemia is due to fasting and about 50% is due to postprandial states.35 Thus, 2 separate drugs can be used: one that acts on FPG (such as metformin37) and another that addresses PPG without increasing the risk of hypoglycemia. Because HbA1c levels . 9% are predominantly driven by FPG, the patient will most likely need to be on a basal insulin therapy. However, once glucose toxicity has resolved, the patient may be able to discontinue basal insulin and use other antihyperglycemic drugs. In the meanwhile it is important to consider other drug(s) to address PPG because I have found that controlling FPG with basal insulin will be unlikely to sufficiently control PPG. Some of these drugs, which do not carry an increased risk of hypoglycemia, include the GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitor, and dopamine agonists.

Table 2. Drugs That Reduce Fasting and Postprandial Hyperglycemia Drugs that work on fasting glucose No increased risk of hypoglycemia: • Metformin37 • SGLT-2 inhibitors (eg, canagliflozin)46 • Long-acting GLP-1 receptor agonists (eg, exenatide once weekly41) and liraglutide once daily58 Associated risk of hypoglycemia: • Sulfonylureaa (eg, glimepiride or glipizide ER)3 Drugs that work on postprandial glucose No increased risk of hypoglycemia: • GLP-1 receptor agonists (liraglutide and exenatide),41,58 DPP-4 inhibitors,41 quick-release bromocriptine,5 AGIs (acarbose),3 SGLT-2 inhibitors (canagliflozin),46 amylin mimetics (pramlintide)3 Associated risk of hypoglycemia: • Short-acting insulin analogues3,b • Short-acting insulin secretogogues (repaglinide and nateglinide)59 a Given strategically at dinner time, in a small dose and adjusted to desired fasting plasma glucose level. If unsuccessful, consider basal insulin glargine/detemir at a low dose (or 0.1–0.2 units/kg) and titrate in a treat-to-target fashion to reach desired fasting glucose (associated with a risk of hypoglycemia, defensive eating, and weight gain that could be minimized with a start low and go slow strategy). b With a strategy to start low and go slow to minimize the risk of hypoglycemia, defensive eating, and weight gain. Abbreviations: AGI, alpha-glucosidase inhibitor; DPP-4, dipeptidyl peptidase 4; ER, extended release; GLP-1, glucagon-like peptide 1; SGLT-2, sodium-glucose linked transporter-2.


Tamer G.Yacoub

The potential to reach the HbA1c goal might determine if . 1 drug is needed.


Drug Considerations Based on Risk of Adverse Effects, Including Hypoglycemia and Weight Gain

Many classes of noninsulin drugs used as monotherapy produce similar reductions in HbA1c.3 As pointed out by the ADA/ EASD 2012 position statement, the expected HbA1c reduction with metformin, SUs, TZDs, and GLP-1 receptor agonists is around 1.0% to 1.5%, whereas that for meglitinides, DPP-4 inhibitors, AGIs, colesevelam, and bromocriptine is 0.5% to 1.0%.5 Thus, selecting an agent becomes a function of individualization based on the mechanism of action, the adverse event profile (in particular, effects on weight and the risk of hypoglycemia), the cost, and patient preferences.6 Patients may not reach HbA1c goals with monotherapy, leading to the need for a combination of drugs.3 I think it is important to start with drugs that do not increase weight or cause hypoglycemia, an approach that can lead to decreased insulin resistance and minimized burden of disease from other comorbidities such as hypertension and dyslipidemia. Hypoglycemic episodes and persistently high HbA1c levels have been correlated in the ACCORD, ADVANCE, and VADT studies with negative cardiovascular outcomes.38 Drugs that are not associated with weight gain

include DPP-4 inhibitors, GLP-1 receptor agonists, metformin, sodium-glucose linked transporter-2 (SGLT-2) inhibitors, and the amylin mimetics.4 For example, treatment with liraglutide, a GLP-1 receptor agonist, was shown to lead to weight loss on the order of . 2 kg at 2 years of treatment.39 Exenatide has also been shown to result in weight loss, such as with a study that showed after 30 weeks a significant loss of 2.8 ± 0.5 kg in patients treated with 10 µg exenatide twice a day40; exenatide taken once weekly has also been shown to result in comparable weight loss over similar time periods.41 Drugs not associated with hypoglycemia or that carry a low risk of hypoglycemia include metformin, DPP-4 inhibitors, TZDs, AGIs, bile acid sequestrants, dopamine agonists, GLP-1 receptor agonists, and SGLT-2 inhibitors.4,38 This is mostly because they either do not directly increase insulin levels independent of glucose levels (eg, the GLP-1 receptor agonists and DPP-4 inhibitors enhance insulin secretion in a glucose-dependent fashion41) or they impact insulin resistance rather than secretion.10 In all cases, the potential adverse effects of drugs can be discussed with patients in advance to get their input and agreement and to avoid possible risks of nonadherence.

Understanding the Drugs’ Mechanisms of Action to Guide Therapy

As previously mentioned, the drugs’ mechanisms of action can be matched to the pathophysiologic defects found in

Figure 1. The author’s pharmacologic approach to effective T2DM management based on HbA1c levels.

Abbreviations: AGI, alpha-glucosidase inhibitor; DPP, dipeptidyl-peptidase; ER, extended release; FPG, fasting plasma glucose; GLP, glucagon-like peptide; HbA1c, glycated hemoglobin; PPG, postprandial plasma glucose; SGLT-2, sodium-glucose linked transporter-2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.

100




T2DM, with drugs having complementary modes of action being used for combination therapy, particularly those having a neutral or beneficial effect on weight (Figure 2). These defects are found in different organ systems and they play important roles in the development of glucose intolerance.11 These organ systems include the muscle, liver, and β cells of the pancreas (insulin resistance), fat cells (accelerated lipolysis), the gastrointestinal tract (incretin deficiency/resistance), α cells of the pancreas (hyperglucagonemia), the kidney (increased glucose reabsorption), and the brain (insulin resistance). Different drugs act on $ 1 of these systems. The DPP-4 inhibitors and GLP-1 receptor agonists carry a low risk of causing hypoglycemia, target multiple organs involved in the pathophysiologic defects found in T2DM, and have beneficial effects on HbA1c levels and weight reduction.41 The incretin effect is based on the observation that an equal amount of glucose administered either orally or intravenously produces a more significant and sustained rise of plasma insulin from the oral route.41,42 This discovery pointed to additional stimuli to insulin secretion triggered by gastrointestinal glucose, which was later identified as the intestinal hormones gastric inhibitory polypeptide and GLP−1.42 In patients with T2DM, postprandial secretion of GLP-1 is blunted.43 The proteolytic enzyme DPP-4 is widely expressed in multiple tissues, including near blood

vessels draining the intestinal mucosa near the sites of GLP-1 secretion.42 Dipeptidyl peptidase-4 results in the inactivation of GLP-1 and accounts for the , 2-minute half-life of GLP-1 in the circulation.42 The GLP-1 receptor agonists stimulate glucose-dependent insulin secretion from the pancreas and also have a number of other effects in the pancreas and other tissues that account for their benefits in T2DM.41,42 For example, they slow gastric emptying, and they suppress glucagon, which in turn suppresses hepatic glucose production.41 Compared with DDP-4 inhibitors, GLP-1 receptor agonists resulted in greater reductions in HbA1c levels and weight loss in head-to-head trials.41 Colesevelam is a bile acid sequestrant shown to have significant lipid and glycemic benefits in adults with T2DM.44 However, as pointed out by the AACE 2011 comprehensive care plan, gastrointestinal side effects may be why bile acid sequestrants are infrequently used in the United States, although they may be of use in select patients.3 Dopamine agonists and SGLT-2 inhibitors are 2 new classes of drugs for the treatment of T2DM. Dopamine agonists, such as bromocriptine mesylate, activate dopamine D2 receptors, and presumably work in patients with T2DM by affecting the hypothalamus through multiple neurophysiologic pathways and reducing PPG without raising plasma insulin levels.45 A quick-release formulation of bromocriptine

Figure 2. Sites of action of different classes of drugs and pathophysiologic defects in T2DM. Drugs have neutral (—), positive (↑), or negative effects (↓) on body weight, and in the case of the glitinides and sulfonylureas, carry a risk of hypoglycemia (*).4,11,37

Abbreviations: DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide; HPG, hepatic glucose production; T2DM, type 2 diabetes mellitus. © Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 101 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Tamer G.Yacoub

mesylate was found after 1 year of treatment to result in a 39% and 52% relative risk reduction in cardiovascular death– inclusive composite cardiovascular end points and major adverse cardiac events (myocardial infarction, stroke, and cardiovascular death) end points, respectively, among 3070 patients with T2DM randomized to the study drug or placebo treatment.45 It also resulted in modest glycemic improvements, a fact possibly due to the generally good glycemic control in the baseline populations.45 Clinical studies with SGLT-2 inhibitors have also shown positive benefits in patients with T2DM. For example, in patients with baseline HbA1c levels of about 8.0%, significantly more patients receiving canagliflozin (44.5% for 100-mg dosage and 62.4% for 300-mg dosage) reached an HbA1c target of , 7.0% compared with those taking placebo (20.6%).46 The unique mechanism of action of SGLT-2 inhibitors involves an insulin-independent reduction in blood glucose levels through inhibition of renal glucose reabsorption.46 Adverse effects include an elevated risk of genital mycotic infections and urinary tract infections.46 As treatment with SGLT-2 inhibitors also results in significant reductions in body weight,46 use of these drugs may be an important addition to certain patients’ regimens. Most of the different classes of drugs for the treatment of T2DM tend to have a synergistic effect with each other. For example, when quick-release bromocriptine was added to a TZD, after 1 year there was a significant reduction in HbA1c and FPG levels compared with placebo.47 The β-cell augmentation and peripheral insulin sensitization by TZDs combined with the centrally acting insulin sensitization of dopamine agonists may thus have synergistic effects.47 This could plausibly work by reducing high FPG and PPG levels to produce long-lasting improvements in PPG control, although further research is needed.47 Another example includes the inhibition of glucagon with DPP-4 inhibitors or GLP-1 receptor agonists.11 When sitagliptin, a DPP-4 inhibitor, was combined with an experimental sodium-glucose cotransporter 1/2 (SGLT-1/SGLT-2) inhibitor in a preclinical study, the combination was associated with statistically significant increases in GLP-1 and improved blood glucose level, with less insulin, compared with sitagliptin monotherapy.48 Determining whether this type of combination can be recommended in clinical practice requires large-scale clinical trials.

Considerations for Intensifying Therapy (Adding a Second or Third Drug)

As recognized by the AACE 2011 comprehensive care plan guidelines, when treatment goals are not achieved or 102

maintained, intensification of pharmacotherapy that requires glucose monitoring and medication adjustment at appro priate intervals may be necessary.3 For patients initially on non-insulin monotherapy at maximally tolerated doses, if this does not achieve or maintain an agreed-upon HbA1c goal over 3 months, then the ADA 2014 SOC recommends adding a second drug, such as a GLP-1 receptor agonist, or insulin.2 To prevent treatment failure or complications in patients with T2DM, other experts recommend that treatment schedules be modified early, with immediate intensification of therapy if patients fail to maintain prescribed goals.1 Drugs with complementary modes of action (for example, an insulin sensitizer and secretogogue) can be used to have a greater effect than a single drug alone. For example, one approach involves prescribing metformin, a GLP-1 receptor agonist, and a long-acting insulin to patients with an HbA1c level . 8.0%.49 Multidrug therapy does carry risks of drug–drug interactions, however, as well as increases in the complexity of therapy and thus potential negative effects on medication adherence, along with rising costs that patients might be unable to afford.6 Nonetheless, given that combination therapy might offer benefits over monotherapy by acting on the multiple pathophysiologic defects found in T2DM, multidrug therapy may be acceptable to patients at any time if the appropriate risks and benefits are discussed.

When to Use Insulin in Newly Diagnosed Patients

Because of differences in the risk of weight gain and hypoglycemia, as well as differences among patients in the contribution of FPG and PPG to their overall hyperglycemia, whether to initiate insulin with a prandial or basal insulin regimen or a combined regimen can be a complex choice in certain patients.27 According to the ADA/EASD 2012 guidelines on pharmacologic therapy, basal insulin alone is usually the optimal initial regimen, beginning at 0.1 to 0.2 units/kg body weight, depending on the degree of hyperglycemia.5 This approach is consistent with that of the AACE/ACE 2013 algorithm, which recommends starting with a basal insulin and intensifying to a prandial insulin if glycemic control is not at goal.4 Treat-to-target trials force-titrate insulin dosages to achieve a prespecified glycemic goal, enabling comparison of important safety responses among insulin regimens, such as hypoglycemic episodes.50 For example, the original Treatto-Target Trial found a high rate of success in reaching an HbA1c target of 7% with the addition of insulin to oral drugs.51 There are limitations with the one-size-fits-all approach of the treat-to-target approach, however, as was found by




subsequent trials.52 Nonetheless, because treat-to-target trials provide tested algorithms for dosing insulin, they can help clinicians manage patients who are taking insulin to achieve their glycemic goals.50 The AACE/ACE 2013 algorithm recommends that insulin be added earlier than recommendations made in the AACE/ACE 2009 guidelines.4,14 With the 2013 guidelines, an algorithm was added on how to add or intensify insulin. In it, insulin analogues are preferred to neutral protamine Hagedorn insulin because they cause less hypoglycemia.4 The AACE/ACE 2013 algorithm also recommends that if basal insulin plus an oral drug is not sufficient to reach the HbA1c goal, one can add either prandial insulin or an incretin-based drug.4 The ADA 2014 SOC guidelines recommend that in newly diagnosed patients with T2DM who are markedly symptomatic or have high blood glucose or high baseline HbA1c levels $ 9.0% (as defined by the ADA/EASD 2012 position statement5), insulin therapy should be considered from the start, with or without the use of additional drugs.2 Insulin may be discontinued once HbA1c levels are reduced. If noninsulin monotherapy at maximal-tolerated doses does not achieve or maintain the HbA1c goal over a 3-month period, a second drug, such as a GLP-1 receptor agonist or insulin, should be included as part of dual or triple therapy.2

that does not express strong preferences for certain drugs (as exemplified by the ADA 2014 SOC2 and its predecessors) is more appropriate. These differences of opinion manifest themselves in the guidelines’ recommendations because the ADA 2014 SOC does not indicate preferences for the many alternative combinations of drugs,2 whereas the AACE/ACE 2013 algorithm orders drugs according to a suggested hierarchy of usage.4 Some of the authors of the AACE/ACE guidelines have criticized the approach of the ADA/EASD guidelines for not being prescriptive enough, which the authors of the AACE/ACE guidelines view as being a useful teaching tool and guide for clinicians treating patients.53 On the other hand, the authors of the ADA/ EASD guidelines have opined that expressing strong preferences for certain drugs would not be correct or conform to a patient-centered approach.54 The AACE/ACE 2013 algorithm provides treatment stratification recommendations based on HbA1c levels, whereas the ADA 2014 SOC guidelines do not.2,4 The AACE/ ACE 2013 algorithm stratification is based on HbA1c levels at cutoffs of , 7.5%, $ 7.5%, and . 9%.4 Basal insulin is recommended early on (in patients with HbA1c $ 7.5% and . 9%), but to be used with caution because of the risk of hypoglycemia.4

Understanding the Guidelines’ Recommendations

Conclusion

Both sets of guidelines from the major diabetes organizations recommend that cardiovascular risk factors, such as hypertension and dyslipidemia, should be addressed and monitored regularly.2,3 Despite other similarities among the recent diabetes guidelines in terms of the importance of lifestyle interventions and personalized approaches, there are some differences. For example, there are differences between the AACE/ACE 2013 algorithm and the ADA 2014 SOC in the target treatment goals for glycemic control and for lipids, blood pressure, and weight loss (Table 3).2,4 Other prominent differences include when to initiate therapy with metformin or another drug, when to add other drugs including insulin, the importance placed on using TZDs and SUs, and the priority for incretin-based therapies.2,4,5 The AACE/ACE 2013 algorithm considers more classes of drugs, number of regimens, and drugs for monotherapy than does the ADA 2014 SOC.2,4 Differences of opinion between the authors of the ADA and AACE/ ACE guidelines center on whether a more prescriptive, algorithm-type approach (as exemplified by the AACE/ ACE 2013 algorithm4) or a patient-centered approach

Although the prominence of HbA1c goals in the latest diabetes guidelines would seem to indicate a preeminent role of managing glucose and HbA1c levels, therapeutic goals and treatment decisions must also be patient-centric to achieve maximum benefit and avoid or at least mitigate disease progression and side effects. All of the major diabetes guidelines recognize the importance of not prioritizing pharmacologic approaches over lifestyle changes. Optimizing diet and physical activity is crucial for the management of T2DM, irrespective of what pharmacotherapy is used. When pharmacologic treatment becomes necessary, however, the clinician can be guided by a patient’s baseline HbA1c levels to determine whether drugs that act on FPG or PPG, or both, would be more appropriate to use. Combination therapy that addresses the different pathophysiologic defects in T2DM can also play a strong role in treatment decisions, using drugs that do not carry the risk of hypoglycemia or weight gain.

Acknowledgments

Medical writing assistance was provided by Steven Tresker of Cactus Communications and was funded by Novo Nordisk.


Tamer G.Yacoub

Table 3. Differences in Treatment Goals Between the Most Recent ADA and AACE/ACE Guidelines Treatment Goals Parameter

Glucose HbA1c, %

Fasting glucose, mg/dL


Postprandial glucose, mg/dL Lipids LDL-C, mg/dL HDL-C, mg/dL Triglycerides, mg/dL Blood pressure Systolic, mm Hg Diastolic, mm Hg Weight loss

American Association of Clinical Endocrinologists/American College of Endocrinology: AACE/ACE 2013 algorithm4

American Diabetes Association: ADA 2014 Standards of Care2

In general # 6.5 for healthy patients without concurrent illness and at low hypoglycemic risk; . 6.5 for patients with concurrent illness and at risk for hypoglycemia (goals should be individualized)

, 7 for many nonpregnant adults More stringent goals (such as , 6.5) if can be achieved without significant hypoglycemia or other adverse effects (eg, patients with short duration of T2DM, long life expectancy, no significant CVD) Less stringent goals (such as , 8) for patients with history of severe hypoglycemia, limited life expectancy, advanced micro- or macrovascular complications, extensive comorbidities, and long-standing T2DM in whom the general goal is difficult to attain Preprandial capillary plasma glucose 70–130

, 110 (Preprandial blood glucose , 110 in the absence of hypoglycemia, for most patients with T2DM) Included as a goal (2h PPG < 140 per 2011 guidelines)3, but precise levels not stated , 70 high risk; , 100 moderate-risk patients Not specified

Peak postprandial capillary plasma glucose , 180

, 100 (, 70 in patients with overt CVD) . 50 , 150

, 150 (both high- and moderate-risk patients) ∼ 130

, 140 (lower targets, such as , 130) for patients who can achieve without undue treatment burden, such as younger patients). , 80

∼ 80 Should be considered in all overweight and obese patients with prediabetes or T2DM

Recommended for all overweight or obese individuals who have or are at risk for T2DM; target weight loss of 7% body weight for those at high risk of developing T2DM

Abbreviations: AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; ADA, American Diabetes Association; CVD, cardiovascular disease; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; T2DM, type 2 diabetes mellitus.

Conflict of Interest Statement

Tamer G. Yacoub, MD, FACE, is a member of Advisory Boards for Amgen, AstraZeneca, and Novo Nordisk. He is a member of the Speaker’s Bureau of the following companies; Novo Nordisk, Eli Lilly, Sanofi, Takeda, AstraZeneca, Bristol-Myers Squibb, Janssen, & Salix.

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Sodium-glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin-metformin.

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Long-term insulin glargine therapy in type 2 diabetes mellitus: a focus on cardiovascular outcomes.

Challenges in achieving optimal glycemic control in type 2 diabetes patients with declining renal function: The Southeast Asia perspective.

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Towards a genotype-based approach for a patient-centered pharmacologic therapy of type 2 diabetes.

Pharmacologic treatment of type 2 diabetes: oral medications.

Effect of combination therapy with repaglinide and metformin hydrochloride on glycemic control in Japanese patients with type 2 diabetes mellitus.

Estimating Cost-Effectiveness in Type 2 Diabetes: The Impact of Treatment Guidelines and Therapy Duration.

Effects of nonsurgical periodontal therapy on clinical response, microbiological profile, and glycemic control in Malaysian subjects with type 1 diabetes.

Add-On Treatment with Liraglutide Improves Glycemic Control in Patients with Type 2 Diabetes on Metformin Therapy.

Family physician clinical inertia in glycemic control among patients with type 2 diabetes.

Nutritional management of type 2 diabetes mellitus and obesity and pharmacologic therapies to facilitate weight loss.

Application of berberine on treating type 2 diabetes mellitus.

Evaluating the effect of u-500 insulin therapy on glycemic control in veterans with type 2 diabetes.

TWO TREATMENT APPROACHES FOR HUMAN REGULAR U-500 INSULIN IN PATIENTS WITH TYPE 2 DIABETES NOT ACHIEVING ADEQUATE GLYCEMIC CONTROL ON HIGH-DOSE U-100 INSULIN THERAPY WITH OR WITHOUT ORAL AGENTS: A RANDOMIZED, TITRATION-TO-TARGET CLINICAL TRIAL.