Emerging Therapeutic Approaches for the Management of Diabetes Mellitus and Macrovascular Complications

Emerging Therapeutic Approaches for the Management of Diabetes Mellitus and Macrovascular Complications Sherita Hill Golden, MD, MHS Type 2 diabetes mellitus (DM) affects an estimated 25.8 million people in the United States and is the 7th leading cause of death. While effective therapy can prevent or delay the complications that are associated with diabetes, according to the Center for Disease Control, 35% of Americans with DM are undiagnosed, and another 79 million Americans have blood glucose levels that greatly increase their risk of developing DM in the next several years. One of the Healthy People 2020 goals is to reduce the disease and economic burden of DM and improve the quality of life for all persons who have, or are at risk for, DM. Achieving this goal requires a concentrated focus on improving the management of diabetes and in targeting prevention of macrovascular complications. This article reviews established and emerging therapeutic approaches for managing DM and prevention of macrovascular complications. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108[suppl]:59B– 67B)

Type 2 diabetes mellitus remains a chronic healthcare condition with a significant public health burden. It is estimated that nearly 25.8 million persons, or 8.3% of the population in the United States, has diabetes.1 An additional 79 million persons are estimated to have prediabetes, a condition that increases the risk for developing diabetes.1,2 Despite advances in the management of diabetes, a significant number of persons develop microvascular complications such as nephropathy, neuropathy, and retinopathy as well as macrovascular disease, including subclinical atherosclerosis and peripheral arterial disease, coronary artery disease (CAD), and cerebrovascular disease. While targeting glycemic control is a primary focus of the management of diabetes, which has been shown to prevent microvascular disease, aggressive management of nonglycemic cardiovascular (CV) risk factors are concurrent therapy goals to prevent macrovascular disease. Standards for the medical management of diabetes highlight the importance of glycemic control (hemoglobin A1c [HbA1c] ⬍7%) as a fundamental component of treatment. Randomized clinical trial data from studies including the Diabetes Control and Complication Trial (DCCT)3 in type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS),4 the Veterans Affairs Diabetes Trial (VADT),5 and the Action in Diabetes and Vascular Disease (ADVANCE)6 studies in type 2 diabetes have demonstrated the impact of intensive glycemic control in reducing microvascular disease compared with standard glycePublication of this supplement was supported by funding from Novo Nordisk. Editorial support was provided by Dr. Ruth Kleinpell and Mary Lou Briglio. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Address for reprints: Sherita Hill Golden, MD, MHS, Division of Endocrinology and Metabolism, Welch Center for Prevention, Epidemiology, and Clinical Research Johns Hopkins University School of Medicine, 2024 E. Monument Street, Suite 2-600, Baltimore, MD 21287. E-mail address: [email protected]. 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.03.017

mic control. In individuals with type 1 diabetes, results from the Epidemiology of Diabetes Intervention and Complications follow-up of the original DCCT participants (EDIC/DCCT) showed that after a mean follow-up of 17 years, individuals assigned to the previous intensive control group had a significant 42% reduction in combined CV outcomes, including nonfatal myocardial infarction (MI), stroke, CV disease (CVD) death, confirmed angina, or need for coronary artery revascularization.7 However, the role of intensive glycemic control for prevention of CV complications in type 2 diabetes is less clear and has been challenged by recent clinical trials data. This article reviews several emerging therapeutic approaches for managing diabetes and preventing CV complications, with a focus on type 2 diabetes.

Optimizing Cardiovascular Risk Reduction in Patients with Diabetes Mellitus Glycemic control and CV risk: CVD is the leading cause of morbidity and mortality in patients with diabetes.8 Prior epidemiological studies showed that increasing levels of HbA1c were associated with an increased risk of developing CAD, stroke, and peripheral arterial disease, even after adjustment for traditional CV risk factors.9 –12 These studies, as well as epidemiological analyses of the UKPDS, suggested that even below the therapeutic target of 7%, HbA1c was associated with CVD risk.13 There data also supported the design of clinical trials to determine whether interventions to improve and intensify glycemic control would reduce the risk of CVD in patients with type 2 diabetes. The association between glycemic control and CVD risk reduction has been demonstrated in several studies (Table 1).4 – 6,14 –17 In the UKPDS, compared with individuals treated with conventional therapy, individuals treated with intensive insulin had a 16% reduction in fatal and nonfatal www.AJConline.org

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Table 1 Trials of glycemic control and cardiovascular outcomes in type 2 diabetes mellitus Study

Intervention

UKPDS 334

Intensive insulin vs conventional Intensive metformin Pioglitazone vs other treatments Rosiglitazone vs other treatments Tight (6.4%) vs standard (7.5%)

UKPDS 3417 PROactive16 RECORD15 ACCORD14

ADVANCE6 VADT5

Tight (6.4%) vs standard (7.0%) glucose control Tight (6.9%) vs standard (8.4%) glucose control

Population (N)

Duration (yr)

Population Type

Results

3,867

10

Pts with new-onset type 2 diabetes

1,740 5,000

10 3

16% 2 fatal and nonfatal MI (p ⫽ 0.052) 39% 2 acute MI 16% 2 all-cause mortality, nonfatal MI, stroke No 2CVD endpoints 1CHF and limb fractures (women) No reduction in primary outcome 1 All-cause (22%) and CVD (35%) mortality; 24%2 nonfatal MI mortality; 24%2 non-fatal MI No reduction in any CVD endpoint

4,447

5.5

10,251

3.5

Pts with new-onset type 2 diabetes Pts with high prevalence of macrovascular disease Pts with type 2 diabetes on metformin and sulfonylurea Pts with type 2 for 10 yr

11,140

5

Pts with type 2 for 8 yr

5.6

Military veterans with type 2 diabetes for 11 yr

1,791

No reduction in any CVD endpoint

ACCORD ⫽ Action to Control Cardiovascular Risk in Diabetes Study; ADVANCE ⫽ Action in Diabetes and Vascular Disease; CHF ⫽ congestive heart failure; CVD ⫽ cardiovascular disease; MI ⫽ myocardial infarction; PROactive ⫽ Prospective Pioglitazone Clinical Trial in Macrovascular Event; Pts ⫽ patients; RECORD ⫽ Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; UKPDS ⫽ United Kingdom Prospective Diabetes Study; VADT ⫽ Veterans Affairs Diabetes Trial.

MI that was of borderline significance, and obese individuals treated with intensive metformin had a significant 39% reduction in acute MI.4,17 Ten-year follow-up of the UKDPS participants showed long-term reductions in MI (15% to 33% for intensive glycemic control with sulfonylurea, insulin, or metformin as initial therapy) and all-cause mortality (13% to 27% for intensive glycemic control with sulfonylurea, insulin, or metformin as initial therapy).18 In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study, individuals treated with pioglitazone had a16% significant reduction in mortality, nonfatal MI, and stroke.16 In contrast, individuals treated with rosiglitazone in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study did not have reduced CVD endpoints.15 However, the results of several recent large-scale randomized clinical trials examining the effect of intensive glucose control on macrovascular outcomes have provided controversy about the effect of glucose levels on CVD risk reduction (Table 1). The ADVANCE trial6 examined the impact of intensive glycemic control (HbA1c 6.4% vs 7.0% in control group) on microvascular events (nephropathy and retinopathy) and major CVD events (MI, stroke, and CVD death) in 11,140 subjects. While intensive glycemic control reduced the incidence of microvascular events, there were no significant reductions in macrovascular outcomes between standard and intensive glycemic control. The Action to Control Cardiovascular Risk in Diabetes Study (ACCORD)14 trial randomized 10,251 subjects with a history of a CVD event or significant CVD risk to intensive glycemic control (target HbA1c ⬍6.0%) or standard glycemic control (HbA1c 7.0%–7.9%). Within 12 months of

randomization, the intensive glycemic group reached a median HbA1c of 6.4% (from a baseline median of 8.1%) compared with a median HbA1c of 7.5% in the standard glycemic group. However, the glycemic control arm was stopped early due to an increased mortality rate in the intensive glycemic control group.14 The exact etiology of the increased mortality in the intensive control arm has remained elusive in follow-up analyses but was associated with higher HbA1c levels in both study arms and not hypoglycemia.19 A recent meta-analysis of the VADT, ADVANCE, and ACCORD studies demonstrated a modest (9%) but statistically significant reduction in CVD outcomes, including nonfatal MI, and no increase in mortality.20 In light of these study results, it becomes clear that additional research is needed that explores therapeutic approaches to management of hyperglycemia that also affect CVD risk reduction. A recent systematic review on glucose control and CVD in diabetes concluded that intensive glucose control reduced the risk for some CVD outcomes such as nonfatal MI, but did not reduce the risk for CVD mortality, and increased the risk for severe hypoglycemia.21 These recent data also suggest that a cornerstone of CVD prevention in diabetes should focus on aggressive management of traditional CV risk factors.8 Blood pressure control and CV risk: Hypertension is a common comorbidity of diabetes and a major CVD risk factor. In an epidemiological analysis of the UKPDS, the risk of MI increased 12% for every 10 mm Hg increase in systolic blood pressure.22,23 Goals for blood pressure control in patients with diabetes include systolic blood pressure ⬍130 mm Hg and diastolic blood pressure ⬍80

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Table 2 Blood pressure goals and treatment strategies for patients with diabetes mellitus Blood Pressure (mm Hg)

Goal Behavior therapy alone (3 mo) then add pharmacologic therapy Behavior therapy ⫹ pharmacological therapy

Systolic

Diastolic

⬍130 130-139

⬍80 80-89

ⱖ140

ⱖ90

Data from Diabetes Care.8 Table 3 Behavior and lifestyle treatment recommendations that target blood pressure control in patients with diabetes mellitus Intervention Sodium restriction (⬃2,000 mg/day) Weight loss Moderately intense physical activity Moderation of alcohol consumption

Blood Pressure Reduction 2 2–8 mm Hg 2 5–20 mm Hg/10 kg weight loss 2 4–9 mm Hg 2 2–4 mm Hg

Data from Diabetes Care8 and JAMA.24

mm Hg (Table 2).8 Additional components of treatment include behavior and lifestyle changes that target further reductions of blood pressure including sodium restriction, weight loss, moderate intensity physical activity, moderation of alcohol consumption, and smoking cessation (Table 3).8,24 The ADA guidelines also outline options for pharmacologic management of hypertension. Initial drug therapy for individuals with diabetes with hypertension but without nephropathy include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), ␤-blockers, thiazide diuretics, and calcium channel blockers.8 All of these agents have been shown to reduce CV events in individuals with diabetes.8 For patients with type 2 diabetes who have hypertension with microalbuminuria, ACE inhibitors or ARBs are recommended as first-line therapy; in those with macroalbuminuria and renal insufficiency, ARBs are recommended as first-line therapy.8 In the UKPDS, compared with conventional blood pressure control (154/87 mm Hg), tight blood pressure control (144/82 mm Hg) was associated with a significant reduction in diabetes-related endpoints, microvascular disease, and stroke but not a significant reduction in MI.23 The blood pressure control in the “tight” arm was higher than the currently recommended target, and because the epidemiological analysis of the UKPDS showed a continuous relation between systolic blood pressure and risk of MI, the question remained whether a lower blood pressure target might result in reduced CV events in patients with diabetes. The intensive blood pressure control arm of the ACCORD trial recently explored this question. Intensive blood pressure

Figure 1. American Diabetes Association (ADA) low-density lipoprotein cholesterol (LDL-C) target recommendations for adults with diabetes mellitus. CAD ⫽ coronary artery disease; CV ⫽ cardiovascular; CVD ⫽ cerebrovascular disease; PVD ⫽ peripheral vascular disease; statin ⫽ 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitor. For conversion of LDL into SI units, 1 mg/dL ⫽ 0.0259 mmol/L.

control did not significantly reduce the primary CV outcome (nonfatal MI, nonfatal stroke, and CVD death) despite sustained blood pressure differences between the 2 groups (systolic blood pressure 119 mm Hg in intensive versus 133 mm Hg in the standard therapy groups).25 Because a lower blood pressure target was associated with more adverse events (eg, hypotension, hyperkalemia, increase in creatinine), the current primary blood pressure target for type 2 diabetes remains unchanged at 130/80 mm Hg. Lipid control and CV risk: Dyslipidemia management is an additional priority area for CVD prevention in patients with diabetes. In individuals with diabetes, randomized clinical trials have consistently shown that compared with placebo, therapy with 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors (statins) significantly reduced the risk of major primary and secondary CVD endpoints.8,25 Clinical trials of fibrate therapy, which target triglycerides and high-density lipoprotein (HDL) cholesterol (HDL-C), have shown mixed results. In the Helsinki Heart Study, fibrate therapy reduced the risk of a primary CAD event, although the results were not statistically significant due to the small number of subjects with diabetes in the study.26 The Veterans Affairs High-Density Cholesterol Intervention Trial (VA-HIT) was a secondary prevention trials that showed a significant reduction in recurrent CVD events in the diabetic subgroup.26 The largest study of fibrate therapy in ⬎9,000 individuals with diabetes, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, failed to demonstrate a significant reduction in the primary outcome of CAD death and nonfatal MI in patients treated with the fibrate compared with placebo.26 Recently, the lipid arm of the ACCORD study examined whether com-

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Figure 2. Algorithm for management of diabetic dyslipidemia. CVD ⫽ cardiovascular disease; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein. For conversion of HDL and LDL into SI units, 1 mg/dL ⫽ 0.0259 mmol/L; for triglycerides, 1 mg/dL ⫽ 0.0113 mmol/L. (Reprinted with permission from Wolters Kluwer.26)

Table 4 Lipoproteins targeted by lipid-lowering drug classes Drug Class

Agents

LDL

Statins

Low potency: fluvastatin, pravastatin High potency: atorvastatin, simvastatin, rosuvastatin Cholestyramine, colestipol, colesevelam Gemfibrozil, fenofibrate Niacin Ezetimibe Omega-3 acid ethyl esters

X

Bile acid–binding resins Fibrates N/A Cholesterol absorption inhibitor N/A

HDL

TG

X X

X X

X X X

X

HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein; N/A ⫽ not applicable; statins ⫽ 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors; TG ⫽ triglycerides.

bination therapy with a statin and fibrate would be beneficial in reducing CVD in individuals with diabetes. The investigators found that there was not a significant reduction in any CVD endpoints (nonfatal MI, nonfatal stroke, or CVD death).25 Based on these clinical trial results, the primary goal for lipids is a low-density lipoprotein (LDL) cholesterol (LDL-C) level of ⬍100 mg/dL [1 mg/dL ⫽ 0.0259 mmol/L] in individuals without a history of CVD (Figure 1).8 In patients ⬎40 years of age with diabetes, statins are recommended to achieve a 30%– 40% reduction in LDL regardless of baseline LDL (Figure 1).8 For patients with prior CVD, a lower LDL goal of ⬍70 mg/dL using a statin is an option, and patients should be treated with a statin to achieve an LDL reduction of 30%– 40% regardless of the baseline LDL level (Figure 1).8 Additional lipid goals include triglycerides (TG) ⬍150 mg/dL [1 mg/dL ⫽ 0.0113 mmol/L] and HDL-C ⬎50 mg/dL in men and ⬎40 mg/dL in women.8 Lifestyle interventions including reduction of saturated fat, trans fat, and cholesterol intake; increased use of

viscous fiber and plant stanols/sterols; and weight loss and increased physical activity are advocated for all patients with diabetes to improve the lipid profile (Table 3).8 An algorithm for management of diabetic dyslipidemia is outlined in Figure 226 and the lipid profile components targeted by various classes of lipid-lowering medications are summarized in Table 4. Treatment of LDL-C is the main priority for therapy. Statins are considered first-line pharmacologic therapy and are recommended for patients with diabetes and overt CVD or those without CVD who are ⬎40 years of age or who are ⱕ40 years of age with ⱖ1 CVD risk factor. Second choice agents include bile acid– binding resins, cholesterol absorption inhibitor (ezetimibe), fenofibrate, or niacin.8 Combination therapy to raise HDL-C and lower TG may also be necessary, particularly in individuals with combined dyslipidemia (Figure 2). In the ACCORD study, a subgroup analysis of individuals with high TG (ⱖ204 mg/ dL) and low HDL-C (ⱕ34 mg/dL) showed that fenofibrate was beneficial in reducing the primary CVD outcome of nonfatal MI, nonfatal stroke, and CVD death.25

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The “ABCDs” of Cardiovascular Disease Risk Management in Diabetes Mellitus In addition to the therapies outlined above, antiplatelet agents (aspirin therapy 75–162 mg/day) is recommended for secondary prevention of CVD in diabetes. The role of aspirin therapy in the primary prevention of CVD in diabetes remains unclear. While there is not sufficient evidence for use of aspirin therapy in primary prevention in low-risk groups, it should be considered for patients with a 10-year CVD risk ⬎10%.8 Taken together, these focused areas of treatment are often identified as the “ABCDs” of CVD management in diabetes: A for antiplatelet therapy, B for blood pressure control, C for cholesterol management, and D for diabetes/glucose management. In addition to focusing on the “ABCD” components of treatment options for reducing CV risk in patients with diabetes, a number of emerging therapies have evolved that offer alternatives for promoting optimal management of diabetes and its CV risk factors.

Emerging Therapies Improved understanding of the incretin effect on the pathophysiology of diabetes has led to the development of new hypoglycemic agents, including glucagonlike peptide–1 (GLP-1) analogues and dipeptidyl peptidase– 4 (DPP-4) inhibitors. The incretin effect, which is mediated through gut hormones, enhances glucose-stimulated insulin secretion by intestinally derived peptides. Gastric inhibitory peptide (GIP) and GLP-1 cause a glucose-dependent increase in insulin secretion and are rapidly inactivated by the enzyme DPP-4. GLP-1 is secreted by the L-cells of the intestine in response to nutrient intake and acts upon pancreatic ␤-cells to stimulate insulin release.27 It also inhibits inappropriate glucagon secretion from pancreatic ␣-cells and has an inhibitory effect on gastric emptying, which has been linked to appetite-suppressing effects.28 The incretin effect is preserved but greatly diminished in type 2 diabetes because there is often a deficiency of GLP-1 and impaired production of amylin, a pancreatic hormone that is secreted along with insulin.29 As a result, incretin-based therapies may offer a new option in the treatment of type 2 diabetes. GLP-1 or agonists of GLP-1 receptors have been demonstrated to exert a number of CV effects including reduction in systolic blood pressure, improved endothelial function, reduced postprandial increases in plasma TG, protection against myocardial ischemia reperfusion injury, and improved myocardial function.30 –34 Thus, this class of agents may have beneficial CV effects beyond glycemic control. A number of relevant clinical trials and related evidence support the use of incretin-based therapies in diabetes management. (For further review of these trials, see discussion by Fonseca in this supplement.35)

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GLP-1 receptor agonists: Currently, several GLP-1 analogues are approved for use in individuals with type 2 diabetes: liraglutide for once-daily injection; exenatide, approved in 2005 by the US Food and Drug Administration (FDA), which is self-injected twice daily; and exenatide long-acting release, which is undergoing regulatory review by the FDA. Other drugs (lixisenatide bid/ZP10 and albiglutide) are in phase 3 trials.36 A number of clinical trials have examined the effect of GLP-1 receptor agonists. The Liraglutide Effect and Action in Diabetes (LEAD) program consisted of a series of phase 3 studies that investigated liraglutide use as monotherapy or in combination with metformin, metformin plus rosiglitazone, or metformin plus a sulfonylurea versus placebo and active comparators. Significant weight reductions versus placebo were observed with liraglutide in combination with metformin, metformin plus rosiglitazone, and metformin plus a sulfonylurea. These studies also provided evidence of the efficacy of liraglutide to achieve good glycemic control over the medium (26 weeks) and long terms (52 weeks), and of clinically meaningful reductions in body weight and systolic blood pressure achieved with liraglutide treatment.37– 42 Lixisenatide, a GLP-1 agonist, as a once-daily monotherapy is being assessed in the GetGoal-M-As phase 3 clinical trial program, which started in May 2008 and has enrolled ⬎4,500 patients. Lixisenatide had been demonstrated to improve glycemic control and promote weight loss in 361 patients with type 2 diabetes during a 12-week, randomized, double-blind, multicenter phase 3 trial. The next results of the GetGoal phase 3 program are expected to be released in the second quarter of 2011.43 There are 2 CV outcome trials with GLP-1 analogues that are ongoing (Table 5).44,45 In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial 9,000 patients with type 2 diabetes are being followed for an average of 4.5 years to assess the impact of liraglutide on major adverse cardiac events including CV death, MI, and stroke. The results are projected to be available in 2016.44 The Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL) trial is exploring the impact on CV events of once-weekly injection of long-acting release exenatide in up to 9,500 patients with type 2 diabetes. The results are anticipated to be completed in 2017.45 DPP-4 inhibitors: Sitagliptin, a selective DPP-4 inhibitor, was approved in 2006 by the FDA as the first oral incretin enhancer for use as monotherapy or in combination with metformin or thiazolidinedione. In clinical trials of sitagliptin, reductions in HbA1c were seen with combination therapy with metformin and with monotherapy. Saxagliptin, another DPP-4 inhibitor, is also approved for use in type 2 diabetes. There are a number of ongoing clinical trials examining the effect of DPP-4 inhibitors on CV outcomes (Table 5).46 – 49 In all of these

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Table 5 Ongoing incretin trials of cardiovascular disease outcomes in type 2 diabetes mellitus⬍/TT Study GLP-1 agonists LEADER44 EXSCEL45 DPP-4 inhibitors TECOS46 SAVOR-TIMI 5347 CAROLINA48 EXAMINE49

N

Agent

Population Characteristics

Year Results Anticipated

9,000 9,500

Liraglutide Exenatide

— —

2016 2017

14,000

Sitagliptin

2014

12,000 6,000 5,400

Saxagliptin Linagliptin Alogliptin

Patients with inadequately controlled diabetes on mono- or dual combination therapy Patients with diabetes and CV risk factors Patients with inadequately controlled diabetes Patients with diabetes and ACS

2015 2018 2014

ACS ⫽ acute coronary syndrome; CAROLINA ⫽ Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes; CV ⫽ cardiovascular; DPP-4 ⫽ dipeptidyl peptidase– 4; EXAMINE ⫽ Cardiovascular Outcomes Study of Alogliptin in Subjects with Type 2 Diabetes and Acute Coronary Syndrome; EXSCEL ⫽ Exenatide Study of Cardiovascular Event Lowering Trial; GLP-1 ⫽ glucagonlike peptide–1; LEADER ⫽ Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation Trial; TECOS ⫽ Sitagliptin Cardiovascular Outcome Study; SAVOR-TIMI 53 ⫽ Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Trial.

trials, the CV outcomes are CV-related death, nonfatal MI, and nonfatal stroke. The Sitagliptin Cardiovascular Outcome Study (TECOS) is a long-term CV outcomes trial evaluating the impact of sitagliptin on composite CV endpoints including CV-related death, nonfatal MI, and nonfatal stroke. TECOS began recruiting participants in December 2008. An estimated 14,000 patients will be recruited, with results expected approximately in 2014.46 The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus trial (SAVORTIMI 53), is an ongoing multicenter, randomized, doubleblind, placebo-controlled phase 4 study evaluating the use of saxagliptin in patients with type 2 diabetes with CV risk factors. The 5-year study will follow approximately 12,000 patients focusing on the composite endpoint of CV death, nonfatal MI, and nonfatal stroke. The results of the study are anticipated in 2015.47 Several studies have investigated the use of linagliptin, a DPP-4 inhibitor, as monotherapy and as add-on therapy in patients with inadequately controlled diabetes. The Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) is a multicenter international randomized study evaluating the CV safety of linagliptin on CV death, nonfatal MI, and nonfatal stroke in 6,000 patients. The study began in October 2010 and is anticipated to be completed in September 2018.48 The (EXAMINE) is evaluating the CV outcomes of alogliptin, a DPP-4 inhibitor, given once daily, compared with placebo in subjects with diabetes and acute coronary syndrome. In several phase 3, double-blind, placebocontrolled studies, the use of alogliptin was effective in reducing HbA1c when used as monotherapy and when added to commonly used antidiabetic agents, including sulfonylureas, metformin, thiazolidinediones, and insulin. The primary outcome measures of the EXAMINE study focus on CV death, nonfatal MI, and nonfatal stroke. An estimated 5,400 subjects will be enrolled in

the study, which started in September 2009 and is anticipated to end in May 2014.49

Role of Incretin-Based Therapies in Management of Diabetes Mellitus The use of incretin-based therapies was included in the 2009 recommendations of an American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) consensus panel that suggested that patients with HbA1c levels in the range of 7.6%–9.0% be treated with dual therapy with metformin (unless contraindicated) plus, in order of preference, GLP-1 receptor agonists, DPP-4 inhibitors, glinides, or sulfonylureas.50 The recommendations identify the lower risk of hypoglycemia with GLP-1 receptor agonists and DPP-4 inhibitors compared with glinides and sulfonylureas. The use of GLP-1 receptor agonists is preferred over DPP-4 inhibitors because of their greater potential for achieving lower postprandial glucose levels and greater weight loss. For patients requiring triple therapy, metformin, a GLP-1 receptor agonist, and a third oral antidiabetic drug—a thiazolidinedione, a sulfonylurea, or a glinide—are recommended.50 The 2009 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus algorithm for initiating and adjusting antidiabetic agents in type 2 diabetes is more conservative in its recommendations regarding the use of incretins because there has not been sufficient clinical experience to be as confident about their safety compared with agents that have been on the market longer.51 In the ADA/EASD algorithm, GLP-1 agonists are considered tier 2 agents to be considered after patients are initiated on tier 1, well-validated core therapies, which include lifestyle change and metformin followed by the addition of sulfonylureas or basal insulin.51 Clearly, there is a need for additional research exploring strategies for achieving appropriate glycemic control targets

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that have an impact on CVD risk reduction. Incretin-based therapies have the potential to affect hyperglycemia and CV risk factors. Additional DPP-4 inhibitors are in clinical development and may offer additional therapeutic options. Vildagliptin has received approval for use in Europe but has not yet been approved for use in the United States, and alogliptin is currently undergoing additional phase 3 clinical trial testing. As additional incretin-based therapies evolve and the long-term safety profile of this class of agents becomes more clear with ongoing use, improvements in glycemic control and CV outcomes for patients with diabetes may be possible with this new class of pharmacotherapies. Conclusions One of the Healthy People 2020 goals is to reduce the disease and economic burden of diabetes and improve the quality of life for all persons who have, or are at risk for, diabetes.52 Achieving this goal requires a concentrated focus on improving the management of diabetes and in targeting prevention of macrovascular complications. Current evidence-based guidelines for CVD prevention in diabetes focus on the ABCDs of CVD management in diabetes (antiplatelet therapy, blood pressure control, cholesterol management, and diabetes/glucose management). Incretinbased therapies (DPP-4 inhibitors and GLP-1 analogues) may offer a new option in the treatment of type 2 diabetes. While results of several clinical trials indicate that GLP-1 receptor agonists produce reductions in blood glucose and HbA1c, their role and the role of other incretin- based therapies in CVD prevention remains to be clarified by trials measuring ongoing and long-term benefits. Author Disclosures The author of this article has disclosed the following industry relationships: Sherita Hill Golden, MD, MHS, reports no relationships to disclose with any manufacturer of a product or device discussed in this supplement. 1. Centers for Disease Control and Prevention (CDC). National diabetes fact sheet: General information and national estimates on diabetes in the United States, 2007. Atlanta, GA: CDC, 2008. 2. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R, Venditti E, Nathan DM, for the Diabetes Prevention Program Research Group. Ten-year followup of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677–1686. 3. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986. 4. UK Prospective Diabetes Study (UKPDS). Group Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837– 853.

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