Steven V. Edelman, MD
Professor of Medicine
Division of Endocrinology and Metabolism
University of California, San Diego
Director of the Diabetes Care Clinic
Veterans Affairs Medical Center
Founder and Director, Taking Control of Your Diabetes [501(c)(3)]
San Diego, California

OVERVIEW

The prevalence of diabetes in the United States has increased dramatically over the last 10 years, from 5.1% in 1997 to 7.8% in 2006 (Figure 1).¹ With increasingly more individuals affected by diabetes, it is important for primary care clinicians to understand and effectively manage the comorbid conditions associated with this disease, says Steven V. Edelman, MD.

He adds that cardiovascular disease (CVD) is of particular concern in patients with diabetes. CVD is the major cause of death in patients with type 2 diabetes. “Statistics show that the incidence of cardiovascular disease in patients with diabetes is 2 to 4 times higher than those without diabetes and the relative risk of stroke in patients with diabetes is 1.8 to nearly 6.0.”²

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SECTION ONE: The Diabetes–CVD Link

Impact of Obesity

SECTION TWO: Evidence-Based Guidelines for Managing Cardiometabolic Risk Factors in Patients
With Diabetes

Glucose Control

Intensive Versus Standard Glucose Control

Blood Pressure, Lipid Control

Weight Control

SECTION THREE: Antidiabetic Agents in the United States

Incretin Mimetics and DPP-IV Inhibitors

SECTION FOUR: Impact of Incretin Mimetics and DPP-IV Inhibitors on Weight and Other CVD Risk Factors

Impact of Incretin Mimetics and DPP-IV Inhibitors on Weight

Impact of Incretin Mimetics and DPP-IV Inhibitors on Postprandial Glucose

Effect of Incretin Mimetics and DPP-IV Inhibitors on Other Cardiometabolic Risk Factors

SECTION FIVE: Conclusion

SECTION ONE: The Diabetes–CVD Link

Patients often have a cluster of risk factors, known as cardiometabolic risk factors, that increase the risk of developing both type 2 diabetes and CVD (Figure 2).³

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Despite the increasing knowledge on the effects of these cardiometabolic factors, most patients with type 2 diabetes are not achieving recommended treatment goals. Data from the National Health and Nutrition Examination Survey (NHANES) show that in 1999-2000, 37.0% of patients achieved an Hb A1C level below 7%, 35.8% achieved blood pressure below 130/80 mm Hg, and 48.2% had total cholesterol below 200 mg/dL (Figure 3).⁴ “However, I think the most striking statistic is that only 7.3% of patients achieve all 3 of these goals,” says Dr. Edelman. “There are a number of barriers against the successful treatment of all 3 of these abnormalities, and these findings show that we have a lot of work to do to try to help our patients to achieve their treatment goals.”

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Impact of Obesity

Obesity is a cardiometabolic risk factor believed to be the primary pathogenetic mechanism for both CVD and type 2 diabetes, and is associated with insulin resistance, hypertension, dyslipidemia and elevated C-reactive protein.³ Abdominal adiposity, in particular, is a greater risk factor than overall obesity.³

The prevalence of obesity among US adults, as defined by a body mass index (BMI) >30 kg/m², has more than doubled in the past 30 or so years, from 15.0% in 1976-1980, to 32.9% in 2003-2004.⁵ Despite this increasing prevalence, obesity is still largely underdiagnosed and undertreated.⁶

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SECTION TWO: Evidence-Based Guidelines for Managing Cardiometabolic Risk Factors in Patients With Diabetes

The American Diabetes Association provides guidelines for the screening, diagnosis, and treatment of patients with type 2 diabetes (Table 1).⁷

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Practice Aid

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Glucose Control

The recommended goals include Hb A1C levels of <7%. Dr. Edelman adds, however, “that all major diabetes organizations, including the ADA, suggest that the real goal is to normalize the Hb A1C into the nondiabetic range—in other words below 6% in an assay whose normal range is 4% to 6%—if you can do it without any significant hypoglycemia, weight gain, or disrupting a patient's lifestyle.”^7-9

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Intensive Versus Standard Glucose Control

Dr. Edelman says a number of recent studies are evaluating whether, “tight control of glucose reduces cardiovascular disease, specifically macrovascular disease,” better than more standard control.

ACCORD evaluated 10,251 patients with type 2 diabetes who were at high risk for heart attack and stroke.¹⁰ Patients were randomized to “intensive” Hb A1C lowering (<6%) or standard lowering (7%-7.9%). An interim review by the Data and Safety Monitoring Board revealed that 257 patients in the intensive-treatment group had died, compared with 203 in the standard-treatment group (hazard ratio [HR], 1.22; 95% CI, 1.01-1.46; P = .04). Dr. Edelman says, “It is important to note that the death rate for both groups was lower than expected compared with matched patients not enrolled in the study. Nevertheless, based on this difference in mortality, the intensive treatment arm was stopped. Data also showed that there was no significant difference between the 2 treatment arms in the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from any cause).

In contrast, data from ADVANCE, which included 11,140 high-risk patients with type 2 diabetes, showed a significant reduction in the combined outcome of major macrovascular and microvascular events in patients who had intensive lowering of their glucose (to Hb A1C ≤6.5%).¹¹ As well, there was no significant effect from intensive glucose lowering on death from cardiovascular causes or from any causes.

Data from the Veterans Affairs Diabetes Trial (VADT), which also compared intensive glucose lowering (Hb A1C <6%) with standard reduction (Hb A1C 8%-9%) in nearly 1,800 people, were presented at the 68th Scientific Sessions of the American Diabetes Association (ADA 2008).¹² With a median follow up of 6 years, researchers found intensive glucose lowering alone, in context of reduced risk factors, had no significant effects on cardiovascular events. Dr. Edelman adds, “In addition, unlike the ACCORD trial, there was no increased risk for CVD in the intensively controlled group, and no safety issues were associated with the use of rosiglitazone.”

Dr. Edelman provides his thoughts on how to interpret data from these trials: “The bottom line is that we need to concentrate on glucose control to reduce microvascular disease, while avoiding hypoglycemia, and aggressively treating macrovascular risk factors, such as hypertension and dyslipidemia.”

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Blood Pressure, Lipid Control

The ADA guidelines also stress the importance of lowering blood pressure and lipid levels (Table 1).⁷

The Steno-2 trial found that after 13.3 years of follow-up, intensive therapy—which included tight glucose regulation (ie, Hb A1C <6.5%) and the use of renin-angiotensin system blockers and lipid-lowering agents to control blood pressure (to <130/80 mm Hg), total cholesterol (to <175 mg/dL), and triglcyerides (to <150 mg/dL)—was associated with a 46% reduction in the risk for death (HR, 0.54; 95% CI, 0.32-0.89; P = .02) and a 57% reduction in the risk for CV-related death (HR, 0.43; 95% CI, 0.19-0.94; P = .04).¹³

“When you look at the cumulative incidence of a composite cardiovascular event over the 13-plus years of the study, you can see the curves start to separate after 4 to 5 years, and by the end of the study, there is a 59% reduction in risk for the group that was intensively controlled [Figure 4],” says Dr. Edelman.¹³ He suggests that this practical study shows the benefit of treating the whole patient rather than just focusing on specific abnormalities such as glucose or blood pressure.

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Weight Control

Waist circumference is now considered to be the key clinical indicator of abdominal adiposity, in contrast to BMI, which has been the traditional measure of overall obesity.³ The American Heart Association notes that a waist circumference ≥40 inches for men or ≥35 inches for women is associated with the metabolic syndrome.¹⁴ As illustrated in Figure 5, to most accurately evaluate abdominal adiposity, waist circumference should be measured at the site where the abdominal circumference is greatest.³

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Practice Aid

The ADA guidelines note that modest weight loss reduces insulin resistance and is recommended for all overweight or obese individuals who have diabetes (Table 1).⁷

“It’s been shown quite clearly that you don’t need to lose an excessive amount of weight to see a large reduction in hyperglycemia, blood pressure, and dyslipidemia,” notes Dr. Edelman.

Dr. Edelman acknowledges that clinicians may not prioritize obesity because it is difficult to treat. They may focus instead on conditions such as blood pressure, cholesterol, and diabetes, for which more effective treatments and management tools are available.

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SECTION THREE: Antidiabetic Agents in the United States

Despite their benefits, diet and exercise can be difficult to maintain and often are not sufficient for controlling glucose levels or ensuring weight loss. In addition, pharmacologic therapy for weight reduction has not proven to be effective to date. As such, many patients require medical intervention to treat diabetes. Several classes of medical therapies are approved to treat this condition (Table 2).^15,16

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Despite their efficacy, some of these agents are associated with negative metabolic effects (Table 3).¹⁷ Dr. Edelman explains that insulin or insulin secretagogues such as sulfonylureas and glinides are associated with hypoglycemia. A number of other agents are not associated with hypoglycemia. Dr. Edelman says that the incretin mimetics, for example, induce insulin secretion only if the blood glucose level is above normal, and thus stimulate insulin release in a more physiologic manner.

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Practice Aid

The other side effect commonly seen with some antidiabetic agents is weight gain. Any agent that chronically elevates insulin levels can lead to weight gain; this includes insulin, sulfonylureas, and glinides. Insulin sensitizers can also lead to weight gain through a mechanism that is not entirely clear, says Dr. Edelman. However, the incretin mimetics have been shown to cause significant and sustained weight loss, and the dipeptidyl peptidase IV (DPP-IV) inhibitors are weight neutral.

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Incretin Mimetics and DPP-IV Inhibitors

“An incretin by definition is a substance that is released when an individual ingests something orally that leads to glucose-dependent insulin secretion,” says Dr. Edelman. “The most well characterized incretin is GLP-1, which turns out to come to originate from the L-cells of the small intestine [Figure 6].”¹⁸ GLP-1 is released upon ingestion of food and leads to several physiologic responses.”

These responses include increasing glucose-dependent insulin secretion (restoring first phase insulin release), decreasing glucagon secretion, thereby reducing glucose production by the liver, and slowing gastric emptying, thus delaying the absorption of nutrients limiting the peak rise in glucose levels in the postprandial state. GLP-1 and the incretin mimetics work centrally in the brain leading to appetite suppression and reduced food intake. Human GLP-1 is broken down by DPP-IV, an enzyme that inactivates incretins within 1 to 2 minutes of ingesting food (Figure 6).¹⁸

Table 4 lists a number of approved and emerging agents, both incretin mimetics and DPP-IV inhibitors.^19,20

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SECTION FOUR: Impact of Incretin Mimetics and DPP-IV Inhibitors on Weight and Other CVD Risk Factors

In addition to improvements reported in Hb A1C levels, a growing body of evidence suggests that incretin mimetics and DPP-IV inhibitors are associated with weight loss (or are weight neutral, in the case of DPP-IV inhibitors), decreased postprandial glucose levels, and improvements in other cardiometabolic risk factors.

Impact of Incretin Mimetics and DPP-IV Inhibitors on Weight

Kendall and colleagues evaluated the effects of exenatide on cardiovascular risk factors.²¹ In their study, patients were initially randomized to exenatide 5 μg or 10 μg or placebo BID for 30 weeks; all patients then received 5 μg exenatide BID for 4 weeks, followed by 10 μg exenatide BID in uncontrolled extension studies. A total of 151 patients completed 3.5 years of therapy with exenatide. The average weight loss in these patients was 2.4 kg at week 30, and 5.3 kg after 3.5 years (Figure 7).²¹ “What's very encouraging is that not only did the weight loss occur,” says Dr. Edelman, “but it continued to drop over the first couple of years. I think this is something that really makes incretin mimetics quite unique compared with other pharmaceutical agents, where they are either weight neutral or actually lead to weight gain.”

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Klonoff and colleagues conducted a post-hoc analysis of 217 patients from 3 placebo-controlled trials (and their open-label extensions), and found that 46% of patients on exenatide had Hb A1C ≤7% at 3 years and 30% had Hb A1C ≤6.5%.²² In all, 84% of patients experienced weight loss (average loss, 5.3 kg ± 0.4 kg), and 50% of patients lost ≥5% of their baseline body weight.

Drucker and colleagues found that the use of once-weekly exenatide over a 30-week period resulted in a significantly greater decrease in Hb A1C (-1.9% vs -1.5%; P = .002) compared with the twice-daily formulation.²³ Patients in both groups lost nearly 4 kg at 30 weeks. No major hypoglycemia was observed with either exenatide regimen, and the once-weekly exenatide was well tolerated. After week 30, all patients were given once-weekly exenatide. Fifty-two week data showed durable glycemic improvement and weight loss, with a loss of 4.1 kg in the original once-weekly group, and 4.5 kg in the BID to QW group.²⁴

Liraglutide, a once-daily human GLP-1 analog, has also demonstrated positive effects on Hb A1C, body weight, and body fat. In a 12-week, placebo-controlled, randomized, double-blind study in 190 patients with type 2 diabetes, Hb A1C reductions were similar with liraglutide and the sulfonylurea glimepiride.²⁵ However, glimepiride led to weight gain and hypoglycemia, whereas liraglutide led to a significant reduction in weight with minimal hypoglycemia. Similar results were seen in a study presented by Jendle and colleagues.²⁶ In this latter study, over 1,000 patients were randomized to one of 3 doses of liraglutide, placebo, or glimepiride, each added to metformin. In addition to improvements in Hb A1C and body weight, the study found that liraglutide reduced fat percentage and central body adipose tissue compared with glimepiride.

Amori and colleagues analyzed 29 randomized-controlled trials of incretin mimetics and DPP-IV inhibitors and found that the use of incretin mimetics resulted in weight loss (-1.4 kg vs placebo; -4.8 kg vs insulin) and that DPP-IV inhibitors were weight neutral.²⁷

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Impact of Incretin Mimetics and DPP-IV Inhibitors on Postprandial Glucose

Postprandial glucose lowering has been identified as an important efficacy measure, because it has been identified as a strong, independent risk factor for CVD.⁸

Studies have shown that the use of exenatide results in decreased postprandial glucose levels compared with placebo²⁸ and insulin glargine.²⁹

To evaluate the effects of the DPP-IV inhibitor sitagliptin on glucose levels, Raz and colleagues conducted a randomized, placebo-controlled trial in 190 patients receiving metformin.³⁰ At 18 weeks, sitagliptin was associated with a significant reduction in 2-hour postprandial glucose compared with placebo (P < .001). Dr. Edelman points out that although the reductions in fasting blood sugar were less dramatic, “When you improve the postprandial glucose, there is usually a carryover effect and improvement in the fasting blood glucose the next day.”

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Effect of Incretin Mimetics and DPP-IV Inhibitors on Other Cardiometabolic Risk Factors

Data are also emerging that indicate these agents may have a beneficial impact on other cardiometabolic risk factors. The long-term study by Kendall and colleagues found that the use of exenatide resulted in modest improvements in blood pressure and lipids over 3.5 years (Table 5).²¹ Buse and colleagues demonstrated similar effects with the once-weekly exenatide over 52 weeks.²⁴

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SECTION FIVE: Conclusion

Dr. Edelman concludes that when managing patients with diabetes, it is vital for clinicians to not just control glucose levels, but also to address all the factors that make up a patient’s cardiometabolic risk profile. “Many experts feel that when looking at the priority of treating the different abnormalities in patients with type 2 diabetes, that blood pressure and cholesterol actually take precedent over glucose control. We know that glucose control will reduce microvascular complications but certainly blood pressure and cholesterol control will have a greater impact on macrovascular disease, which is the most common cause of death.”

The emerging evidence that some antidiabetic agents can not only aid in controlling blood glucose levels, but also improve other cardiometabolic risk factors, including weight reduction, may allow clinicians to use these medications for multiple purposes.

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References

1. Centers for Disease Control and Prevention. Early release of selected estimates based on data from the January–September 2007 National Health Interview Survey. Hyattsville, MD: National Center for Health Statistics. http://www.cdc.gov/nchs/data/nhis/earlyrelease/200803_14.pdf. Accessed June 14, 2008.
2. American Heart Association/American Stroke Association. Heart Disease and Stroke Statistics. 2008 Update. http://americanheart.org/downloadable/heart/1200078608862HS_Stats%202008.final.pdf.
3. Watson K. Crit Pathw Cardiol. 2007;6:5-14.
4. Saydah SH et al. JAMA. 2004;291:335-342.
5. Centers for Disease Control and Prevention. Overweight and obesity. Atlanta, GA: CDC. http://www.cdc.gov/nccdphp/dnpa/obesity/index.htm. Accessed June 14, 2008.
6. Bardia A et al. Mayo Clin Proc. 2007;82:927-932.
7. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S5-S11.
8. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13(suppl 1):1-68.
9. Rydén L et al, for the Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC); European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28:88-136.
10. Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358:2545-2559.
11. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.
12. Duckworth W. 68th Scientific Sessions of the American Diabetes Association (ADA 2008). VA Diabetes Trial Symposium. June 8, 2008.
13. Gaede P et al. N Engl J Med. 2008;358:580-581.
14. Grundy SM et al. Circulation. 2005;112:e285-e290.
15. Nathan DM. N Engl J Med. 2007;356:437-440.
16. Edelman SV, Henry RR. Diagnosis and Management of Type 2 Diabetes. 8th ed. West Islip, NY: Professional Communications, Inc; 2008.
17. Inzucchi SE et al. Circulation. 2008;117:574-584.
18. Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.
19. Exenatide injection [prescribing information]. http://www.fda.gov/cder/foi/label/2008/021773s012lbl.pdf. Accessed June 14, 2008.
20. Sitagliptin [prescribing information]. http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed June 14, 2008.
21. Kendall DM et al. 67th Scientific Sessions of the American Diabetes Association (ADA 2007). Poster 0557-P.
22. Klonoff DC et al. Curr Med Res Opin. 2008;24:275-286.
23. Drucker DJ et al. ADA 2008. Oral presentation 107-OR.
24. Buse J et al. ADA 2008. Late-breaking oral presentation.
25. Madsbad S et al. Diabetes Care. 2004;27:1335-1342.
26. Jendle J et al. ADA 2008. Oral presentation 106-OR.
27. Amori RE et al. JAMA. 2007;298:194-206.
28. Kolterman OG et al. J Clin Endocrinol Metab. 2003;88:3082-3089.
29. Heine RJ et al. Ann Intern Med. 2005;143:559-569.
30. Raz I et al. Curr Med Res Opin. 2008;24:537-550.

Beyond Glycemic Control: Managing Obesity and Cardiovascular Disease Risk for Patients With Type 2 Diabetes in the Primary Care Setting

Program Description & Educational Objectives

In this activity, an expert in the treatment of diabetes investigates the importance of addressing the many cardiometabolic risk factors that are present in patients with type 2 diabetes. The activity also features an analysis of the impact of newer antidiabetic agents, including incretin mimetics and DPP-IV inhibitors, on improving a number of these risk factors.

Upon completion of this activity, participants will be able to:

• Address barriers to successful management of all risk factors for poor outcomes in patients with type 2 diabetes, such as weight control and adherence
• Provide practical guidance to patients with type 2 diabetes on current recommendations regarding lifestyle interventions
• Develop treatment plans that address multiple risk factors in patients with type 2 diabetes

Target Audience

This activity has been designed to meet the educational needs of primary care physicians active in the management of patients with diabetes.

Requirements for Successful Completion

In order to receive credit, participants must view the activity and complete the post-test and evaluation form. There are no pre-requisites and there is no fee to participate in this activity or to receive CME/CE credit. Certificates are awarded upon successful completion of the post-test and evaluation form.

Media:

Internet

Release and Expiration Dates:

July 2, 2008 - July 1, 2009

Time to Complete:

30 minutes

Faculty & Disclosure

Course Director and Interviewee

Steven V. Edelman, MD
Professor of Medicine
Division of Endocrinology
and Metabolism
University of California, San Diego
Director of the Diabetes Care Clinic
Veterans Affairs Medical Center
Founder and Director, Taking Control of Your Diabetes [501(c)(3)]
San Diego, California

Steven V. Edelman, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Amylin Pharmaceuticals, Inc.; Eli Lilly and Company; GlaxoSmithKline; Novo Nordisk Inc.; and sanofi-aventis.

CME Reviewer

James M. Smith, MD
Clinical Assistant Professor
and Program Director
Department of Internal Medicine
University of Florida College of Medicine
Gainesville, Florida

James M. Smith, MD, currently has no financial interests/relationships or affiliations in relation to this activity.

CE Reviewers

Katie Spong, RN, LSW
University of Minnesota
Home Health Care
St. Paul, Minnesota

Kristine Kemp, RN
Abbott-Northwestern Hospital
Minneapolis, Minnesota

Alexis Houck, RN, MA
Health Partners
Minneapolis, Minnesota

Sponsorship, Credit & Support

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Florida College of Medicine and PVI, PeerView Institute for Medical Education. The University of Florida College of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The University of Florida College of Medicine designates this educational activity for a maximum of 0.5 AMA PRACategory 1 Credit(s)^TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Amedco, St. Paul, MN, is an approved provider of continuing nursing education by the Wisconsin Nurses Association Continuing Education Approval Program Committee, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.

This course is co-provided by Amedco and PVI, PeerView Institute for Medical Education. 0.5 contact hour(s).
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