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Patient and treatment perspectives: Revisiting the link between type 2 diabetes, weight gain, and cardiovascular risk

December 1, 2009|Cleveland Clinic Journal of Medicine
Anne L. Peters, MD, CDE
Author and Disclosure Information

Anne L. Peters, MD, CDE
Director, USC Clinical Diabetes Programs, and Professor of Clinical Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA

Correspondence: Anne L. Peters, MD, CDE, Director, USC Clinical Diabetes Programs, 150 N. Robertson Blvd., Suite 210, Beverly Hills, CA 90211; momofmax@mac.com

Dr. Peters reported that she has received consulting/advisory fees from Abbott Laboratories, Amylin Pharmaceuticals, Inc., Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk, and Takeda Pharmaceutical Company Limited; and honoraria from Amylin Pharmaceuticals, Inc., Novo Nordisk, and Takeda Pharmaceutical Company. Dr. Peters reported that she did not receive an honorarium for writing this article.

Dr. Peters reported that she wrote this article and received no assistance with content development from unnamed contributors. She reported that BlueSpark Healthcare Communications, a medical communications company, assisted with preliminary literature searches, reference verification, proofing for grammar and style, table and figure rendering based on author instructions, copyright permission requests, and identification of topical overlap with other manuscripts in this supplement.

ABSTRACT

Lifestyle modifications in conjunction with antidiabetes medications can produce near-normal blood glucose concentrations in patients with type 2 diabetes mellitus (T2DM). Because these patients have increased cardiovascular morbidity and mortality, treatment strategies should also address the cardiovascular aspects of the disease, including blood pressure, lipids, and body weight. Since the prevalence of these abnormalities is increasingly secondary to poor diet and sedentary lifestyles and because most patients with T2DM are overweight/obese, clinicians are encouraged to help patients reduce body weight while correcting hyperglycemia by selecting treatment options that improve both parameters. The glucose-lowering properties of insulin and sulfonylureas are well known but they are also associated with weight gain. Thiazolidinediones are associated with weight gain as well as edema. However, this weight gain may be more peripheral than central, which may mitigate the risks associated with increased body fat. Metformin, the consensus first-line drug for the treatment of patients with T2DM, is weight neutral. Newer antidiabetes agents include incretin-based medications, such as the glucagon-like peptide–1 receptor agonists, which tend to decrease weight, and the dipeptidyl peptidase–4 inhibitors, which are weight neutral.

KEY POINTS

  • Control of cardiovascular risk factors is as important as glycemic control in patients with T2DM.
  • Intensive glucose control has shown mixed results in terms of correlation with improved cardiovascular risk factors.
  • Newer agents target the fundamental pathophysiologic defects of T2DM, with beneficial effects on weight and other cardiovascular risk factors.

Type 2 diabetes mellitus (T2DM), excess weight, and obesity are increasing in prevalence at alarming rates.1–3 Concurrent with the increased prevalence is increased risk of morbidity and mortality. A healthy diet and exercise in conjunction with antidiabetes medications can help lower glucose concentration in patients with T2DM. Because these patients are at increased risk of cardiovascular (CV) morbidity and mortality, however, treatment strategies should address the CV risk factors, including blood pressure (BP), lipids, and body weight, as well as glycemic aspects of the disease.

To help clinicians manage the complex issues in treating patients with T2DM, this article presents an overview of patient and treatment perspectives relevant to overweight/obesity and CV disease (CVD). It includes an examination of the latest guidelines and algorithms for the management of T2DM, which continue to be updated and modified.

T2DM, WEIGHT GAIN OR OBESITY, AND CV RISK: A CHALLENGING TRIAD

Despite therapeutic advances in the diagnosis and treatment of diabetes and CVD over the last decade, the estimated number of persons in the United States older than 35 years with self-reported diabetes (with T2DM accounting for 90% to 95% of diagnosed cases) and CVD has increased from 4.2 million in 1997 to 5.7 million in 2005.3,4 The CV risk for patients with T2DM who have not had a CV event such as a myocardial infarction (MI) is similar to that of individuals without diabetes who have had a prior MI.5 Patients with T2DM have nearly double the mortality of those without the disease.6 Adding to their risk, about 80% of patients with T2DM are overweight or obese, conditions associated with worsened insulin resistance and increased CV risk and disease burden.7,8 Even a modest weight gain (5 kg) may increase the risk of coronary heart disease (CHD) by 30%, while associated changes in lipids and BP can increase the risk by another 20%.9

It is as important to control CV risk factors as it is to control glycemia in patients with T2DM, and both are difficult to achieve. Data from a recent nationwide Norwegian survey showed that only 13% of patients with T2DM achieved study-defined target levels; ie, glycosylated hemoglobin (HbA1c) less than 7.5%, BP less than 140/85 mm Hg, and total cholesterol/high-density lipoprotein (HDL-C) ratio less than 4.0.10

BENEFITS OF MANAGING GLYCEMIA, WEIGHT REDUCTION, AND CV RISK FACTORS

Several large studies, many ongoing, are generating data on the relationships among glycemia, weight reduction, and CV risk. It is well established that individuals with T2DM need aggressive risk factor reduction (glucose control, blood pressure management, and treatment of dyslipidemia) to optimize outcomes. However, characterization of the benefits of various components of risk factor reduction, particularly over many years, is only now occurring.

Results from the United Kingdom Prospective Diabetes Studies (UKPDS) showed the benefits and risks of pharmacologic glycemic control—essentially monotherapy with insulin or a sulfonylurea—compared with conventional dietary therapy in reducing diabetic complications in patients with newly diagnosed T2DM. In UKPDS 33, both insulin and sulfonylureas (intensive treatment) reduced the risk of microvascular end points (retinopathy, nephropathy) in patients whose median HbA1c was lowered to 7.0% at 10 years of follow-up, compared with patients who reached an HbA1c of 7.9%. However, intensive glycemic control did not translate into a statistically significant reduction in macrovascular complications, including MI, stroke, CVD, and death. Additionally, patients assigned to insulin had greater weight gain (+4.0 kg) than did patients assigned to receive the sulfonylurea chlorpropamide (+2.6 kg) or glyburide (+1.7 kg) (P < .01).11

The UKPDS showed that intensive treatment with metformin reduced the risk of T2DM-related end points compared with conventional treatment (primarily diet alone) in overweight patients.12 Although there were fewer patients in the metformin-treated subset (n = 342) than in the conventional treatment cohort, a secondary analysis showed that metformin was associated with less weight gain and fewer hypoglycemic episodes than either insulin or sulfonylurea therapy.12 Since HbA1c levels in the treatment groups were equal, the additional benefits seen with metformin in overweight patients with T2DM were not based solely on glycemic control.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial involved 10,000 individuals with T2DM. The primary outcome measure was a composite of CV events. The intensively treated group was controlled to a target HbA1c of less than 6.0%, with most patients receiving insulin. The trial was terminated early because an increased risk of sudden death was observed.13 A similar study, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), evaluated more than 11,000 patients with T2DM, starting with a sulfonylurea-based regimen. In this study, there was no reduction in macrovascular events, but there was a reduction in nephropathy in the intensively treated group.14 In both studies, hypoglycemia and weight gain were more frequent in intensively treated patients; and in ACCORD, there were more episodes of severe hypoglycemia in the intensive-treatment group.13,14

The Veterans Affairs Diabetes Trial (VADT) evaluated the effect of intensive glucose control on CVD in 1,791 patients (mean age, 60 years) with poorly controlled T2DM (average duration, 11.5 years). The primary end points included MI, stroke, new or worsening congestive heart failure (CHF), limb amputation, and invasive intervention for coronary or peripheral arterial disease. The hazard ratio for these end points in the intensive-treatment group was 0.88 (95% confidence interval [CI], 0.74 to 1.05).15,16 Specifically, the following beneficial effects were achieved:

  • HbA1c reduced by –1.0% to –2.5% in absolute units,
  • systolic BP (SBP) reduced by –4 to –7 mm Hg,
  • diastolic BP (DBP) reduced by –7 to –8 mm Hg,
  • low-density lipoprotein cholesterol (LDL-C) reduced by –27 to –28 mg/dL,
  • triglycerides reduced by –44 to –50 mg/dL, and
  • HDL-C increased by 4 to 5 mg/dL.

Despite these benefits, body weight increased approximately 9 to 18 lb (4 to 8 kg) during therapy.15

Since overweight and obesity are independent risk factors for CHD and CVD in patients with T2DM,17 weight management is an integral component in treatment. In the Action for Health in Diabetes (Look AHEAD) trial, an intensive exercise and weight-loss program resulted in clinically significant (P < .001) weight loss at 1 year in patients who had T2DM and a body mass index (BMI) greater than 25 kg2/m (> 27 kg2/m if receiving insulin).18 When compared with patients who received less structured, infrequent support and minimal education about diabetes, participants in the intensive program showed more weight loss, improved glucose control, decreased CV events, and reduced medicine use. The Look AHEAD trial is currently evaluating whether these improvements will continue to result in lower CV risk.

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