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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.

GLP-1 receptor agonists

Many of the GLP-1 receptor agonists developed or under development have glucoregulatory effects similar to GLP-1 but are resistant to degradation by DPP-4.28 Exenatide, an exendin-4 receptor agonist, has compared favorably with sitagliptin and with insulin analogues. Long-acting (once-weekly and once-daily) GLP-1 receptor agonists are under development.

In a 2-week, head-to-head study in metformin-treated patients with T2DM, exenatide had a greater effect than sitagliptin in lowering PPG and was more potent in increasing insulin secretion and reducing postprandial glucagon secretion. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake.49

In two studies of patients treated with exenatide, on a background of either metformin alone or metformin plus a sulfonylurea, patients who received metformin lost more weight (–1.6 to –2.8 kg; P ≤ .01) and experienced more significant decreases from baseline HbA1c (–0.4% to –0.8%; P < .002) at 30 weeks than did patients who received placebo.50,51 In a 16-week trial of exenatide in patients previously treated with a TZD with or without metformin, exenatide reduced HbA1c –0.98%, fasting blood glucose –1.69 mmol/L, and body weight –1.51 kg.52

When compared with insulin analogues, exenatide has been associated with weight loss (~ –3 kg) while the insulin analogues were associated with weight gain (~ +3 kg).53 After 26 weeks, body weight decreased –2.3 kg with exenatide and increased +1.8 kg with insulin glargine.54 Similar results were found in a crossover noninferiority trial, where the least-squares mean difference in weight change was significantly (P < .001) different (2.2 kg) between the treatments.55 When exenatide was compared with insulin aspart in an open-label, noninferiority trial, there was a between-group difference in weight of –5.4 kg after 52 weeks.32

Exenatide has also demonstrated these benefits in open-label extension studies. After 2 years, mean HbA1c reductions of –1.1% from baseline were sustained (P < .05), and weight loss of –4.7 kg was maintained (P < .001).56 After 82 weeks, similar HbA1c decreases (–1.1%) and weight loss (–4.4 kg) were exhibited.57 Even after 3 years, these benefits were maintained in patients who remained on the drug (HbA1c reduction from baseline, –1.0%; weight loss, –5.3 kg [P < .0001 for both]).58

Long-acting formulations of GLP-1 receptor agonists are in clinical development; two of these are once-weekly exenatide and once-daily liraglutide. Exenatide once weekly has the advantage of less frequent dosing and has elicited greater reductions in HbA1c than exenatide BID. After 15 weeks of once-weekly administration, the 0.8-mg formulation reduced HbA1c –1.4% and the 2-mg formulation reduced it –1.7% (P < .0001 for both compared with placebo). Body weight was lowered –3.8 kg (P < .05 compared with placebo) with the 2-mg formulation.59 Compared with exenatide BID, exenatide 2 mg once weekly showed greater reductions in HbA1c (–1.9% vs –1.5%; P = .0023) after 30 weeks of therapy.60 In a 1-year noncomparative trial, treatment with exenatide once weekly improved HbA1c (–2.0%) and weight (–4.1 kg), as well as BP and lipid profiles compared with baseline.61

Liraglutide, a once-daily human analogue GLP-1 receptor agonist, is under review by the FDA.28 In a 26-week study of patients with T2DM, liraglutide was associated with reductions in HbA1c (mean, –1.04%; P = 0.067 compared with insulin) and body weight (mean, –2.5 kg; P < .001 compared with insulin) at dosages of 0.6 to 1.8 mg/day SC. Liraglutide produced a decline in SBP from 0.6 to 3 mm Hg but was not associated with a decrease in DBP.62 In a 52-week study comparing liraglutide with glimepiride monotherapy, liraglutide 1.2 mg was associated with an HbA1c reduction of –0.84% (P = .0014) and the 1.8-mg dose with a reduction of –1.14% (P < .0001) compared with –0.51% for glimepiride. SBP decreased –0.7 mm Hg with glimepiride compared with –2.1 mm Hg for liraglutide 1.2 mg (P = .2912) and –3.6 mm Hg for liraglutide 1.8 mg (P < .0118). Mean DBP fell slightly but not significantly in all treatment groups.63 No effects on lipid parameters were reported in these two liraglutide studies.

The Liraglutide Effect and Action in Diabetes (LEAD-6) trial was undertaken to compare exenatide (10 mg BID SC) and liraglutide (1.8 mg/day SC) as add-on therapy to metformin, a sulfonylurea, or a combination of both in 464 patients with T2DM. After 26 weeks of treatment, liraglutide was associated with a significant reduction in HbA1c of –1.12%, compared with –0.79% with exenatide (P < .0001). Patients treated with liraglutide lost –3.2 kg while those on exenatide lost –2.9 kg. Among patients previously treated with metformin alone, there was a 1-kg difference in favor of liraglutide (P = NS).64

Safety profile

All of the drugs discussed have potential adverse effects. Metformin continues to have a black box warning for lactic acidosis.65 Sulfonylureas and insulin can cause hypoglycemia. TZDs can cause fluid retention and, in rare cases, CHF (for which these drugs also carry a black box warning).66,67 TZDs also increase the risk of distal fracture.66,67 The most common side effects of exenatide are gastrointestinal, but there have been reported cases of pancreatitis, some of which have been fatal.68,69 It has been difficult to prove whether exenatide increases the risk of pancreatitis, as patients with T2DM are already at an increased (three- to fourfold) risk for this condition compared with persons who do not have T2DM.69 Exenatide should not be used in patients with severe renal impairment or end-stage renal disease; it should be used with caution in patients who have undergone renal transplantation and in patients with moderate renal impairment.

The prescribing information for sitagliptin includes pancreatitis among the adverse reactions identified during the drug’s postapproval use.70 As with exenatide, it is not fully known whether a true association exists between the agent and pancreatitis. However, since pancreatitis can occur in this patient population, it is recommended that abdominal pain be fully evaluated to rule out pancreatitis. Continued postmarketing surveillance is important for all of these agents.

THE ROLE OF GUIDELINES

The American Association of Clinical Endocrinologists (AACE),26 the American Diabetes Association (ADA),71 and the ADA in conjunction with the European Association for the Study of Diabetes (EASD)24 have recently revised their recommendations for the management of patients with diabetes. The guidelines are unanimous in setting a glycemic goal (HbA1c < 7.0% for the ADA, HbA1c ≤ 6.5% for the AACE) and advocating individualized care for a treatment goal of HbA1c lower than 6.0% in patients who stand to benefit from near euglycemia without inducing severe hypoglycemia.24,26,71

CVD is the major cause of morbidity and mortality associated with T2DM and is a source of increasing concern.5 Accordingly, special consideration should be given to patients with coexisting CV risk factors, including hypertension and dyslipidemia. The ADA and the EASD advocate lifestyle modification to decrease body weight and the concurrent initiation of metformin as first-line therapy.24 If that strategy is insufficient, then two tiers of treatment guide the choice of next steps24:

  • Tier 1, in addition to metformin, includes the sulfonylureas and insulin. Although these are excellent glucose-lowering drugs, they are associated with weight gain, hypoglycemia, and no improvement in BP or lipid levels. They are relatively low in cost and have been used for many years. Their main drawback is evidence that despite their use, beta-cell failure continues unabated over time.
  • Tier 2 treatments include pioglitazone and the GLP-1 receptor agonist exenatide. Consideration may be given to the use of pioglitazone or exenatide when hypoglycemia is of concern, with exenatide being preferred when weight loss is a major objective and HbA1c is close to target (< 8.0%).24 Additionally, both the TZDs and exenatide probably help slow the rate of beta-cell failure, particularly if they are used early in the course of the disease.72,73 The AACE recommends different pharmacologic approaches based on HbA1c at diagnosis.26

The American Heart Association and the ADA have issued a joint scientific statement on the primary prevention of CVD in patients with diabetes.74 They advocate lifestyle management of body weight, nutrition, and physical activity.74 In addition, they stress the need for attention to BP, lipid levels, and smoking status, and the use of antiplatelet agents in patients at increased CV risk (> 40 years of age and a family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).

CONCLUSION

T2DM, weight gain/obesity, and CV risk present a continuing challenge to patients and clinicians. Anti­diabetes agents have varying degrees of evidence to support their effects on HbA1c, body weight, BP, and lipid levels. A better understanding of the pathophysiology of T2DM has led to the development of newer antidiabetes agents that target the fundamental defects of the disease. Evidence continues to accumulate for the improved benefits of glycemic control and weight loss in T2DM with GLP-1 receptor agonists such as exenatide currently having robust data in terms of beneficial effects on weight and CV risk factors. As clinicians continue to incorporate this knowledge into their practice patterns, patient adherence and clinical outcomes are expected to improve. Newer agents, such as incretin-based therapies, address T2DM as well as other factors that increase cardiometabolic risk through their effects not only on glycemic control but on body weight, BP, and lipids.

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