Current antihyperglycemic treatment strategies for patients with type 2 diabetes mellitus

Long-term risk reduction

A 10-year, postinterventional follow-up study (UKPDS 80) of the UKPDS survivor cohort was reported recently.²⁰ Results showed that despite an early loss of glycemic differences between patients treated with diet and those treated with intensive regimens (sulfonylurea or insulin; metformin in overweight patients), the pharmacotherapy group demonstrated a prolonged reduction in microvascular risk as well as a significant reduction in the risk for myocardial infarction (15% [P = .01] in the sulfonylurea-insulin group and 33% [P = .005] in the metformin group) and death from any cause.²⁰ This suggests that early improvement in glycemic control is associated with long-term benefits in the micro- and macrovascular health of patients with T2DM.

Additionally, the recent long-term follow-up of the Steno-2 study²¹ showed that a multifactorial intervention striving for intensive glucose, BP, and lipid control that included the use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents not only reduced the risk of nonfatal CVD among patients with T2DM and microalbuminuria, but also had sustained beneficial effects on vascular complications and on rates of death from any cause and from CV causes. From a health care payer perspective, intensive multifactorial intervention was more likely to be cost-effective than conventional treatment in Denmark, especially if applied in a primary care setting.²²

Comprehensive care needed

The lower-than-expected rates of CV outcomes in the ACCORD, ADVANCE, VADT, and Steno-2 studies reinforce the importance of comprehensive diabetes care that treats not only hyperglycemia but also elevated BP and dyslipidemia; these are considered the “ABCs” of diabetes.^11,19 The 2009 ADA standards of medical care guidelines recommend that for most T2DM patients, HbA1c should be maintained at less than 7.0%,³ while the American Association of Clinical Endocrinologists (AACE) 2007 guidelines state that HbA1c should be 6.5% or less.¹¹ Both organizations stress the importance of individualized goals, as discussed above, and advocate BP goals of less than 130/80 mm Hg and dyslipidemia goals of low-density lipoprotein cholesterol (LDL-C) less than 100 mg/dL, high-density lipoprotein cholesterol (HDL-C) greater than 40 mg/dL for men and 50 mg/dL for women, and triglycerides less than 150 mg/dL. It is recommended that an optional LDL-C goal of less than 70 mg/dL be considered for individuals with overt CVD.

CURRENT ANTIHYPERGLYCEMIC TREATMENT STRATEGIES

In response to new insights from clinical research and emerging treatment strategies, disease-specific organizations and medical specialty societies regularly revise and update their treatment guidelines and algorithms. These resources recommend that glycemic progress should be regularly monitored and pharmacologic therapy titrated or new drugs added promptly if glycemic goals are not met after 2 to 3 months.

Several algorithms combine scientific evidence with expert clinical opinion to guide physicians in treating their patients with T2DM. The American College of Endocrinology (ACE)/AACE road maps are designed to help develop individualized treatment regimens to achieve an HbA1c of 6.5% or less.²³ The algorithm from a writing group assembled by the ADA and the European Association for the Study of Diabetes (EASD) similarly promotes pharmacologic treatment together with lifestyle modifications to maintain a glycemic goal of HbA1c less than 7.0%.²⁴

OVERVIEW OF ANTIHYPERGLYCEMIC TREATMENT APPROACHES

Initial oral therapy

T2DM is usually treated initially with a single oral agent. Consistent with the progressive nature of the disease, patients often eventually require one or more additional oral agents and in many cases insulin.^13,27 Choice of specific agents is based on individual patient circumstances, including the need for weight loss and control of fasting versus postprandial glucose, the presence of dyslipidemia and hypertension, and the risk for and potential consequences of hypoglycemia.²⁴ T2DM patients with severely uncontrolled and symptomatic hyperglycemia are best treated, at least initially, with a combination of insulin therapy and lifestyle intervention, often with metformin.

Metformin. The recently revised ADA/EASD writing group algorithm recommends that patients not requiring initial insulin begin treatment with metformin at the time of diagnosis unless there are contraindications.²⁴ Metformin is not associated with hypoglycemia and is considered weight-neutral, although some patients may lose weight.²⁸

Sulfonylureas. Sulfonylureas stimulate insulin secretion from pancreatic beta cells; their use may be associated with hypoglycemia and weight gain. Mechanisms for weight gain with sulfonylureas include reduction of glucosuria and increased caloric intake to prevent or treat hypoglycemia.^11,28 Nateglinide and repaglinide are nonsulfonylurea oral insulin secretagogues. They result in rapid and relatively short-lived insulin responses and are usually administered three times a day, before each meal. Their use may be associated with weight gain and hypoglycemia.¹¹

Thiazolidinediones. Thiazolidinediones (TZD) increase insulin sensitivity in muscle, adipose tissue, and the liver. Hypoglycemia is uncommon with TZD monotherapy but weight gain related to increased and redistributed adiposity and fluid retention frequently occurs.

Alpha-glucosidase inhibitors. The alpha-glucosidase inhibitors are administered before meals and primarily reduce postprandial hyperglycemia. They are generally weight-neutral.²⁸

Insulin. Insulin and insulin analogues are the most effective antihyperglycemic agents, but their use can be associated with hypoglycemia and clinically significant weight gain.²⁸

Colesevelam. Colesevelam is a bile acid sequestrant that was recently approved by the US Food and Drug Administration as an antihyperglycemic therapy in people with T2DM. At a dosage of 1.875 g BID or 3.75 g QD in combination with a sulfonylurea, metformin, or insulin therapy, reductions in HbA1c compared with placebo in clinical trials of colesevelam have ranged from ­–0.5% to –0.7% (P < .02). Frequency of hypoglycemia and weight gain is low with this agent.²⁶

Weight management. Weight reduction is important for overweight or obese patients with T2DM.^27,28 Even moderate weight loss (5% of body weight) can be associated with improved insulin action and reduced hyperglycemia.²⁹ Conversely, weight gain has been shown to worsen hyperglycemia and other CV risk factors. Treatment-related weight gain can also lead to decreased regimen adherence, contributing to poor glycemic control.²⁸