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Literature Compendium |
Current Concepts in Type 2 Diabetes
Volume 2
The Appropriate Application of Oral Pharmacological Therapy, Non-Insulin Injectable Agents, and Insulin in the Management of Type 2 Diabetes
Chapter 2
Antihyperglycaemic Agents: Metformin and Insulin Secretagogues and Sensitizers
The management of Type 2 diabetes is focused on long-term glycaemic control. While diet and exercise can improve glycaemic control, lifestyle intervention without pharmacological therapy has limited long-term success, and the majority of individuals typically require the addition of pharmacotherapy.
Metformin is a biguanide that decreases hepatic glucose output and increases peripheral insulin sensitivity. Sulfonylureas and meglitinides (‘glinides’) are insulin secretagogues that increase insulin secretion by the pancreas. Thiazolidinediones are insulin sensitizers that increase peripheral insulin sensitivity and decrease hepatic glucose output. Together, these drug classes form the mainstay of oral anti-diabetic therapy—they have been available longer than other agents and are among the most widely studied. This chapter highlights 3 major studies that evaluated outcomes associated with metformin, insulin secretagogues, and insulin sensitizers in individuals with Type 2 diabetes.
The United Kingdom Prospective Diabetes Study (UKPDS) Paper 28 describes a 3-year, multicenter, randomized, open-controlled trial performed to evaluate the efficacy of adding metformin to a maximized sulfonylurea regimen in individuals with Type 2 diabetes.1 This trial enrolled 591 individuals who had sub-optimal glycaemic control despite maximal sulfonylurea doses. After 3 years of treatment with metformin plus a sulfonylurea, median fasting plasma glucose (FPG) was 8.6 mmol/l (155.0 mg/dl) compared with 9.9 mmol/l (178.4 mg/dl) in the sulfonylurea-only group (P<0.00001), and median HbA1c levels were 7.5 % and 8.1 %, respectively (P=0.006). Adjustment for baseline body mass index or FPG level did not affect outcome. The improvements in glycaemic control were attained without a commensurate increase in the incidence of hypoglycaemic events. In fact, the incidence of hypoglycaemic events did not differ significantly between individuals treated with the combination of metformin plus a sulfonylurea and those treated with sulfonylurea monotherapy. This landmark trial showed that the addition of metformin can improve glycaemic control in individuals taking maximal doses of a sulfonylurea, without substantially increasing the risk of hypoglycaemia.
ADOPT (A Diabetes Outcome Progression Trial) was a large-scale, randomized, double-blind, controlled study performed to evaluate the long-term glucose-lowering efficacy of a thiazolidinedione compared with that of metformin and sulfonylureas.2 A total of 4360 individuals with recently diagnosed Type 2 diabetes were randomized to receive either rosiglitazone (n=1456), metformin (n=1454), or glyburide (n=1441) monotherapy. At 5 years, the cumulative incidence of treatment failure—defined as confirmed hyperglycaemia (FPG level, >180 mg/dl [10.0 mmol/l]) on consecutive testing after at least 6 weeks of treatment at the maximum-dictated or maximum-tolerated dose of the study drug—was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. Rosiglitazone was associated with a greater risk of cardiovascular events than was glyburide, and the risk associated with metformin was similar to that with rosiglitazone. Weight gain and oedema were more common with rosiglitazone than with either metformin or glyburide. Gastrointestinal adverse events were most common with metformin, and hypoglycaemia was most common with glyburide. In this study, the durability of glycaemic control achieved with rosiglitazone was offset by the greater risk of cardiovascular events—a result that foreshadowed widely publicized concerns regarding the safety of thiazolidinediones.
PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) was a multicenter, prospective, randomized, placebo-controlled trial performed to evaluate whether pioglitazone reduced macrovascular morbidity and mortality in high-risk individuals with Type 2 diabetes.3 A total of 5238 individuals with existing macrovascular disease were randomized to receive either pioglitazone (n=2605) or placebo (n=2633) in addition to their regular glucose-lowering regimen. Mean age of enrolled individuals was 61.8 years. Median baseline HbA1c was 7.8 % in the pioglitazone group and 7.9 % in the placebo group. At randomization, 62% of individuals were taking metformin, 62% were taking a sulfonylurea alone or in combination with another agent, and >30% were taking insulin. The primary endpoint was the proportion of individuals who experienced a composite of all-cause mortality, non-fatal myocardial infarction (MI), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. The main secondary endpoint was a composite of all-cause mortality, non-fatal MI, and stroke. After a mean of 34.5 months, 514 individuals in the pioglitazone group (19.7%) and 572 in the placebo group (21.7%) had at least 1 event in the primary endpoint (P=0.095), and 301 (11.6%) and 358 (13.6%) individuals in these groups, respectively, had at least 1 event in the main secondary endpoint (P=0.027). In this trial, unfortunately, pioglitazone treatment resulted only in a modest reduction in the risk of the primary composite endpoint. In addition, limitations in the study design are likely to slow acceptance of the data. For example, because the sample consisted primarily of Caucasian subjects with a relatively high rate of cigarette smoking and a relatively low rate of statin use for persons with known macrovascular disease, it is not all that surprising that the event rates were greater than expected. In addition, the 36-month trial duration may not have been long enough to detect an actual difference between groups. Finally, it is unclear whether the results of the PROactive study can be applied to the other available thiazolidinedione, rosiglitazone.
UKPDS, ADOPT, and PROactive provide evidence that treatment with oral hypoglycaemic agents can effectively reduce blood glucose concentration, maintain glycaemic targets over time, and, in many cases, reduce the likelihood of developing diabetes-related complications, without appreciably increasing the risk of hypoglycaemia. They provide the foundation upon which the practice guidelines reviewed in the previous chapter are built.
References
Click to proceed to Chapter 3.
Click to proceed to Chapter 4.
Click to proceed to Programme Evaluation and Post-test.
Click to return to Opening Page.
Click to return to Table of Contents.
Click to return to Introduction.
Click to return to Chapter 1.
The Literature Compendium is funded by an educational grant from Pfizer Inc.
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