The results of the Diabetes Control and Complications Trial(DCCT) and UK Prospective Diabetes Study trials in type 1 andtype 2 diabetes, respectively, have proved the importance ofintensive glucose management in the prevention of microvascularcomplications (retinopathy, nephropathy, and neuropathy). Bothtrials showed encouraging trends for a decrease in macrovascularcomplications, and this is being pursued in new studies. Thesefindings have led to more strict goals for glucose control.As glucose levels are aimed to be closer to the normal range,the risk for hypoglycemia also increases dramatically. The choiceof the agent therefore is more influenced currently by the riskfor hypoglycemia. There are presently four classes of oral antihyperglycemicagents. These agents differ greatly in terms of mechanisms ofaction, efficacy, side effect profiles, and cost. Except forAcarbose, all classes decrease the glycosylated hemoglobin bya similar magnitude: 1.0 to 1.5%. In chronic renal failure,the oral agents that can be used therefore include the insulinsecretagogues repaglinide and nateglinide and the thiazolidinediones(rosiglitazone and pioglitazone) with caution. Insulin alsocan be used safely in renal failure.
Type 2 diabetes occurs as a result of a complex interplay amongmultiple genetic and environmental factors that lead to bothincreased insulin resistance and impaired pancreatic insulinsecretion. Epidemiologic studies have shown a relationship betweenincreasing levels of glucose and increased risk for both micro-and macrovascular complications. The threshold for increasedcardiovascular risk occurs in the "nondiabetic" range, and evenminimal elevations of glucose are associated with increasedcardiovascular risk (1). There is much less randomized controlledtrial evidence on the value of glucose control in preventingmacrovascular disease. In the UK Prospective Diabetes Study,intensive treatment of individuals with newly diagnosed type2 diabetes reduced the risk for myocardial infarction by 16%(P = 0.052), amputation or death from peripheral vascular diseaseby 35% (P = 0.15), fatal myocardial infarction by 6% (P = 0.63),nonfatal myocardial infarction by 21% (P = 0.057), fatal suddendeath by 46% (P = 0.047), and amputation by 39% (P = 0.099)(2). Every 1% reduction in glycosylated hemoglobin (HbA1c) wasassociated with reductions in risk of 21% for any end pointrelated to diabetes, 21% for diabetes-related deaths, 14% formyocardial infarction, and 37% for microvascular complications(all P < 0.0001) (3). No threshold of risk was observed forany end point; however, the lowest risk was in individuals withan HbA1c in the normal range (<6%). In the obese subset,metformin therapy was associated with a lower risk for diabetes-relatedend points (P = 0.0034) and all-cause mortality (P = 0.021)compared with the other intensive therapies (4).
The diagnosis of type 2 diabetes is often delayed, and 20 to50% present with microvascular or macrovascular complicationsat the time of diagnosis of type 2 diabetes. The managementregimens of patients with type 2 diabetes should be tailoredto the individual patient, aiming for glycemic targets as closeto normal as possible (A1c <6% when agents that do not causehypoglycemia are used) and, in most people, as early as possible(5).
It is known that both weight loss and increased physical activitycan improve insulin resistance and thus improve hyperglycemia(6). It is recommended that lifestyle modification strategiesbe used in all patients with type 2 diabetes, whether medicationis used or not (5).
Mechanisms of Action of Oral Antihyperglycemic Agents
The antihyperglycemic agents that are available include theinsulin secretagogues (sulfonylureas and meglitinides), metformin,-glucosidase inhibitors, and the thiazolidinediones. These agentsdiffer greatly in terms of mechanisms of action, efficacy, sideeffect profiles, and cost (Table 1).
Sulfonylureas and meglitinides increase insulin secretion bypancreatic cells. Metformin decreases hepatic gluconeogenesis.-Glucosidase inhibitors delay the absorption of glucose fromstarch and sucrose, attenuating postprandial glucose increases.Thiazolidinediones are potent, highly selective agonists forperoxisome proliferator–activated receptor-. Thiazolidinedionesdecrease insulin resistance, enhance peripheral disposal ofglucose, and have some effect on hepatic production of glucose.
Glucose-Lowering Efficacy of Antihyperglycemic Agents
A large number of clinical trials comparing the efficacy ofthe oral antihyperglycemic agents have been completed. The comparativeglycemic effect of some of these agents are well known whenused as monotherapy and in combination with other oral antihyperglycemicagents or insulin (Table 1). In general, metformin, the thiazolidinediones,and the insulin secretagogues (sulfonylureas and repaglinide)have approximately equivalent efficacy (reductions in HbA1cof 1.0 to 1.5% compared with placebo) (7–11). Higher reductionsare generally seen in treatment-naïve patients and thosewith higher baseline glycemic values (9,11). Treatment withacarbose seems somewhat less effective with reductions in HbA1cof 0.5 to 1% compared with placebo in previously untreated patients(12–14).
Most of the oral antihyperglycemic agents can be combined witheach other and insulin therapy with additive effects. The initialuse of combinations of submaximal doses of oral antihyperglycemicagents produces more rapid and improved glycemic control comparedwith monotherapy with the maximal dose of one agent, withouta significant increase in side effects (15).
Therapy with exogenous insulin is recommended when individualshave not achieved glucose targets with oral agents either aloneor in combination (5). Oral agents may be continued or addedon to insulin therapy as necessary.
Hypoglycemia
Within the oral antihyperglycemic agents, insulin secretagoguesare associated with the highest occurrence of hypoglycemic episodes,ranging from 10 to 35% (4,7,10). However, severe episodes thatrequire intervention are relatively rare (0 to 1.3%). Metformin,thiazolidinediones, and -glucosidase inhibitors do not usuallycause hypoglycemia when used alone but can potentiate the hypoglycemicpotency of insulin secretagogues (4,7,9,12,14). Repaglinideand nateglinide are particular in having a rapid onset and shortduration of action and can be given at mealtimes. They havebeen shown to decrease hypoglycemia when given to patients withirregular mealtimes. Insulin therapy in patients with type 2diabetes is associated with the highest frequency of hypoglycemia(16 to 34%) (4,7,12), although this frequency is much lowerthan that seen with insulin therapy of patients with type 1diabetes.
Although -glucosidase inhibitors do not cause hypoglycemia,they may prevent sucrose or starch from being absorbed in atimely manner for the treatment of hypoglycemia caused by othertreatments. Patients who take -glucosidase inhibitors thereforemust use glucose (dextrose tablets), grape juice, or honey totreat hypoglycemia.
Body Weight
Insulin secretagogues, both sulfonylureas and repaglinide, areassociated with an increase in body weight compared with placeboof up to approximately 4.5 kg over 3 yr (7). The use of rosiglitazoneand pioglitazone in the treatment of type 2 diabetes has beenassociated with weight gain of 1 to 3 kg. -Glucosidase inhibitorsdemonstrate neutral effects on weight, whereas metformin isusually associated with no weight gain and occasionally weightloss.
Other Side Effects
Metformin is associated with a high frequency of nausea anddiarrhea. This side effect can be reduced by taking the pillsin the middle of the meal. Acarbose, by inhibiting proximalabsorption of starch and sucrose, can cause flatulence. Thisside effect is present in >70% of patients in the first months,but some adaptation occurs and the magnitude of this side effectdecreases over subsequent months. The major risk of metforminis lactic acidosis. It is a rare side effect, occurring particularlyin the presence of renal failure, hepatic dysfunction, or tissueischemia.
The thiazolidinediones rosiglitazone and pioglitazone have beenassociated with small decreases in hemoglobin in patients withtype 2 diabetes, likely explained by a modest increase in plasmavolume. Edema was noted with greater frequency in patients whowere treated with pioglitazone or rosiglitazone compared withthose who were treated with placebo in clinical trials. A recentAmerican Diabetes Association/American Heart Association positionstatement recommended avoiding the use of thiazolidinedionesin the presence of class III or IV NYHA congestive heart failure(CHF) and to use with caution in those who have less severeCHF or are at risk for CHF (history of heart failure, previousmyocardial infarction or angina, hypertension, left ventricularhypertrophy, significant aortic or mitral valve disease, age>70 yr, diabetes duration >10 yr, preexisting edema ortreatment with loop diuretics, development of edema or weightgain on thiazolidinediones, insulin co-administration, and chronicrenal failure) (16).
Use of Antihyperglycemic Agents in Patients with Renal Failure
Metformin is contraindicated in renal failure because of theassociated risk for lactic acidosis. It can be used at low dosagesup to a creatinine clearance of 30 to 60 ml/min and should beavoided with clearances <30 (17). Although the metabolismof thiazolidinediones is unaffected by renal failure, they mustbe used with caution in this context because of their volume-retainingeffect with a risk for heart failure (18).
The sulfonylureas (glyburide, gliclazide, glipizide, glibenclamide,tolbutamide, and chlorpropamide) have increased potency as therenal function decreases and are contraindicated in severe renalfailure (19). The nonsulfonylurea insulin secretagogues repaglinideand nateglinide can be used in renal failure without dose adjustments(20). -Glucosidase inhibitors (acarbose and miglitol) are contraindicatedin renal failure.
In the absence of contraindications, metformin should be preferredover other agents for a number of reasons. Compared with insulinsecretagogues in general, metformin has equal potency and alow risk for hypoglycemia and causes less weight gain. In obesepatients, there is strong clinical evidence of reduced microvascularand macrovascular outcomes.
In the presence of contraindications or intolerance to metforminor when metformin alone does not result in optimal control,thiazolidinediones should be used. They should be favored overinsulin secretagogues because they are not associated with hypoglycemia.Compared with acarbose, thiazolidinediones have more potentantihyperglycemic effects. Sulfonylureas and other insulin secretagoguesshould be reserved for combination therapy because of the riskfor hypoglycemia.
In chronic renal failure, the oral agents that can be used thereforeinclude the insulin secretagogues repaglinide and nateglinideand the thiazolidinediones (rosiglitazone and pioglitazone)with caution. Insulin also can be used safely in renal failure.
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Top
Abstract
Introduction
-glucosidase inhibitors, and the thiazolidinediones. These agents differ greatly in terms of mechanisms of action, efficacy, side effect profiles, and cost (Table 1). 
cells. Metformin decreases hepatic gluconeogenesis. 
. Thiazolidinediones decrease insulin resistance, enhance peripheral disposal of glucose, and have some effect on hepatic production of glucose. 
