Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus

INTRODUCTION — Sulfonylureas and meglitinides directly stimulate release of insulin from pancreatic beta cells and thereby lower blood glucose concentrations. Because they work by stimulating insulin secretion, they are useful only in patients with some beta cell function. Adverse effects may include weight gain and hypoglycemia. The pharmacology, efficacy, indications, and side effects of these drugs will be discussed here. A general discussion of initial and subsequent treatment of type 2 diabetes is reviewed separately.

●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

●(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

●(Related Pathway(s): Diabetes: Initial therapy for non-pregnant adults with type 2 DM.)

●(Related Pathway(s): Diabetes: Medication selection for non-pregnant adults with type 2 DM and persistent hyperglycemia despite monotherapy.)

SULFONYLUREAS

Mechanism of action — The sulfonylurea receptor is a component of the adenosine triphosphate (ATP)-sensitive potassium channel (K-ATP channel) in the pancreatic beta cells [1]. The K-ATP channel regulates the release of insulin from pancreatic beta cells. Sulfonylurea binding leads to inhibition of these channels, which alters the resting potential of the cell, leading to calcium influx and stimulation of insulin secretion. The net effect is increased responsiveness of beta cells to both glucose and non-glucose secretagogues (such as amino acids), resulting in more insulin being released at all blood glucose concentrations. Sulfonylureas may also have extrapancreatic effects, one of which is to increase tissue sensitivity to insulin, but the clinical importance of these effects is minimal [2].

The K-ATP channel is a functional complex of the sulfonylurea 1 receptor (SUR1) and an inward rectifier potassium channel subunit Kir6.2. Mutations in either the SUR1 gene or the Kir6.2 gene lead to the loss of K-ATP activity; as a result, the cell is persistently depolarized, resulting in calcium influx, high cytosolic calcium concentrations, and the release of insulin, producing a syndrome called persistent hyperinsulinemic hypoglycemia of infancy. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)

Mutations in the Kir6.2 and, to a lesser extent, the SUR1 gene, have also been identified that activate the K-ATP channel [3,4]. Activating mutations increase the number of open K-ATP channels at the plasma membrane, hyperpolarizing the beta cells and preventing the release of insulin. These mutations have been found in patients with permanent neonatal diabetes mellitus; insulin secretion in these patients can be restored with glyburide [5]. (See "Neonatal hyperglycemia".)

Clinical use of sulfonylureas

Initial therapy — Initial treatment of patients with type 2 diabetes mellitus includes education, with emphasis on lifestyle changes including diet, exercise, and weight reduction when appropriate. Initial therapy with metformin, rather than a sulfonylurea, is indicated for most patients. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Choice of initial therapy'.)

Sulfonylureas can be used as initial therapy in the following settings:

●Contraindications to metformin – A short-acting sulfonylurea (eg, glipizide) is an option for patients who have contraindications to or intolerance of metformin, particularly if cost is a concern. In a meta-analysis of 31 trials, sulfonylurea monotherapy (nine trials) lowered A1C by 1.5 percentage points more than placebo [6].

●Severe hyperglycemia (fasting plasma glucose >250 mg/dL [13.9 mmol/L], random glucose consistently >300 mg/dL [16.7 mmol/L], glycated hemoglobin [A1C] >9 percent [74.9 mmol/mol]) but without ketonuria or unintentional weight loss – In this setting, insulin or a glucagon-like peptide 1 (GLP-1) receptor agonist are the preferred initial therapies. However, for patients who refuse or cannot afford injectable agents, initial therapy with high-dose sulfonylurea is an alternative option and can rapidly reduce hyperglycemia in patients with severe hyperglycemia [7].

Insulin should be used in patients (regardless of age) who are underweight, are losing weight, or are ketotic despite adequate caloric intake. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Symptomatic (catabolic) or severe hyperglycemia' and "Insulin therapy in type 2 diabetes mellitus", section on 'Indications for insulin'.)

Some of these latter patients may actually have type 1 diabetes, which can be confirmed by the presence of autoantibodies (eg, glutamic acid decarboxylase [GAD]-65 and islet antigen [IA]-2). (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Distinguishing type 1 from type 2 diabetes'.)

●Maturity onset diabetes of the young (MODY) – MODY is a clinically heterogeneous disorder characterized by non-insulin-dependent diabetes diagnosed at a young age (<25 years) with autosomal dominant transmission and lack of autoantibodies. Several different genetic abnormalities have been identified, each leading to a different type of disease. The subtypes of MODY are defined by specific descriptions of the known genetic defects (table 1). Patients with mutations in the HNF1A and HNF4A gene (formerly known as MODY subtypes 3 and 1, respectively), two of the three most common MODY subtypes, can be successfully treated with sulfonylurea monotherapy. Such patients can be safely transitioned from insulin to sulfonylureas with as good or better glycemic management [8]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Monogenic diabetes (formerly called maturity onset diabetes of the young)'.)

Combination therapy — Sulfonylureas are more commonly used in combination with other oral hypoglycemic drugs in patients who fail initial therapy with lifestyle intervention and metformin. Sulfonylureas generally are not used in combination with insulin. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)

Sulfonylureas usually lower A1C by 1 to 2 percent [6,9]. In a meta-analysis of 31 trials, the addition of sulfonylureas to other oral diabetes treatment (metformin or thiazolidinediones, four trials) lowered A1C by 1.62 percentage points more than placebo [6].

In a meta-analysis of 179 trials and 25 observational studies evaluating the effects of oral or injectable diabetes medications in combination with other oral agents or insulin on intermediate outcomes (A1C, body weight, lipid profiles), most combinations (including sulfonylurea combinations) similarly reduced A1C levels [10]. In the GRADE comparative effectiveness trial in 5047 patients with type 2 diabetes with a mean five-year follow-up, participants who were randomly assigned to glimepiride as add-on treatment to metformin monotherapy had a cumulative incidence of A1C ≥7 percent (72 percent) that was only modestly higher than the incidence with liraglutide (68 percent) or glargine (67 percent) and lower than that with sitagliptin (77 percent) [11].

The choice of a sulfonylurea over other oral or injectable agents balances glucose-lowering efficacy, universal local availability, and low cost with risk of hypoglycemia and weight gain. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

Precautions

Sulfonamide allergies — Concern regarding potential crossreactivity of sulfonamide antimicrobials (eg, sulfamethoxazole, sulfasalazine) and sulfonylureas, with an increased risk for allergic reactions to sulfonylureas in patients with a history of "sulfa allergies," appears to be unfounded and is no longer listed as a contraindication in the package insert for immediate-release glipizide. Although hypersensitivity to sulfonamides is still listed as a warning for glyburide and glimepiride and a contraindication for gliclazide and glipizide extended release, sulfonylureas are commonly used in patients with professed allergies to sulfonamide antimicrobials without any problems. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Between sulfonamide antimicrobials and nonantimicrobials'.)

Use in chronic kidney disease — Sulfonylurea metabolites are renally excreted. Some of these metabolites (such as those of glyburide [glibenclamide]) are active or have weak hypoglycemic activity. Therefore, the risk of hypoglycemia is higher in patients with chronic kidney disease. Shorter-acting sulfonylurea medications with mostly inactive metabolites (eg, glipizide, glimepiride) are preferred. (See 'Choice of sulfonylurea' below and "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Patients not on dialysis'.)

Choice of sulfonylurea — When a decision has been made to treat with a sulfonylurea, we suggest a shorter-duration sulfonylurea (eg, glipizide, gliclazide [not available in the United States]) or one with relatively lower risk for hypoglycemia (eg, glimepiride). Observational and randomized studies have supported lower frequency of hypoglycemia with gliclazide or glipizide than with longer-acting sulfonylureas [12-14]. (See 'Hypoglycemia' below.)

●For patients with nondialysis chronic kidney disease, glipizide or glimepiride are preferred formulations since glipizide is shorter acting than glyburide and both are metabolized by the liver and primarily excreted in the urine as inactive metabolites. (See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Treatment' and "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Patients not on dialysis'.)

●For patients with established cardiovascular disease (CVD), we prefer an agent that has demonstrated cardiovascular benefit (eg, GLP-1 receptor agonist or sodium-glucose co-transporter 2 [SGLT2] inhibitor). (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Established cardiovascular or kidney disease' and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

If these agents are unavailable or not tolerated, and a sulfonylurea is required for additional glucose-lowering, we prefer to use glimepiride based on the results of the CAROLINA (Cardiovascular Outcomes Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes) randomized clinical trial, which compared glimepiride with linagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in 6033 patients over a median 6.3 years and found no difference in cardiovascular outcome [15]. This trial, along with a similarly designed trial comparing linagliptin with placebo that did not show an increased risk of major adverse cardiovascular events, provides reassurance of the cardiovascular safety of glimepiride [16,17]. (See 'Cardiovascular effects' below.)

There is a paucity of trials comparing the relative effectiveness and safety of the individual sulfonylureas. There is a relatively high incidence of hypoglycemia and other adverse effects in patients taking glyburide (glibenclamide), due in part to the formation of active metabolites [18] (see 'Hypoglycemia' below). First-generation sulfonylureas (eg, chlorpropamide, tolbutamide) are not commonly available or used. They differed from currently available sulfonylureas owing to their long duration of action and increased risk for hypoglycemia (chlorpropamide), other adverse effects such as hyponatremia and disulfiram-like effects (chlorpropamide), and because of old studies that suggested increased cardiovascular risk (tolbutamide) (table 2).

Dosing and monitoring — The recommended dose range for most of the available drugs is shown in the table (table 2). The art of sulfonylurea dosing departs somewhat from the "science" or recommended dose range on the package insert. For patients who are lean, have chronic kidney disease, or are frail or older, who are taking a sulfonylurea rather than a medication that does not cause hypoglycemia, we start at the lower end of the dose range and advance slowly. For younger, more insulin-resistant patients with severe hyperglycemia, we start with higher doses. For patients with variable diet and activity, we recommend variable dosing appropriate to meal size and scheduled activity. All patients treated with sulfonylureas should receive education regarding when to hold the medication (for increased physical activity or when not eating) and recognition and management of hypoglycemia. (See 'Hypoglycemia' below.)

A typical low-dose initial sulfonylurea regimen consists of:

●Glipizide, 2.5 mg of glipizide taken 30 minutes before breakfast.

●Glimepiride, 1 to 2 mg with breakfast. For patients at increased risk for hypoglycemia (older, chronic kidney disease), the initial dose should be 1 mg daily.

●Gliclazide, 40 to 80 mg daily (40 mg for older patients and those with chronic kidney disease) or gliclazide MR 30 mg daily (one tablet of gliclazide 80 mg is comparable with gliclazide MR 30 mg daily, a longer-acting formulation).

The glucose-lowering effects of sulfonylureas with dose changes are seen quickly, and rapid titration can be performed if adequate glycemic management is not attained based on blood glucose monitoring. We typically recommend spot checking before meals and bedtime over the course of the week, to cover all time points; however, routine testing four times every day is usually not required. Routine blood glucose monitoring may be stopped when the safety and stability of the regimen is established. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Non-insulin treated'.)

The dose can be adjusted every one to four weeks based on response and risk of hypoglycemia.

●For glipizide, 5 mg and then 10 mg, given before breakfast or before breakfast and the evening meal may be sufficient. The maximum dose of glipizide is noted to be up to 40 mg/day in the labeling. However, doses higher than 20 mg/day rarely improve glycemic management, and higher doses should generally be avoided [19].

●For glimepiride, the dose can be increased in 1 or 2 mg increments based upon glycemic response (usual daily dose 2 to 4 mg daily, but up to 4 mg twice daily or 8 mg daily).

●For gliclazide, the dose can be increased in 40 to 80 mg increments (usually 40 mg). Doses of 160 mg or greater should be taken in divided doses with breakfast and dinner (maximum daily dose 320 mg) (table 2). For gliclazide MR, the dose is increased in 30 mg increments (maximum daily dose 120 mg).

A typical high-dose sulfonylurea regimen (for severe or symptomatic hyperglycemia) is glimepiride 4 or 8 mg once daily. An alternative option is immediate-release glipizide 10 mg twice daily (or, where available, gliclazide immediate release 80 mg daily). (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Symptomatic (catabolic) or severe hyperglycemia'.)

For patients taking a sulfonylurea, we measure A1C every three to six months. For patients with impaired kidney function, creatinine should be measured every 6 to 12 months.

Cardiovascular effects — Overall, there does not appear to be an increased risk of cardiovascular events with second-generation sulfonylureas [15,20-23]. Any increase in relative risk for CVD events compared with metformin is thought to be secondary to the benefits of metformin, which appears to reduce the risk for myocardial infarction [24]. Our general recommendation is to have most patients with type 2 diabetes treated with metformin as a first medication, with sulfonylureas as one of the medication classes to add if needed. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

●Overall cardiovascular risk – In a meta-analysis of 115 trials (of at least six months duration) comparing sulfonylureas with an active comparator in patients with type 2 diabetes, there was no difference in the incidence of major cardiovascular events, although overall mortality (but not cardiovascular mortality) was increased (odds ratio [OR] 1.22, 95% CI 1.01-1.49) [20]. In a subsequent meta-analysis of 47 trials (of at least one year duration) comparing second-generation sulfonylureas (glibenclamide, glimepiride, glipizide, and gliclazide) with diet, placebo, or an active comparator, sulfonylureas were not associated with an increased risk of overall mortality, cardiovascular mortality, myocardial infarction, or stroke [21]. The trials in these meta-analyses were not specifically designed to evaluate cardiovascular safety.

In a specifically designed cardiovascular outcomes trial (CAROLINA) comparing linagliptin with glimepiride in 6042 patients with type 2 diabetes and elevated cardiovascular risk (median follow-up of 6.3 years), the occurrence of the composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was similar in the two groups (11.8 versus 12 percent with glimepiride, hazard ratio [HR] 0.98, 95% CI 0.84-1.14) [15]. Hospitalization for heart failure did not differ between the two groups. Rates of severe hypoglycemia (0.07 versus 0.45 per 100 patient-years) and hospitalization for hypoglycemia (0.01 versus 0.18 per 100 patient-years) were low in both groups, albeit higher in the sulfonylurea group. This trial, along with a similarly designed trial (CARMELINA) comparing linagliptin with placebo that did not show an increased risk of major adverse cardiovascular events, provides reassurance of the cardiovascular safety of glimepiride [16,17].

Similarly, in the GRADE trial in 5047 participants with type 2 diabetes and low baseline cardiovascular risk, the rates of prespecified cardiovascular secondary outcomes including major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular mortality were similar with glimepiride relative to sitagliptin and glargine when added to metformin monotherapy [22]. The GRADE trial is discussed in detail elsewhere. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Without established cardiovascular or kidney disease'.)

●In comparison with metformin – A randomized trial and retrospective studies suggest higher rates of cardiac events with sulfonylureas than metformin [24-29]. The relative increased risk for CVD associated with sulfonylureas appears to be due to protective effects of metformin, rather than an adverse cardiovascular effect of sulfonylureas. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

•In a trial of metformin or glipizide (median follow-up five years) in 304 Chinese patients with a history of coronary heart disease and type 2 diabetes, there were fewer cardiovascular events (composite of nonfatal myocardial infarction [5 versus 6], stroke [10 versus 15], arterial revascularization [21 versus 25], or death from cardiovascular or any cause [7 versus 14]) in the metformin group (total events 43 versus 60; HR 0.54, 95% CI 0.3-0.9) [25]. After three years, the mean achieved A1C level was similar (7 and 7.1 percent) in the two groups. However, body weight, waist circumference, and body mass index (BMI) were significantly lower in the metformin group.

•In a retrospective Canadian study using pharmaceutical data for 5795 patients who received initial monotherapy with either a sulfonylurea or metformin, deaths per 1000 person-years during the follow-up period (mean 4.8 years) were 67.6 for first-generation sulfonylurea medications, 61.4 for glyburide, and 39.6 for metformin [26]. The risk of death or an acute ischemic event was greater for individuals exposed to higher, compared with lower, doses of the sulfonylurea, but not metformin [26]. The greatest risk was for patients taking higher, compared with lower, doses of tolbutamide or chlorpropamide (HR 2.1, 95% CI 1.0-4.7).

•In a retrospective cohort study comparing cardiovascular outcomes in 253,690 United States veterans who initiated metformin or sulfonylurea for diabetes, the risk of a composite cardiovascular outcome (hospitalization for acute myocardial infarction or stroke, or death) was higher in sulfonylurea users (18.2 versus 10.4 per 1000 person-years; HR 1.21, 95% CI 1.13-1.30) with median follow-up of less than one year [27]. There was no difference in CVD risk in patients taking glipizide versus glyburide. In a subsequent report from the same group, the higher risk of major adverse cardiovascular events noted in sulfonylurea compared with metformin users was also evident in patients with reduced kidney function [29].

Many other retrospective cohort studies have shown results favoring metformin over sulfonylureas. All of these studies are hindered by various forms of bias, including allocation bias (ie, confounding by indication) in which sulfonylureas are prescribed to patients who cannot take metformin, frequently due to comorbidities (eg, chronic kidney disease), or time lag bias, owing to sulfonylurea usually being started at a later disease stage since metformin is the recommended first medication. Even in studies that use the most sophisticated methods to adjust for allocation bias, there is concern that residual confounding cannot be eliminated, which is why randomized trials provide a much higher quality of evidence.

●In patients with acute myocardial infarction – Some studies suggest that treatment with sulfonylureas may be associated with poorer outcomes in patients who have a myocardial infarction. Increased mortality from CVD in patients with diabetes taking tolbutamide was noted over three decades ago in the University Group Diabetes Study [30]. While this study was not supported by results from the United Kingdom Prospective Diabetes Study (UKPDS), which reported no increase in fatality for patients taking sulfonylurea therapy at the time of myocardial infarction [31], other studies have supported the association [32,33]. Most other studies have been observational, have not been able to address allocation bias, and have provided conflicting data.

Of note, the newer sulfonylureas (such as gliclazide and glipizide) are highly selective for the pancreatic sulfonylurea receptors over the cardiac K-ATP channel receptors and do not appear to be associated with increased cardiovascular mortality compared with metformin or other diabetes medications. As noted, however, the only comparative effectiveness clinical trials have been the CAROLINA and GRADE trials, which found no evidence of increased CVD risk with glimepiride compared with linagliptin, sitagliptin, or insulin glargine [11,15,28,34,35].

Adverse effects

Hypoglycemia — Hypoglycemia is a common side effect, although it is generally not severe. In a systematic review of 25 trials comparing sulfonylureas with GLP-1 receptor agonists or DPP-4 inhibitors in patients with type 2 diabetes, severe hypoglycemia (requiring assistance from others) occurred in 0.8 percent of sulfonylurea users, whereas hypoglycemia with glucose ≤56 mg/dL (3.1 mmol/L) or ≤50 mg/dL (2.8 mmol/L) occurred in 10.1 and 5.9 percent, respectively [36]. The overall safety of sulfonylureas when added to metformin is further supported by the GRADE comparative effectiveness trial in which the cumulative incidence of severe hypoglycemia over five years was low with glimepiride add-on therapy (2.2 percent), albeit higher than that for liraglutide (1 percent), glargine (1.3 percent), or sitagliptin (0.7 percent) [11].

For initial glucose-lowering therapy, however, sulfonylureas have a higher risk of hypoglycemia than metformin. As an example, in an observational study using the UK Clinical Practice Research Datalink, the rate of hypoglycemia requiring hospitalization was 4.1 per 1000 patient-years with sulfonylureas compared with 0.9 with metformin (HR 4.53, 95% CI 2.76-7.45) [37].

Hypoglycemia may be less common with shorter-acting (gliclazide, glipizide) than longer-acting (glyburide) sulfonylureas [36,38-40]. In the meta-analysis described above, gliclazide was associated with the lowest risk of hypoglycemia [36]. In a four-year, retrospective study of 14,000 patients 65 years or older with type 2 diabetes treated with different sulfonylurea drugs, episodes of serious hypoglycemia were rare [41,42]. The incidence was highest in those patients taking glyburide; the adjusted relative risk of severe hypoglycemia among glyburide compared with glipizide users was 1.9 (95% CI 1.2-2.9) [41].

The relative effects of different sulfonylureas with regard to hypoglycemia must be considered with caution, however, as there are very few comparative effectiveness studies that perform head-to-head randomized comparisons. In a short-term study, which compared randomly assigned glimepiride with gliclazide MR (available in much of the world, but not in the United States), either as monotherapy or combined with other glucose-lowering drugs, glimepiride was associated with a higher frequency of episodes of hypoglycemia, none of which were classified as severe [43]. A1C was reduced similarly by the two drugs. Of the "third-generation" sulfonylureas (glimepiride and gliclazide MR), gliclazide MR appears to have a lower risk of hypoglycemia [44].

Patients should be cautioned about those situations in which hypoglycemia is most likely to occur. They are as follows:

●After exercise or a missed meal

●When the medication dose is too high

●With the use of longer-acting drugs (glyburide or extended-release formulations)

●In patients who are undernourished or have food insecurity [45]

●In the setting of acute or chronic alcohol use

●In patients with impaired kidney or cardiac function or gastrointestinal disease

●With concurrent therapy with salicylates, sulfonamides, fibric acid derivatives (such as gemfibrozil), and warfarin [46]

●After being in the hospital [42]

The prevention and treatment of sulfonylurea-induced hypoglycemia are reviewed in detail separately. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Strategies to manage hypoglycemia' and "Sulfonylurea agent poisoning", section on 'Management'.)

Weight gain — Modest weight gain can be a common side effect of sulfonylureas [47]. In one large trial (6033 patients with type 2 diabetes and elevated cardiovascular risk), mean weight gain over 6.3 years was 1.54 kg greater with glimepiride than with linagliptin [15]. Similarly, in the GRADE trial, addition of glimepiride to metformin monotherapy resulted in very stable mean body weight over five years [11]. However, the incidence of body weight gain of ≥10 percent was higher with glimepiride (12.1 percent) or glargine (13.1 percent) add-on therapy than with sitagliptin (9.1 percent) or liraglutide (6.1 percent) [11].

Weight gain can be mitigated with diabetes education and lifestyle interventions (eg, exercise, diet). However, some individuals seem to be very sensitive to sulfonylurea-associated weight gain. We have a low threshold to stop sulfonylureas in people with substantial weight gain, especially if the weight gain does not stabilize or if it is associated with deterioration, rather than improvement, of glycemic management. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education'.)

Other — Other, infrequent side effects that can occur with all sulfonylureas include nausea, skin reactions (including pruritus, erythema, rash, urticaria, photosensitivity), and abnormal liver function tests. In a patient with a past allergic reaction to one sulfonylurea, it is best to avoid other similar medications and treat with an unrelated, nonsulfonylurea medication [48]. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Choice of initial therapy'.)

MEGLITINIDES

Mechanism of action — Meglitinides are structurally different than sulfonylureas and exert their effects via different pancreatic beta cell receptors, but they act similarly by regulating adenosine triphosphate (ATP)-sensitive potassium channels (K-ATP channels) in pancreatic beta cells, thereby increasing insulin secretion [49]. Meglitinides have a rapid onset and short duration of action [50]. They are administered with meals to reduce postprandial hyperglycemia.

Clinical use of meglitinides

Choice of meglitinide and indications — Repaglinide and nateglinide are short-acting glucose-lowering drugs for therapy of patients with type 2 diabetes. The clinical efficacy of meglitinide monotherapy is similar to that of the sulfonylureas [50-53]. Meglitinides are dosed before each meal, which may limit adherence in some but can be useful in people with unpredictable mealtimes (eg, the medication is not taken if the patient is not eating).

We generally prefer repaglinide because of slightly superior glycemic efficacy [54,55]. A meta-analysis of 15 trials to assess the efficacy of meglitinides compared with placebo, metformin, or in combination with insulin reported that both meglitinides reduced A1C values, with a greater reduction in A1C occurring in those receiving repaglinide compared with nateglinide (0.1 to 2.1 versus 0.2 to 0.6 percentage-point reduction, respectively) [56]. Repaglinide had similar efficacy in reducing A1C values as metformin, whereas nateglinide was similar or slightly less effective.

Repaglinide may be useful in the following settings:

●As initial monotherapy for patients who are intolerant of or have contraindications to metformin or sulfonylureas.

•Meglitinides are pharmacologically distinct from sulfonylureas and may be used in patients who have an allergy to sulfonylurea medications.

•Repaglinide is particularly useful in patients with chronic kidney disease who cannot or prefer not to take other glucose-lowering medications. Repaglinide is short acting and is principally metabolized by the liver, with less than 10 percent renally excreted. Thus, it can be used safely in patients with nondialysis chronic kidney disease (eg, estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²). (See 'Dosing and monitoring' below and "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Patients not on dialysis'.)

●As add-on therapy for patients who do not reach glycemic goals with metformin, particularly if there are contraindications to sulfonylureas or patient preference limits the use of insulin or other agents. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)

●For patients who have highly variable diets (eg, inconsistent timing, size, and/or carbohydrate content of meals) or substantial postprandial hyperglycemia with large meals, but do not need additional medication the rest of the time, repaglinide may be taken at those large or carbohydrate-rich meals only.

Precautions — Nateglinide is hepatically metabolized, with renal excretion of active metabolites. It should be used with caution, if at all, in patients with chronic liver or severe kidney disease (eGFR <15 mL/min/1.73 m²).

Repaglinide is metabolized in the liver by CYP2C8, 3A4, and UDP-glucuronosyltransferases (UGT). Strong inhibitors of CYP2C8 (eg, clopidogrel) can decrease repaglinide clearance, causing hypoglycemia [57,58]. In addition, the coadministration of gemfibrozil prolongs the plasma concentration of repaglinide, and therefore, they should not be used concomitantly.

Dosing and monitoring

●Repaglinide – The recommended starting dose of repaglinide is 0.5 mg before each meal for patients with A1C <8 percent. For patients previously treated with oral hypoglycemic drugs and/or whose A1C is ≥8 percent, the starting dose is 1 or 2 mg prior to each meal.

The dose may be adjusted at intervals of ≥1 week based on blood glucose monitoring results. The maximum dose of repaglinide is noted to be up to 4 mg before each meal in the labeling. However, doses higher than 1 or 2 mg prior to each meal are infrequently used. A dose of 1 mg before each meal (3 mg/day) provides most of the glucose-lowering effect [59]. The dose should be skipped if the patient is not eating.

Blood glucose monitoring (typically before meals and bedtime over the course of the week, checking all time points but not four times every day) can be performed initially to document efficacy, using blood glucose before the subsequent meal to guide titration of the pre-meal dose. For evaluation of long-term glycemic management, A1C should be measured every three to six months. Routine glucose monitoring may be stopped once the safety and effectiveness of the regimen have been established. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Non-insulin treated'.)

Repaglinide is principally metabolized by the liver, with less than 10 percent renally excreted. Dose adjustments with this agent do not appear to be necessary in patients with mild to moderate kidney impairment (eGFR ≥40 mL/min/1.73 m²). For patients with eGFR between 20 and 40 mL/min/1.73 m², repaglinide 0.5 mg should be initiated before the largest meal and then advanced to 0.5 mg prior to other meals, based upon glucose levels [60]. Repaglinide has not been studied in patients with an eGFR of <20 mL/min/1.73 m².

●Nateglinide – The recommended dose of nateglinide is 120 mg taken immediately before each meal [55,61]. For people who are near glycemic goals, the initial dose is 60 mg before each meal. If glucose levels are still above target after one to four weeks, the dose may be increased to 120 mg before each meal.

No dose adjustments are recommended in patients with mild to severe kidney impairment, but as with all medications that increase endogenous insulin release, they should be titrated slowly based on effect on blood glucose levels.

Cardiovascular effects — There are no long-term studies of meglitinides to assess cardiovascular outcomes or mortality in patients with type 2 diabetes. Whether meglitinides are associated with poorer outcomes in patients who have had a myocardial infarction is not known. However, since their mode of action is so similar to sulfonylureas, the same concern exists. In a retrospective cohort study of patients with type 2 diabetes taking gliclazide, glyburide, or repaglinide prior to a hospitalization for coronary heart disease, there was no difference in adverse cardiovascular outcomes at 30 days among the three drugs [62]. Of note, comparisons with other oral or injectable diabetes medications were not performed in this study. (See 'Cardiovascular effects' above.)

Nateglinide has been evaluated for the prevention of diabetes and cardiovascular disease (CVD) in patients with impaired glucose tolerance and one or more risk factors for CVD [63]. It was not effective in the prevention of diabetes or CVD. (See "Prevention of type 2 diabetes mellitus".)

Adverse effects — Meglitinides have a similar risk for weight gain as sulfonylureas but possibly less risk of hypoglycemia [64,65].

●In a meta-analysis of 15 trials comparing the efficacy of meglitinides with placebo, metformin, or in combination with insulin, symptomatic hypoglycemia (three trials) was reported in 17 to 44 percent of patients [56]. Four trials reported no severe hypoglycemic episodes. Compared with placebo, mean difference in weight ranged from 0 to 2.3 kg.

●In a meta-analysis of 22 trials comparing repaglinide plus metformin with metformin alone, the number of hypoglycemic events (nine trials) was similar in the two groups (320 versus 304 with metformin alone, risk ratio [RR] 1.21, 95% CI 0.72-2.04) [66].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults".)

SUMMARY AND RECOMMENDATIONS

●Sulfonylureas

•Mechanism of action – Sulfonylureas bind to the sulfonylurea receptor on the adenosine triphosphate (ATP)-sensitive potassium channel (K-ATP channel) of the pancreatic beta cells, leading to inhibition of the channels with subsequent alteration of the resting potential of the cell, calcium influx, and stimulation of insulin secretion. (See 'Mechanism of action' above.)

•Clinical use – Sulfonylureas usually lower glycated hemoglobin (A1C) by 1 to 2 percent.

-Initial therapy – A short-acting sulfonylurea (or one with relatively lower risk for hypoglycemia) is a reasonable option for initial therapy (along with lifestyle intervention) in patients without established cardiovascular disease (CVD) who have contraindications to or intolerance of metformin, particularly if cost is a concern. (See 'Initial therapy' above and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Contraindications to or intolerance of metformin'.)

-Combination therapy – Sulfonylureas are most often used in combination with other oral hypoglycemic drugs in patients with persistent hyperglycemia after lifestyle intervention and metformin. They are generally not used in combination with insulin. (See 'Combination therapy' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)

-Choice of sulfonylurea – When a decision has been made to treat with a sulfonylurea, we suggest a shorter-duration sulfonylurea or one with relatively lower risk for hypoglycemia, such as glipizide, gliclazide (not available in the United States), or glimepiride (Grade 2C). Glyburide and other long-acting sulfonylureas have a higher incidence of hypoglycemia. (See 'Choice of sulfonylurea' above and 'Hypoglycemia' above.)

•Side effects – The most common side effects of sulfonylureas are weight gain and hypoglycemia. (See 'Adverse effects' above.)

●Meglitinides

•Mechanism of action – Meglitinides are structurally different from sulfonylureas and exert their effects via different pancreatic beta cell receptors, but they act similarly by regulating K-ATP channels in pancreatic beta cells, thereby increasing insulin secretion. The clinical efficacy of meglitinide monotherapy is similar to that of the sulfonylureas. (See 'Mechanism of action' above.)

•Clinical use – Meglitinides are most commonly used as add-on therapy for patients who do not reach glycemic goals with metformin, particularly if there are contraindications to sulfonylureas or patient preference limits the use of insulin or other agents. Meglitinides are pharmacologically distinct from sulfonylureas and may be used as initial therapy in patients who have an allergy to sulfonylurea medications. For patients who have highly variable diets (eg, inconsistent timing, size, and/or carbohydrate content of meals) or substantial postprandial hyperglycemia with large meals, but do not need additional medication the rest of the time, repaglinide may be taken at those large or carbohydrate-rich meals only. (See 'Clinical use of meglitinides' above.)

•Choice of meglitinide – When a decision has been made to treat with a meglitinide, we suggest repaglinide (Grade 2B). Repaglinide has slightly superior glycemic efficacy compared with nateglinide. Repaglinide is principally metabolized by the liver, with less than 10 percent renally excreted. Thus, it can be used safely in patients with chronic kidney disease. Nateglinide is hepatically metabolized, with renal excretion of active metabolites. It should be used with caution, if at all, in patients with chronic liver or advanced kidney disease. (See 'Choice of meglitinide and indications' above and "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Patients not on dialysis'.)

•Side effects – Meglitinides have a similar risk for weight gain as sulfonylureas but possibly less risk of hypoglycemia. (See 'Adverse effects' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.