TABLE Noninsulin Agents for Treatment of Type 2 Diabetes

TABLE Mechanisms to Lower Blood Glucose by Each Antidiabetic Agent

Note: X, main mechanism; (X) less-clear mechanism.

Sulfonylurea

Sulfonylurea preparations have a long record of safety and effectiveness. They work by stimulating insulin secretion by the pancreatic /3-cell, binding to an adenosine triphosphate-sensitive potassium channel, which results in its depolarization, a subsequent influx of intracellular calcium, and the release of insulin. Sulfonylureas are effective both as monotherapy and in combination with other agents that have different mechanisms of action. A significant percentage of patients (up to 10% per year) who are initially properly managed with sulfonylurea monotherapy lose glycemic control over time. Their main side effects include hypoglycemia and weight gain. Hypoglycemia is a serious adverse effect in the elderly and can trigger serious events such as myocardial infarction and stroke. These drugs must be used cautiously in patients with significant renal and hepatic insufficiency, since the liver is the primary site of metabolism and they are excreted by the kidneys. In these settings, the preferred option may be glipizide, whose metabolites are inactive, or glimepiride, which is substantially excreted through the bile.

A commonly used sulfonylurea in younger populations, glyburide, may have age-related impaired absorption and elimination, and elderly subjects appear to have enhanced insulin responses to the drug as well. This may explain, in part, the age-related exponential increase in the frequency of severe or fatal hypoglycemia with this drug.

TABLE Limiting Factors in the Use of Antidiabetic Agents in the Elderly

May impede ischemic preconditioning Frequent dosing may affect compliance; no long-term experience Risk of lactic acidosis; diarrhea Edema; expensive; no long-term experience Frequent dosing may affect compliance; intestinal gas; expensive Injection; expensive; no long-term experience

Note: X, main side effect; XX, pronounced side effect. Abbreviation: wt, weight.

In addition to the type of sulfonylurea, other potential risk factors for hypoglycemia with these drugs in elderly persons include black race, multiple medications, male sex, renal dysfunction, and ethanol consumption. Sulfonylureas should be considered as first-line therapy in lean elderly patients with diabetes. The result in hemoglobin Ale (HbAlc) lowering is approximately 1% to 2% as monotherapy.

Meglitinides

Meglitinides (repaglinide and nateglinide) are nonsulfonylurea drugs that have a distinct β-cell binding profile and stimulate insulin secretion from the β-cell by a mechanism similar to that of sulfonylureas. The potential advantage of this type of drug is that it has a rapid onset and very short duration of action. Meglitinides have been associated with lower frequency of hypoglycemic events when compared with conventional sulfonylureas, presumably because of their shorter duration of action and the fact that the kinetics are not altered with age. Repaglinide lowers HbAlc by 1% to 2%, a reduction similar to that of the sulfonylureas, whereas the glucose-lowering effect of nateglinide is somewhat less potent. Similar changes in fasting glucose and HbAlc values are seen in middle-aged and elderly subjects, suggesting that there is similar efficacy in each age group. Both repaglinide and nateglinide are extensively metabolized by the liver; therefore, they should be used cautiously in patients with hepatic dysfunction. Meglitinides may be considered as an appropriate strategy for elderly patients who have irregular eating habits or have frequent hypoglycemic events on conventional sulfonylureas. These potential benefits must be balanced against the cost of these newer drugs and the compliance problems that could result from a three-times-a-day dosing schedule, particularly in patients who have impaired memory or take may other drugs.

α-Glucosidase Inhibitors

α-glucosidase inhibitors (miglitol and acarbose) impair the breakdown and limit the absorption of carbohydrates from the gut; therefore their major effect is reduction in postprandial glucose excursions. These drugs are associated with less weight gain and a lower frequency of hypoglycemia than sulfonylureas. The residual carbohydrates in the intestinal lumen cause diarrhea in about 25% of patients taking these drugs. Gradual dose titration is crucial to minimize gastrointestinal side effects and achieve better compliance. Their overall effect on HbAlc concentration is a modest reduction of 0.5% to 1%. In a recent randomized multicenter trial of the a-glucosidase inhibitor acarbose in obese elderly patients with diabetes, acarbose reduced HbAlc by about 0.8% when compared with placebo and also resulted in an improvement in insulin sensitivity. α-glucosidase inhibitors are useful drugs as primary therapy for elderly patients with modest fasting hyperglycemia, especially if they are obese. They can also be used in patients taking other oral agents to enhance glycemic control. Hypoglycemia may occur if these agents are used in combination with sulfonylureas or insulin; consequently, only glucose should be used for prompt treatment of hypoglycemia because the absorption of other carbohydrates is delayed. Acarbose has minimal systemic absorption, yet some hepatic metabolism occurs and because of rare but possible hepatotoxicity, it is contraindicated in patients with advanced liver disease. In contrast, as much as 50% to 90% of the miglitol dose may be absorbed but is not metabolized in the liver but rather eliminated through the kidney. Therefore, miglitol should not be used in patients with renal failure.

Metformin

Metformin is currently the only biguanide available in North America. Its mechanism of action is to improve insulin sensitivity, chiefly by reducing insulin resistance in the liver, thereby decreasing hepatic glucose production. In addition, its glucose-lowering effect is accompanied by a reduction in plasma insulin concentration, and some experts refer to metformin as an insulin sensitizer. Metformin lowers HbAlc by 1% to 2%. Although, the most important side effect associated with biguanides is lactic acidosis, this is rare with metformin; and aging itself does not appear to be a risk factor provided that careful attention is paid to the contraindications for this drug (significant liver, renal, and cardiac disease). Clinical studies suggest that the drug is safe and effective as monotherapy in obese older people. In our view, metformin is an ideal drug for first-line therapy of obese older patients, because it increases insulin sensitivity, assists with weight loss, reduces lipid levels, and does not cause hypoglycemia. The recently published ADA management algorithm suggests the use of metformin, together with lifestyle intervention, as initial monotherapy.

In addition, metformin is a useful adjunct for patients who are inadequately controlled on maximum doses of sulfonylureas. Metformin is contraindicated in older subjects with renal insufficiency, in men with a serum creatinine level of 1.5 mg/dL or higher or women with a serum creatinine level of 1.4 mg/dL or higher. Serum creatinine should be measured at least annually and with any increase in dose of metformin. It should be noted, however, that serum creatinine does not adequately reflect the renal function in the elderly. For those aged 80 years or older or those suspected to have reduced muscle mass, a timed urine collection for creatinine clearance should be obtained. Metformin should be avoided if the value is less than 60 mL/ min. Metformin should be temporarily discontinued during radiographic studies that use iodinated contrast agents, during acute illness, and during most hospitalizations. Clinical situations where tissue perfusion is compromised (sepsis, dehydration, pulmonary disease with hypoxemia, and acute or advanced heart failure) also contraindicate the use of metformin.

Thiazolidinediones

Thiazolidinediones (rosiglitazone and pioglitazone) improve insulin sensitivity primarily in muscles and adipocytes, thereby increasing peripheral uptake and utilization of glucose. They are generally well tolerated and appear to be as effective in older patients as in younger patients, with an approximate 1.5% reduction in HbAlc and with a dose-dependent glucose-lowering effect, which may take four to eight weeks. In addition to benefits of these drugs on cardiovascular and metabolic markers, a recent randomized trial has shown the effect of pioglitazone on the reduction of cardiovascular outcomes in patients with type 2 diabetes. Thiazolidinediones do not lead to hypoglycemia unless they are used in conjunction with secretagogues or insulin. Hepatic toxicity has not been reported in elderly subjects, but liver function tests should be monitored regularly. The incidence of edema and anemia is higher in elderly patients than in middle-aged patients treated, and volume status and blood count need to be carefully monitored. Thiazolidinediones-related fluid retention is a major contributor to increased body weight, typically manifests as peripheral edema, and develops predominantly within the first months of treatment. Thiazolidinediones can be a useful first-line therapy in obese elderly patients, particularly for those patients who cannot tolerate metformin or those who have a contraindication to it. In fact, thiazolidinediones can be safely used in patients with renal impairment provided that the cardiac function is preserved. In addition, they may be a beneficial adjunct therapy in elderly patients who have suboptimal glycemic control, despite insulin requirements of 50 or more units per day.

Brand Name Drug: Prandin in the U.S., GlucoNorm in Canada, NovoNorm elsewhere

Benzoic acid derivatives are the most recent addition to the list of treatment options for type 2 diabetes. In 1998, the FDA approved the first agent in this class, repaglinide. Benzoic acid derivatives are similar to sulfonylureas in that they are insulin secretagogues. However, they differ in that they bind to a different receptor on the beta cell membrane. Also, in contrast to sulfonylureas, benzoic acid derivatives do not cause direct exocytic insulin release in the absence of glucose stimulation.

The true benefit of these agents stems from the fact that they have a short duration of action. Repaglinide is administered just before the start of the meal and stimulates insulin secretion. However, the duration of action is much shorter than the sulfonylureas, and the main effect is to reduce postprandial hyperglycemia. Due to the short half-life, repaglinide is useful in patients who have erratic meal schedules.

The main advantage of repaglinide is the potential for decreased incidence of hypoglycemia, making it an effective agent in elderly patients and those with renal insufficiency or other predisposition to hypoglycemia. It is given only at the meal time in 1-mg and 2-mg tablets. Most patients are started on 0.5 mg prior to meals. It often is useful to initially monitor pre- and one-hour postprandial fingerstick glucoses to assess the effects of this agent.

Conclusion

Much of the benefit from tight control in patients with type 1 diabetes has now been extrapolated to the much larger group of patients with type 2 diabetes. Recent data have shown that tight control of type 2 diabetes is strongly associated with a decreased incidence and rate of progression of microvascular complications. Multiple new oral agents recendy have been developed for the treatment of this disorder. Effective use of these agents by physicians is imperative in controlling this disease and preventing or delaying acute and chronic complications in African Americans. It is important to remember that these new agents are relatively ineffective without proper dietary counseling and increased physical activity. In addition to glycemic control, treatment of hypertension and hyperlipidemia will also result in significant decreases in micro- and macrovascular disease in individuals with type 2 diabetes.

Comprehensive screening also is essential as it is estimated that 50% of Americans with the disease are unaware of their illness. The ADA now recommends testing of fasting glucose every three years for all adults >45 years. For higher risk groups, such as African Americans and those with a history of gestational diabetes, screening is recommended on a yearly basis. Those patients with a fasting glucose >126 mg/dL must receive proper dietary and exercise instruction as well as diabetic teaching about the importance of foot care and home glucose monitoring. These measures combined with the effective use of pharmacologic agents in those who fail conservative therapy will improve the control of the type 2 diabetes epidemic in the black community.

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Repaglinide). A white or almost white powder. It exhibits polymorphism. Practically insoluble in water freely soluble in dichloromethane and in methyl alcohol. Protect from light.

The United States Pharmacopeia 31, 2008 (Repaglinide). A white to off-white solid. Solubleinme-thyl alcohol. Store in airtight containers.

Adverse Effects and Precautions

Repaglinide may cause gastrointestinal adverse effects including abdominal pain, diarrhoea, constipation, nausea, and vomiting. Hypoglycaemia (usually mild), back and joint pain, hypersensitivity reactions including pruritus, rashes and urticaria, and elevated liver enzyme values may occur. There have been rare cases of transient visual disturbances attributed to changes in blood glucose concentrations associated with starting repaglinide treatment. There have also been rare reports of myocardial infarction in patients who were treated with repaglinide and isophane insulin the combination is not recommended.

Precautions are similar to those which apply with the shorter-acting sulfonylurea hypoglycaemics. Repaglinide should be given with caution to patients with hepatic impairment (consideration should be given to extending the interval between doses), and possibly avoided in severe impairment.

Effects on the liver. Hepatotoxic reactions have been reported for repaglinide’ including cholestatic hepatitis and jaundice with pruritus.

Fasting. For mention that nateglinide or repaglinide can probably be used with low risk of hypoglycaemia in fasting Muslim patients during Ramadan see under Precautions of Insulin.

Hypoglycaemia. Mild hypoglycaemia has been reported in patients receiving repaglinide, although in a study comparing flexible repaglinide dosing with frxed glibenclamide dosing, all hypoglycaemic events recorded were in the glibenclamide group.Other studies have found rates of hypoglycaemia in patients receiving repaglinide to be less than, or similar to, sulfonylureas.The risk of hypoglycaemia may be reduced as patients can omit a dose of repaglinide if a meal is missed.

Pregnancy. Insulin is generally preferred to oral antidiabetics in the treatment of diabetes mellitus during pregnancy. Repaglinide has been used in 3 women during the first 6 to 7 weeks of gestation treatment was then changed to insulin for the rest of the pregnancy. Their babies were delivered at term, with adequate weight for birth age and no congenital malformations.

Interactions

As with other oral antidiabetics, the efficacy of repaglinide may be affected by drugs independently increasing or decreasing blood glucose concentrations (see Sulfonylureas).

Drugs that affect the cytochrome P450 isoenzymes CYP2C8 and CYP3A4 may alter the metabolism of repaglinide. Use of repaglinide with the CYP2C8 inhibitor gemfibrozil has resulted in marked reduction in repaglinide clearance, and severe hypoglycaemia UK licensed product information contra-indicates concomitant use.

Antibacterials. A study in healthy subjects found that the plasma concentration of a single dose of repaglinide was reduced, and its half-life shortened, when it was given 12.5 hours after the last dose of a 5-day course ofrifampicin. This effect was attributed to the induction of the cytochrome P450 isoenzyme C YP3A4 by rifampicin. In another study repaglinide was given either with the last dose of a 7-day course of rifampicin or 24 hours later, and the effects on repaglinide were found to be greater on day 8 than day 7. The authors suggested that rifampicin acted as both an inducer and an inhibitor of C YP3 A4 and possibly C YP2C8, and that after rifampicin was stopped its inductive effect lasted longer, thereby having a greater effect 24 hours later. A study in healthy subjects reported that clarithromycin can increase the plasma concentrations and prolong the elimination half-life of repaglinide, probably by inhibition of CYP3A4. Telithromycin, another inhibitor of CYP3A4, also increased plasma concentrations of repaglinide in a study of healthy subjects, although the elimination half-life of repaglinide was not significantly affected. Trimethoprim can have a similar effect by the inhibition of CYP2C8.

For a report of hypoglycaemia when gatifloxacin was given to a patient already receiving repaglinide.

Ciclosporin. Ciclosporin markedly increased plasma concentrations of repaglinide in healthy subjects there is a possibly increased risk of hypoglycaemia if these 2 drugs are taken together.

Grapefruit juice. Grapefruit juice increased the bioavailability of repaglinide in a study of healthy subjects. The half-life of repaglinide was not affected, suggesting that grapefruit juice inhibited its presystemic metabolism by the cytochrome P450 isoenzyme CYP3A4 in the gut wall. Blood-glucose concentrations were not affected.

Lipid regulating drugs. A study in healthy subjects found that gemfibrozil significantly increased the plasma concentrations of repaglinide and enhanced and prolonged its glucose-lowering effect. Use of this combination should be avoided. Another study in healthy subjects found, however, that repaglinide was not affected by bezafibrate or fenofibrate.

Pharmacokinetics

Repaglinide is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 hour. The mean bioavailability is about 60%. Repaglinide is highly bound to plasma proteins, and has a plasma elimination half-life of about 1 hour. It undergoes almost complete hepatic metabolism involving the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. The metabolites, which are inactive, are excreted in the bile. Higher plasma concentrations and prolonged half-life of repaglinide may occur in patients with renal impairment (creatinine clearance less than 40 mL/minute) or chronic liver disease.

Uses and Administration

Repaglinide is a meglitinide antidiabetic used for the treatment of type 2 diabetes mellitus. It has a chemical structure different from that of the sulfonylureas, but appears to have a similar mode of action. Repaglinide is given up to 30 minutes before meals, in usual initial oral doses of 0.5 mg initial doses of 1 or 2 mg are usually given to patients who have had previous hypoglycaemic treatment. The dose maybe adjusted, at intervals of 1 to 2 weeks, up to a maximum of 4 mg before meals a total of 16 mg daily should not be exceeded. Repaglinide is also given with metformin or a thiazolidinedione in type 2 diabetes not adequately controlled by monotherapy.

Administration in renal impairment. Although repaglinide is cleared mainly by hepatic metabolism, small pharmacokinetic studies have reported that exposure to repaglinide may be increased in patients with renal impairment. A larger open-label study that included 151 patients with normal renal function and 130 patients with varying degrees of renal impairment found that the incidence of adverse effects was not influenced by renal function. However, at the end of the 3-month maintenance treatment period, there was a trend towards lower effective doses of repaglinide with increasing degree of renal impairment.

Preparations

The United States Pharmacopeia 31, 2008: Repaglinide Tablets.

Proprietary Preparations

Argentina: Glukenil NovoNorm Sestrine

Australia: NovoNorm

Austria: NovoNorm

Belgium: NovoNorm

Brazil: Gluconorm NovoNorm Prandin

Canada: Gluconorm

Chile: Hipover NovoNorm

Czech Republic: NovoNorm Prandin

Denmark: NovoNorm

Finland: NovoNorm

France: NovoNorm

Germany: NovoNorm

Greece: NovoNorm

Hong Kong: NovoNorm

Hungary: NovoNorm

India: Rapilin

Ireland: NovoNorm

Israel: NovoNorm

Italy: NovoNorm

Malaysia: NovoNorm

Mexico: NovoNorm

The Netherlands: NovoNorm Prandin

Norway: NovoNorm

New Zealand: NovoNorm

Philippines: NovoNorm

Poland: NovoNorm

Portugal: NovoNorm Prandin

Russia: NovoNorm

South Africa: NovoNorm

Singapore: NovoNorm

Spain: NovoNorm Prandin

Sweden: NovoNorm

Switzerland: NovoNorm

Thailand: NovoNorm

Turkey: NovoNorm

UK: Prandin

USA: Prandin

Oral antidiabetic drugs fall into several classes (Table 5). Of particular interest are the insulin sensitizers because they specifically target insulin resistance. Other agents address different aspects of glycemic control.

Insulin secretion stimulators (secretagogues)

For more than 40 years, sulfonylureas have been the first line of therapy for individuals with type 2 diabetes. These agents directly stimulate pancreatic b-cells to produce insulin by increasing the influx of calcium. Sulfonylureas increase circulating insulin and reduce both fasting and postprandial glucose, but they are not insulin sensitizers and therefore do not address the problem of insulin resistance. Sulfonylureas lower A1C an average of 1% to 2% and offer effective glycemic control in up to 75% of patients; however, efficacy lapses over time, with about 5-10% of patients per year failing to maintain the initial glycemic control. Primary adverse effects include hypoglycemia and weight gain (typically 2-5 kg). Glimepiride (Amaryl) is emerging as the sulfonylurea of choice due to its once-a-day dosing, extrapancreatic effect, and the fact that it causes less weight gain and hypoglycemia and is priced as low as generic glyburide.

Another class of secretagogues, derivatives of meglitinide or phenylalanine, also stimulate insulin but act at a different site on pancreatic beta-cells than the sulfonylureas. Because these agents have a very short onset of action and short half-life, they must be taken immediately before every meal (compared to once-daily dosing for sulfonylureas), so treatment adherence may be an issue for some patients. They have a side effect profile similar to the sulfonylureas; however, because meglitinides are shorter-acting agents, they carry a lower risk of sustained hypoglycemia. Efficacy is similar to that of sulfonylureas. The two products currently available are nateglinide (Starlix) and repaglinide (Prandin).

Alpha-glucosidase inhibitors

Drugs in this group produce mild reductions in postprandial hyperglycemia by inhibiting the enzyme responsible for metabolizing complex carbohydrates in the small intestine. Taken right before a meal, these agents reduce glucose levels by slowing absorption of carbohydrates and delaying entry of glucose into liver and muscle tissue. Gastrointestinal side effects (ie, abdominal pain, diarrhea, and flatulence) are the most common reactions to alpha-glucosidase inhibitors (reported in up to 75% of patients), leading some patients to discontinue therapy with these drugs. Available agents include acarbose (Precose) and miglitol (Glyset). Gastrointestinal side effects can be greatly reduced if low doses are started and then gradually titrated over 10-12 weeks to the maximum and effective doses. At present, these agents are seldom used in the United States.

Thiazolidinediones

The thiazolidinediones (TZDs or glitazones) are a relatively new class of agents that reduce insulin resistance. TZDs do not stimulate the secretion of insulin but rather enhance the effects of circulating insulin by improving insulin sensitivity in muscle and adipose tissue and by inhibiting hepatic gluconeogenesis. TZDs work by stimulating certain receptors (peroxisome proliferator-activated receptor gamma, or PPAR-gamma) in the nucleus of the cells. Activation of PPAR-gamma modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism. In response to thiazolidinediones stimulation, the genes produce a protein called GLUT-4. Insulin works by recruiting GLUT-4 to the cell’s outer membrane. This partnership, in turn, promotes transport of glucose across the membrane and into the cell’s interior.

Examples of insulin sensitizers include pioglitazone hydrochloride (Actos) and rosiglitazone maleate (Avandia). Another drug in this class, troglitazone (Rezulin), was removed from the market because it was linked to idiosyncratic cases of hepatotoxicity. In clinical trials, there has been no evidence of drug-induced hepatotoxicity with pioglitazone or rosiglitazone, but there have been rare postmarketing case reports of liver damage in patients receiving rosiglitazone and pioglitazone (causality not established). The safe use of these agents, therefore, requires careful monitoring of liver function: ALT enzyme levels should be measured at baseline and monitored every 2 months for 1 year and periodically thereafter. Patients with hepatic impairment should not be treated with thiazolidinediones.

In large placebo-controlled trials lasting up to 26 weeks, monotherapy with pioglitazone or rosiglitazoneproduced significant improvements in A1C and fasting blood glucose concentrations (Table 6). Pioglitazone also led to significant improvements in A1C and improvements in FPG when combined with a sulfonylurea, metformin, or insulin. Rosiglitazone resulted in significant decreases in A1C and FPG levels when combined with metformin or a sulfonylurea.

In addition to reducing insulin resistance, thiazolidinediones also have effects on lipids (Table 6). In a 26-week placebo-controlled study, pioglitazone was associated with decreases in triglycerides of 9.0%, 9.6%, and 9.3% in patients treated with 15-, 30-, and 45-mg, respectively, compared with baseline. HDL (“good”) cholesterol increased by 14%, 12%, and 19% in the 15-, 30-, and 45-mg groups, respectively. No consistent differences were reported for LDL (“bad”) cholesterol and total cholesterol in patients treated with pioglitazone versus placebo.

In a similar 26-week pla-cebo-controlled study, rosiglitazone raised HDL cholesterol by 11.4% and 14.2% in doses of 4- and 8-mg per day, respectively, compared to baseline, but the drug also raised LDL cholesterol by 14.1% and 18.6%, respectively. Changes in triglycerides were variable and generally not statistically significant compared to placebo controls. A recent retrospective review of type 2 diabetes patients treated with either pioglitazone (n=525) or rosiglitazone (n=590) suggested that pioglitazone provides a greater benefit in terms of blood lipid profile than does rosiglitazone.

Because TZDs do not affect insulin secretion, they do not induce hypoglycemia. Dose-related weight gain is seen with both pioglitazone (average increase 0.5 kg to 2.8 kg) and rosiglitazone (median increase 1.0 kg to 3.1 kg). Also, a small number of patients experience mild to moderate edema and anemia. TZDs can cause fluid retention, which may lead to or exacerbate heart failure; thus, patients should be observed for signs and symptoms of congestive heart failure, and TZDs should not be used in patients with class III or IV cardiac status. Studies are currently underway to determine whether thiazolidinediones may be effective in preventing progression of insulin resistance to full-blown type 2 diabetes.

After 4 weeks, fasting blood glucose levels decreased significantly in both groups; 11.2 to 9.6 mmol/L in REP2, and 11.2 to 8.4 mmol/L in the REP3 group. The overall glycemic control was better in REP3 when compared to REP2, as blood glucose was 8.91 mmol/L in REP2 and 7.00 mmol/L in REP3. There was also a significant decrease in HbA1c levels in REP3 (7.5 to 6.5%) but a non-significant decrease in REP2 (7.1 to 6.8%). In both groups plasma insulin decreased to pre-treatment levels prior to the next meal and there was no increase in plasma insulin during the night time in comparison to pre-treatment levels.

Although these are just preliminary findings, they suggest that drugs of this class, can have a beneficial effect on blood sugar control in persons with diabetes.