The Pharmacological Reduction
of Blood Glucose in Patients With
Type 2 Diabetes Mellitus

John R. White, Jr., PharmD

The options available to clinicians for the management of hyperglycemia secondary to type 2 diabetes in the United States recently have changed dramatically. In the past 3 years, the number of categories of drugs that are approved by the Food and Drug Administration (FDA) for this indication has expanded threefold from two to six.

FDA-approved medications for the management of type 2 diabetes include insulins, sulfonylureas, thiazolidinediones, meglitinides, biguanides, and -glucosidase inhibitors. In addition to the currently available medications, novel and potentially more effective medications within these categories may be on the horizon. The utility of various permutations of combinations of these medications continues to be evaluated.

Decision-making to select the best medication or combinations of medications for the management of hyperglycemia in patients with type 2 diabetes continues to reside to a large degree in the realm of "art." While there are relatively clear beneficial situations that dictate the use of one medication over another, as well as some obvious contraindications for all of the medications, often the choices are not clear cut. Hopefully, as more is learned about diabetes and the medications used to manage it, the rationale behind medication choice will become more clear.

Several factors should be considered when choosing a medication, including cost, contraindications, degree of glycemic-lowering needed to get patients into their goal ranges, ease of compliance, patients’ weight and ideal weight, and patients’ lipid profiles. This article briefly reviews the use of the above-mentioned categories of medications. A discussion of mechanisms of action, efficacy of monotherapy and combination therapy, and information regarding side effects and contraindications is included.

SULFONYLUREAS
Sulfonylureas have been used widely in the management of type 2 diabetes since their introduction in the 1950s. In the 1980s, sulfonylureas accounted for ~1% of all prescriptions written in the United States.¹ Seventy-five percent of this market was controlled by three agents: glyburide (Micronase®, Glynase®, Diabeta®), glipizide (Glucotrol®, Glucotrol XL®), and chlorpropamide (Diabinese®).² In the past, it was estimated that 40% of all type 2 diabetes patients were treated with sulfonylureas. However, the introduction of new oral agents has probably reduced this percentage.

Mechanism of Action
Sulfonylureas exert both pancreatic and extrapancreatic effects but are useful only in patients with viable ß-cells.^2,3 The primary mechanism of action of sulfonylureas is direct stimulation of insulin release.² In vivo, sulfonylureas sensitize ß-cells to glucose, increasing insulin secretion indirectly. Thus, under the influence of sulfonylureas, more insulin is secreted at all glucose levels than would be secreted in the absence of the sulfonylurea.²

Other potential pancreatic effects include inhibition of glucagon release. Sulfonylureas may also affect glucose levels by several extrapancreatic mechanisms, such as increasing insulin receptor binding affinity, increasing insulin’s effect by a post-receptor action, and decreasing hepatic insulin extraction. The relative clinical importance of each of these mechanisms of action is still a subject of research and debate.²

Efficacy
Several factors have been shown to be predictive of a significant response to sulfonylureas. These factors include an age of >40 years, an actual weight that is between 110 and 160% of ideal body weight, a duration of disease of <5 years, no prior treatment with insulin or control with <40 U/day, and fasting blood glucose (FBG) level of <200 mg/dl.^4-6

Failure rates can be as low as 15% if these criteria are met. The secondary failure rate (failure of adequate response after a period of response) of sulfonylureas has been estimated to be 10% per year,² although in many populations the failure rate may be much higher. In a responding patient, one can expect a reduction in fasting plasma glucose (FPG) of ~50–60 mg/dl and a 1–2% reduction in HbA_1c.⁷

The most recent addition to the sulfonylurea ranks, glimepiride (Amaryl®), apparently has similar effects. Mean HbA_1c reductions of 2% were observed in patients treated with glimepiride 8 mg daily.⁸ Studies with glimepiride have also demonstrated 46.0–77.5 mg/dl reductions in FPG levels when compared to placebo.^9-10 The monotherapeutic effects of glimepiride are very similar to those noted with other sulfonylureas.

Side Effects and Contraindications
The primary significant adverse effects of sulfonylureas are hypoglycemia and weight gain.

The incidence of hypoglycemia is variable and depends on the particular sulfonylurea and the population being evaluated. However, one study revealed a 20% chance of hypoglycemia every 6 months in patients treated with sulfonylureas.² In this review, severe hypoglycemia was reported to be more frequent with chlorpropamide and glyburide, followed by glipizide, and finally the first generation sulfonylureas (acetohexamide [Dymelor®], tolbutamide [Orinase® and generics], and tolazamide [Tolinase® and generics].² The United Kingdom Prospective Diabetes Study (UKPDS) recently reported the incidence of hypoglycemia after therapy with chlorpropamide, glyburide, or insulin to be 13.5%, 27.8%, and 33.4%, respectively.¹³

Weight gain is a common adverse effect of sulfonylurea therapy, the clinical significance of which is unknown. One study evaluating the effects of glyburide reported a mean weight increase of 2.8 (± 0.7) kg, while another study evaluating the effects of tolbutamide reported a mean weight increase of 1.8 kg.^12,13 While a clear relationship between weight gain and plasma insulin concentrations has not been firmly established, the UKPDS reported significant elevations in fasting plasma insulin concentrations in patients treated with sulfonylureas, while those treated with metformin experienced significant reductions in fasting plasma insulin concentrations. Although it has been hypothesized that increases in insulin concentrations may contribute to complications, weight gain, and possibly cardiovascular disease, it is important to remember that the exact nature of the relationship between insulin concentrations and cardiovascular disease remains to be determined.

Additional, less common, side effects include dermatological reactions, hematological reactions, and gastrointestinal disturbances.² Disulfiram-like reactions and hyponatremia have been reported with chlorpropamide.²

All of the sulfonylureas undergo hepatic metabolism and should be used cautiously in patients with hepatic dysfunction.²

Acetohexamide and chlorpropamide should not be used in patients with renal dysfunction because the active metabolite of acetohexamide, hydroxyhexamide, is renally cleared and 20% of chlorpropamide is excreted unchanged in the urine. Additionally, tolazamide and glyburide have partially active metabolites that accumulate in patients with clearances of <30 ml/min. Glimepiride is converted to a partially active metabolite that is excreted renally.⁸ While the clinical significance of this is unknown, glimepiride should be avoided in patients with renal dysfunction. Glipizide and tolbutamide are preferred in patients with moderate to severe renal dysfunction.²

MEGLITINIDES
Repaglinide (Prandin™), was the first meglitinide compound to be granted FDA approval. (It is also being referred to as a benzoic acid derivative.) It received FDA approval in December 1997 and is expected to be available for use before summer of this year.

Mechanism of Action
Repaglinide is a nonsulfonylurea insulinotropic agent whose biochemical mechanism of action, closure of ATP-sensitive K⁺ channels in ß-cells, is similar to sulfonylureas.¹⁴ Closure of ATP-sensitive K⁺ channels causes an influx of Ca²⁺ via voltage-dependent Ca²⁺ channels.¹⁵ Insulin release is stimulated when intracellular Ca²⁺ concentrations reach a threshold. Thus, like sulfonylureas, repaglinide reduces blood glucose levels by stimulating insulin release from the pancreas.¹⁶

As with sulfonylureas, the action of this drug is dependent on functioning ß-cells. Insulin release is glucose-dependent and is reduced at low glucose concentrations. Repaglinide is structurally unrelated to sulfonylureas.

In contrast to sulfonyureas, repaglinide is rapidly absorbed, with maximum concentrations (C_max) occurring within 1 hour (T_max), and is rapidly eliminated (t 1/2 < 1 hour).¹⁶ The pharmacodynamic effects of repaglinide roughly parallel the pharmacokinetic profile. Thus, the drug is relatively rapid and short-acting. It is most effective when given three times daily before meals.¹⁷

Efficacy
Currently, repaglinide is approved for monotherapeutic use and for use in combination with metformin. Given its mechanism of action, it would seem reasonable that repaglinide would also be effective when used in combination with troglitazone or acarbose. Enhanced metabolism of repaglinide via troglitazone-induced p-450 enzyme system 3A4 might reduce the effectiveness of this combination.16 However, this has not been studied. Given the additional benefits of adding insulin to sulfonylurea therapy, it might also be reasonable to use repaglinide in combination with a basal insulin in some cases.

In contrast to some of the oral agents, most of the FBG-lowering effect was demonstrated within 1–2 weeks of initiation of therapy.¹⁶ In a double-blind, placebo-controlled, 3-month trial, FPG and postprandial plasma glucose concentrations were 61 mg/dl and 104 mg/dl lower, respectively, in patients treated with repaglinide versus placebo. FPG and postprandial plasma glucose concentrations were 31 mg/dl and 47.6 mg/dl less than at baseline, respectively, in patients treated with repaglinide. HbA_1c concentrations were 1.7% lower in the repaglinide group than those in the placebo group.¹⁶ Another double-blind, placebo-controlled, 24-week study of 362 patients with type 2 diabetes (some medication naïve and some previously treated with oral hypoglycemic agents) demonstrated HbA_1c reductions of 2.1% and 1.7%, respectively, when compared to placebo.¹⁶

A multicenter study of 195 patients with type 2 diabetes who were previously treated with sulfonylureas compared the effects of repaglinide to glibenclamide over 14 weeks.18 The study design was double-blind, randomized, parallel group, and included a 1- to 2-week washout, 4-week titration, and 10-week maintenance period.

There was no statistically significant difference in FBG, HbA_1c, fructosamide, lipid profiles, fasting C-peptide, fasting insulin, or fasting pro-insulin between the repaglinide- and glibenclamide-treated groups. A significant difference in mean blood glucose derived from 8-point blood glucose profiles (P = 0.0003) and in post-breakfast blood glucose (P = 0.09) was reported (mean BG repaglinide = 203 mg/dl, mean BG glibenclamide = 212 mg/dl; post-breakfast BG repaglinide = 221 mg/dl, post-breakfast BG glibenclamide = 237 mg/dl).

Side Effects and Contraindications
The side effects of repaglinide, as could be expected, include adverse events common to exogenous insulin therapy and other insulinotropic hypoglycemic agents, namely weight gain and hypoglycemia.

In the phase III trials in the United States, hypoglycemia was one of the most common causes of withdrawal. In the previously mentioned study of 362 type 2 patients, sulfonylurea-naïve patients who had HbA_1c concentrations of < 8% at initiation of the study had a higher frequency of hypoglycemia (value not reported) than patients who received placebo.¹⁶ Patients previously treated who had baseline HbA_1c = 8% reported hypoglycemia at the same rate as those treated with placebo.

In another efficacy and safety trial of 1 year duration, hypoglycemia was reported in 16% of 1,228 repaglinide-treated patients, 20% of 417 glyburide-treated patients, and 19% of 81 glipizide-treated patients. None of the repaglinide-treated patients became comatose or required hospitalization.¹⁶ It is recommended that repaglinide be administered with food to reduce the risk of hypoglycemia.

In the study of 362 type 2 patients, previously sulfonylurea-naïve patients experienced a weight gain of 3.3% (e.g., a 2.1-kg [4.6-lb] weight gain in a 70-kg individual), while patients previously treated with sulfonylureas experienced no additional weight gain.¹⁶ Based on this data, it would appear that expected weight gain secondary to repaglinide is similar to that occurring with sulfonylurea therapy.

Additional, less frequently observed (<1%) adverse effects include thrombocyopenia, leukopenia, elevated hepatic enzymes, and one case of anaphylactic reaction.

Repaglinide is metabolized via oxidative biotransformation and conjugation with glucaronic acid to three major metabolites that do not contribute to the glucose-lowering effect of the parent drug. Less than 2% of the parent drug is excreted unchanged in the feces and <0.1% is cleared renally. Most of the parent compound is hepatically metabolized and excreted via the feces. Because of this, repaglinide should be used cautiously, with longer intervals between dose adjustments, in patients with hepatic dysfunction.

Efficacy trials in patients with renal dysfunction are to be carried out in the future. The current recommendation is that repaglinide should be used cautiously, with longer intervals between dose adjustments, in patients with renal impairment or those being managed with hemodialysis.

-GLUCOSIDASE INHIBITORS
Acarbose (Precose®) is the only marketed oral -glucosidase inhibitor indicated for the management of hyperglycemia secondary to type 2 diabetes. This drug was released for use in the United States in early 1996. Acarbose had been used extensively in Europe and Canada for several years before its release in the United States.

Acarbose is a mild antihyperglycemic agent and may be used as monotherapy in new-onset or mild type 2 diabetes and also in combination with insulin or other agents in more severe type 2 disease.

Another -glucosidase inhibitor, miglitol, has received FDA approval. However, there is some question about whether it will be marketed in this country.

Mechanism of Action
Acarbose’s primary mechanism is competitive inhibition of -glucosidase enzymes in the brush border of the small intestine.¹⁹ Additionally, acarbose inhibits pancreatic -amylase.²⁰

-amylase is responsible for the hydrolysis of complex starches to oligosaccharides in the lumen of the small intestine. The -glucosidase enzymes are responsible for the hydrolysis of oligosaccharides, trisaccharides, and disaccharides in the brush border of the small intestine and include maltase, isomaltase, glucoamylase, and sucrase. Inhibition of these enzyme systems effectively reduces the rate of complex carbohydrate digestion and the subsequent absorption, lowering postprandial glucose excursions in patients with diabetes.

Efficacy
One monotherapeutic study, comparing the effects of acarbose monotherapy to placebo in 212 obese subjects with type 2 diabetes who were medication-naïve, reported a 5.4 mg/dl reduction in FPG, a 38 mg/dl reduction in 2-hour postprandial plasma glucose, and a 0.06% reduction in HbA_1c in acarbose-treated patients when compared to baseline.²¹ Acarbose-treated patients when compared to placebo patients had lower HbA_1c (0.59% lower), FPG (16 mg/dl lower), and postprandial plasma glucose (50 mg/dl lower) concentrations.

Another study reported reductions from baseline in HbA_1c of 0.54%, a mean reduction in FPG of 20 mg/dl, and a 51 mg/dl reduction in 1-hour postprandial glucose concentrations in patients treated with acarbose.¹³ Yet another trial of 94 patients with type 2 diabetes reported that acarbose-treated patients experienced a mean reduction in HbA_1c of 0.65% below baseline after 24 weeks of therapy.²² While acarbose was not associated with reductions in fasting plasma insulin, it was associated with a 30% reduction in postprandial insulin concentrations.

Side Effects and Contraindications
The most common side effects of acarbose are dose-related gastrointestinal complaints, flatulence, diarrhea, and abdominal pain. In many cases, these side effects can be reduced by continued administration of the medication. In phase III trials in the United States, flatulence, diarrhea, and abdominal pain occurred with an incidence 45%, 21%, and 12% higher than, respectively, that reported with placebo.²⁰

While elevated hepatic enzymes have been reported at higher doses (200 and 300 mg three times daily is used in Europe), the occurrence with doses of 100 mg or less three times daily is rare. Elevated serum transaminase levels were no more frequent than those observed with placebo when doses of 100 mg three times daily or less were used.²⁰

Patients treated with acarbose and hypoglycemic agents (i.e., insulin or sulfonylureas) may encounter difficulty in treating hypoglycemic episodes with oral complex carbohydrates. The absorption rates of sucrose and other complex carbohydrates are drastically reduced with the administration of acarbose, and their use may result in prolonged hypoglycemia. Therefore, patients treated with combination therapy that includes a hypoglycemic agent should always be counseled to have oral glucose tablets or gel on hand in the event of a hypoglycemic episode.

Because of its adverse effects on the gastrointestinal tract, acarbose should be avoided in patients with inflammatory bowel disease, colonic ulceration, or obstructive bowel disorders. Relative contraindications to the use of this drug include chronic intestinal disorders of digestion or absorption and medical conditions that might deteriorate with increased intestinal gas formation.²⁰

Studies have suggested increases in acarbose plasma concentrations in patients with renal dysfunction, and long-term studies have not been carried out in this population. Therefore, acarbose therapy should be avoided in patients with serum creatinine levels of >2.0 mg/dl.²⁰

THIAZOLIDINEDIONES
In 1982, the search for an "insulin-sensitizing" agent led to the discovery of the thiazolidinedione derivative ciglitazone.²³ This was followed by the development of pioglitazone, englitazone, and troglitazone.

Troglitzone (Rezulin®) is the first of the thiazolidinedione agents to be marketed in the United States. This compound was synthesized with an -tocopherol moity in an effort to produce a drug that might inhibit lipid peroxidation and have an effect on insulin sensitivity.

Mechanism of Action
Troglitazone appears to work by enhancing insulin action without affecting insulin secretion. As mentioned above, it has been referred to as an "insulin sensitizer." The insulin sensitizer effects involve direct stimulation of receptors on the nuclear surface, which causes an increase in the transriptional processes for the production of key proteins. These receptors are referred to as PPAR (peroxisome proliferative-activated receptors).^23,24 Troglitazone is now being referred to as a PPAR- activator.

Stimulation of PPAR leads to a reduction in hepatic glucose production and to increases in insulin-dependent glucose disposal in skeletal muscle. Stimulation of PPAR probably causes an increase in the production of key glucose transporters GLUT1 and GLUT4.

Efficacy
Two monotherapeutic trials (one 12-week and one 24-week), evaluating a total of ~1,600 patients with type 2 diabetes, were carried out in the United States as part of the phase III trials. Included were patients who were medication-naïve and, after an appropriate washout period, patients who had been previously treated with other agents. In the 12-week trial, mean fasting serum glucose and HbA_1c concentrations for patients receiving 200, 400, and 600 mg daily were reduced 14 mg/dl and 0.6%, 20 mg/dl and 0.6%, and 38 mg/dl and 0.8%, respectively, from baseline. In the 24-week trial, mean fasting serum glucose and HbA_1c concentrations for patients receiving 200, 400, and 600 mg daily were changed 224 mg/dl and 20.2%, 217 mg/dl and +0.3% (an increase), and 248 mg/dl and 21.0%, respectively, compared to baseline.

In a double-blind, multicenter, parallel-group study, 284 patients with type 2 diabetes were randomized to receive either placebo or troglitazone 400 mg daily for 12 weeks.²⁵ In the troglitazone group, FPG and HbA_1c concentrations were reduced 23 mg/dl and 0.5%, respectively, below baseline. A positive response in this study was defined as a reduction in HbA_1cof >1% at 12 weeks. Using this criterion, 45.6% of those treated with troglitazone were classified as responders.

Another trial that evaluated 330 patients previously treated with diet or oral agents randomized patients to placebo or troglitazone (doses up to 800 mg per day).²⁶ At 12 weeks, HbA_1c was unchanged in the once-daily 800 mg/day group when compared to baseline. However, HbA_1c was lower in all of the troglitazone-treated groups (7.0–7.4%) regardless of dose when compared to placebo (8%). FPG levels were also significantly lower in the troglitazone groups (167–198 mg/dl) than in the placebo group (232 mg/dl) at 12 weeks.²⁸

Troglitazone also has effects on lipoprotein and plasma insulin concentrations.

Troglitazone monotherapy and combination therapy with sulfonylureas is associated with an increase in LDL (as much as 13%), HDL (up to 16%), and total cholesterol (up to 5%).24 However, total cholesterol/HDL and LDL/HDL ratios reportedly do not change.

Troglitazone does not cause an increase in ApoB fractions. Additionally, patients treated with troglitazone monotherapy or combination therapy may have reductions of up to 26% in fasting triglyceride levels, as well as reductions in postprandial triglyceride concentrations. ²⁴

Troglitazone reduces insulin resistance, and its use also results in reductions in serum insulin concentrations. In the Kumar study mentioned above, insulin concentrations were lower at all doses (200–800 mg) and with both regimens (once daily and twice daily) when compared to baseline and when compared to placebo. For example, patients treated with 600 mg of troglitazone once daily had baseline fasting plasma insulin concentrations of 12.4 µIU/l and 12-week values of 8.6 µIU/l.

Side Effects and Contraindications
Troglitazone has been associated with rare idiosyncratic hepatocellular injury, which has resulted in one death and one liver transplant.²⁴ Because of this, it is now recommended that patients undergo liver function testing (serum transaminases) monthly for the first 6 months of therapy, every 2 months for the second 6 months, and periodically thereafter. Patients should also be counseled to report any symptom suggestive of hepatic dysfunction.

While troglitazone may also cause resumption of ovulation in premeno-pausal anovulatory patients with insulin resistance, this is probably considered a positive effect in many cases.

Troglitazone monotherapy does not cause hypoglycemia. When troglitazone is added to other hypoglycemic medications, there may be an increased risk of hypoglycemia. In the setting of combination therapy with insulin or sulfonylureas, a reduction in the dose of the concomitant medication may be warranted when troglitazone is added to the regimen.

A weight gain of 5.8–13.1 lb has been observed in patients treated with glyburide and troglitazone. Dose adjustment is not needed in patients with renal dysfunction.

In general, troglitazone is well tolerated. However, it can, on rare occasions, cause headache, dizziness, and edema.²⁷ Mild clinically insignificant reductions in hematologic indices, secondary to dilution, may occur in the first 1–2 months of therapy. Additionally, caution should be exercised when using this drug in patients with New York Heart Association functional class III or IV heart failure.

BIGUANIDES
The biguanide metformin (Gluco-phage®) was introduced in 1957 as an antihyperglycemic agent for use in patients with type 2 disease. However, it was not approved for use in the United States until the 1990s.²⁸

Mechanism of Action
Metformin causes a plethora of metabolic effects, including changes in carbohydrate, lipid, and lipoprotein metabolism.²⁹ The primary effect of metformin on carbohydrate metabolism is via its effects on insulin resistance. The effects of metformin on carbohydrate metabolism occur at two primary sites of action: the liver and muscle tissue.

Metformin lowers blood glucose by enhancing insulin-stimulated glucose transport in skeletal muscle. The range of observed enhancement of glucose uptake ranges from 10 to 40% depending on the population being evaluated.³⁰

Metformin has also been shown in numerous studies to reduce hepatic glucose production in patients with type 2 diabetes. One study suggested that this effect was mediated via a reduction in glycogenolysis, while another study suggested that this effect may be secondary to a reduction in gluconeo-genesis.^31-32

Efficacy
In a 29-week, randomized, parallel, double-blinded trial of 289 moderately obese patients with type 2 diabetes, metformin reduced FPG levels a average of 58 mg/dl and HbA_1c an average of 1.8% compared to diet-plus-placebo.³³ These changes represented reductions in FPG and HbA_1c in the metformin-treated group when compared to baseline of 52 mg/dl and 1.4%, respectively.

In addition to its effects on glucose, metformin therapy compared to baseline was also associated with a reduction in triglyceride concentrations (16%), LDL cholesterol (8%), and total cholesterol (5%), and was associated with an increase in HDL cholesterol (2%).³³ Also, patients treated with metformin lost a mean of 0.6 kg body weight.³³

A dose-response trial of metformin (500–2,500 mg) demonstrated the greatest glycemic effect at a dose of 2,000 mg per day. FPG was reduced by 86 mg/dl and HbA_1c by 0.8% below baseline.³⁴

Side Effects and Contraindications
Patients treated with metformin had 30% more reports of abdominal bloating, nausea, cramping, a feeling of fullness, and diarrhea, particularly in the initiation phases, than patients receiving placebo.³⁵ These side effects are usually self-limiting and transient. They can be mitigated by starting with a low dose and titrating up slowly and also by taking the medication with food.

Additional less-common side effects include a metallic taste and a reduction in vitamin B12 levels. Lactic acidosis can occur with the administration of metformin but is extremely rare (0.03 cases per 1,000 patient-years) and has occurred primarily in patients with significant renal dysfunction.³⁵

Metformin is contraindicated for patients with renal dysfunction (serum creatinine of >1.5 mg/dl in men or >1.4 mg/dl in women), since metformin is excreted renally and can accumulate in these patients.

Because acidosis is sometimes associated with hepatic dysfunction, metformin is contraindicated in patients with clinical or laboratory evidence of hepatic dysfunction. It is also contraindicated in patients with acute or chronic lactic acidosis or a history of alcoholism or binge drinking.

Metformin also should not be used in patients requiring pharmacological management of congestive heart failure. Finally, it should be temporarily withheld in patients with acute conditions predisposing them to acute renal failure or acidosis, such as cardiovascular collapse, acute myocardial infarction, acute exacerbation of congestive heart failure, or a major surgical procedure.

Metformin should be discontinued prior to the administration of intravenous iodinated contrast media and not reinstituted until 48 hours after the procedure, after the patient’s renal function has been verified.³⁵

INSULIN
Insulin has been widely used as monotherapy since 1922 and in combination therapy for management of hyperglycemia since the late 1950s. It has been estimated that ~29% of all patients diagnosed with diabetes are type 2 diabetes patients treated with insulin.³⁶ While a multitude of studies that delineate the metabolic effects of insulin have been published, there is a paucity of studies evaluating insulin therapy in patients with type 2 diabetes.

Mechanism of Action
Insulin (available in numerous types and brands) binds to the -subunit of the insulin receptor, activating tyrosine kinase activity of the ß-subunit. Activation of tyrosine kinase initiates a complex cascade of biochemical reactions, which in turn result in several physiological events.³⁷

Insulin’s physiological effects include inhibition of hepatic glucose production, stimulation of hepatic glucose uptake, stimulation of glucose uptake by muscle tissue, and a mild stimulation of glucose uptake by the adipose tissue. Insulin therapy has been associated with a 40–44% reduction in hepatic glucose output and a 17–80% increase in peripheral glucose uptake.²⁹

Efficacy
The ability of insulin therapy to lower blood glucose levels is governed by dose, regimen, level of insulin resistance, and other factors. Insulin is effective in reducing blood glucose levels in patients with type 2 diabetes when used as monotherapy and when used in combination with sulfonyulreas, metformin, troglitazone, and acarbose.

Reduction in hyperglycemia and an improvement in glucose toxicity will occur in almost all patients with type 2 diabetes given sufficient doses of insulin.²⁹ Patients with moderately severe type 2 disease, (FPG 140–200 mg/dl) will usually show sufficient response to a single or twice-daily dose of insulin in the range of 0.3–0.4 U/kg/day.³⁸

While the most appropriate time for a single daily injection is still being debated, one study suggested that bedtime administration is superior to morning administration when using intermediate-acting insulin. Another study suggested that 9:00 p.m. is a reasonable time for the single daily insulin dose when used in combination with sulfonylureas.^38,39 The former study reported improved glycemic control, and the later study reported less weight gain with the bedtime or evening insulin doses when compared to morning insulin doses.

Patients with severe type 2 diabetes (FPG >200 mg/dl) or patients not responsive to the above-mentioned regimens may require around-the-clock insulin.³⁸ This usually necessitates the addition of short-acting insulin before meals with total daily insulin doses ranging from 0.5–1.2 U/kg/day. However, in insulin-resistant patients, doses of >1.5 U/kg/day may be needed.

The degree of glucose lowering is dose-related. Studies have demonstrated a lowering of fasting glucose of up to 190 mg/dl from baseline in patients with type 2 diabetes treated with insulin monotherapy.^36,40

Side Effects and Contraindications
Several possible side effects, including hypoglycemia, weight gain, and the potential for accelerated macrovascular disease, should be considered with insulin therapy in patients with type 2 diabetes. Severe hypoglycemia, while a major concern in patients with type 2 diabetes, probably occurs with a lesser frequency than is observed in patients with type 1 diabetes.³⁶

The annual rates of hypoglycemia and severe hypoglycemia (requiring the assistance of another person) in insulin-taking patients in the 3-year follow-up of the UKPDS were 33.4% and 1.4%, respectively.¹¹ By comparison, the annual rates of hypoglycemia and severe hypoglycemia in glyburide-managed patients in this trial were 27.8% and 1.3%, respectively. In a 6-year follow-up of this trial, it was re-ported that 62% of patients treated with insulin had experienced at least one epi-sode of hypoglycemia during the trial.²⁸

Insulin therapy has also been associated with significant weight gain. Studies in patients with type 1 diabetes treated with insulin for 6–12 months have reported average weight gains of up to 6 kg.³⁶

Epidemiological studies that have demonstrated a correlation between hyperinsulinemia (patients with and without diabetes, treated and not treated with exogenous insulin) and the risk of macrovascular disease have raised the possible specter of insulin therapy accelerating macrovascular disease.³⁶ While the question remains controversial, no prospective studies to date have demonstrated that exogenous insulin accelerates macrovasular disease. A recent consensus statement from the American Diabetes Association concluded that "exogenous insulin administration does not have direct adverse effects on cardiovascular events and may even favorably affect the cardiovascular risk profile if improved glycemic control and lipid profile are sustained."⁴²

COMBINATION THERAPY
With the introduction of several new oral agents, the number of possible combinations of medications that may be used in the management of type 2 diabetes has increased dramatically. Combination therapy has been reviewed in detail in other articles, and an extended discussion of the topic is beyond the scope of this article. However, some of the salient nonglycemic metabolic effects of various combinations will be briefly reviewed below. A review of the metabolic effects of mono- and combination oral therapy will be summarized in Table 1, and combination oral/insulin therapy will be summarized in Table 2.

Sulfonylureas are effective when combined with acarbose.^21,43 When acarbose and sulfonylureas are given, there may be a partial attenuation of the insulin rise encountered in patients treated with sulfonulurea monotherapy.²¹ When acarbose is added to sulfonylurea therapy, no change in serum insulin (C-peptide was actually measured) was observed.⁴³

The addition of metformin to patients who have failed sulfonylurea therapy is an effective method of reducing hyperglycemia.³³ Conversely, the addition of a sulfonlylurea to a patient who is not responding to metformin monotherapy is also effective.12 While metformin/sulfonylurea combination therapy does not seem to have a significant effect on weight or plasma insulin, it has been associated with reductions in triglycerides, total cholesterol, and LDL cholesterol, and increases in HDL cholesterol.³³

Sulfonylureas are also effective when combined with troglitazone.²⁴ In addition to effective glycemic reduction, this combination was also associated with statistically significant reductions in insulin concentrations at doses of 400 and 600 mg of troglitazone daily.²⁴ Additionally, a slight increase in total cholesterol, LDL cholesterol, and HDL cholesterol (with no change in LDL/HDL or TC/HDL ratios) along with a decrease in triglycerides was observed in patients treated with this combination therapy.

The addition of acarbose to metformin therapy is effective in slightly reducing glycemic indices.⁴³ In this trial, no significant effects on serum insulin concentrations, lipid profiles, or body weight were observed.

When repaglinide was added to patients not satisfactorily controlled on metformin, significant reductions in glycemic indices were noted. Unfortunately, other metabolic indices were not reported.16

Insulin has been shown to be effective when used in combination with sulfonlyureas, acarbose, metformin, and troglitazone.^24,43-45 Insulin doses may be significantly reduced with the addition of sulfonlureas, metformin, or troglitazone. The addition of metformin to insulin regimens in patients with type 2 disease resulted in significant reductions in triglycerides and total cholesterol, along with increases in HDL cholesterol.

STEP-DOWN THERAPY
Given the introduction of several new oral agents, it has become increasingly possible to use step-down therapy (from insulin back to oral therapy, or reduction of insulin dose with the addition of an oral agent) in patients with type 2 disease. Given the possible adverse effects of insulin and the better control sometimes offered, this course of action may be prudent in some patients.

A study evaluating the effects of adding troglitazone (200 or 400 mg/day) or placebo to insulin therapy reported that a >50% reduction in insulin doses occurred in 51% and 70%, respectively, in the 200-mg and 400-mg groups.²⁴ Insulin therapy was discontinued in 15% of patients in the 400-mg group and in 7% in the 200-mg group.

A recent study demonstrated that 76% of insulin-treated patients (42 of 55 patients) successfully discontinued insulin when treated with the combination of metformin and glyburide.⁴⁷ In addition to discontinuance of insulin, HbA_1c was significantly reduced 1.3%, and the patients lost an average of 11 lb. The study found that patients most likely to respond were those with a shorter duration of insulin therapy (mean 5 years), lower insulin requirements (mean 0.77 U/kg), and lower body mass indices (mean of 30).

Table 2. Effects of Insulin/Oral Therapy in Selected Studies and Summaries
Combination Insulin and	FPG reduction (mg/dl)	PPG reduction (mg/dl)	HbA1c reduction (%)	Insulin dose reduction (%)	Lipid effect (+increase, -decrease, none)
Sulfonylurea (ref. 44,45)	41–43 from monotherapeutic baseline	not reported	0.8–1.1 from monotherpeutic baseline	–24	none
Acarbose (ref. 43)	1.8 increase from insulin monotherapy baseline*	48.63 from insulin mono-therapy baseline	0.4 from insulin monotherapy baseline	not attempted	none
Metformin (ref.46)	91.5 below baseline treatment with insulin*	not reported	–1.9 below baseline treatment with insulin	–25	–TC, TG +HDL
Troglitazone (600 mg/day) (ref. 24)	not reported**	not reported**	– 1.41 from baseline treatment with insulin	-40	no significant change in TG, + TC LDL, HDL
* average glucose concentration FPG = fasting plasma glucose ** fasting serum concentrations         PPG = postprandial glucose TC/HDL ratio was unchanged

CONCLUSION
The recent introduction to the U.S. market of several new oral agents has dramatically increased the number of monotherapeutic and combination therapy options available to practitioners managing patients with type 2 diabetes.

Currently, no consensus exists regarding when and how various pharmacological modalities should be instituted. Clinicians must use their own clinical judgment to determine which therapy is appropriate for a particular patient. Considerations that should be included in designing a pharmacological regimen for patients with type 2 diabetes include contraindications, amount of glycemic-lowering needed to get patients into their goal range, ease of compliance, patients’ weight and ideal weight, and patients’ lipid profile.

Patients who are currently treated with insulin may be able to obtain equivalent or even superior glycemic control and significant weight loss with oral step-down therapy.

As more is learned about the pathogenesis of type 2 diabetes and the comparative effectiveness of various regimens (including triple-therapy regimens) on long-term outcomes, the most appropriate methods of management will become more evident.

References

¹Kennedy DL, Piper JM, Baum C: Trends in use of oral hypoglycemic agents, 1964-1986. Diabetes Care 11:558-62, 1988.

²Gerich JE: Oral hypoglycemic agents. N Engl J Med 321:1232-45, 1989.

³Skillman TG, Feldman JM: The pharmacology of the sulfonylureas. Am J Med 70:361-69, 1981.

⁴Leahy JL, Cooper H, Deel DA, Weir CG: Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion: a study of normal rats using chronic in vivo glucose infusions. J Clin Invest 77:908-15, 1986.

⁵Lebovitz H: Clinical utility of oral hypoglycemic agents in the management of patients with non-insulin-dependent diabetes mellitus. Am J Med 75 (Suppl. 5B):94-99, 1983.

⁶Jackson JE, Bressler R: Clinical pharmacology of sulfonylurea hypoglycaemic agents. Drugs 22:211-45, 295-320, 1981.

⁷Lebovitz H: A new oral therapy for diabetes management: alpha-glucosidase inhibition with acarbose. Clinical Diabetes 13:99-102, 1995.

⁸Amaryl package insert, Hoechst Marion Roussel Pharmaceuticals, Somerville, N.J.

⁹HOE 490 8/USA/202/DM—Glimepiride Studies, Hoechst Marion Roussel Pharmaceuticals, Somerville, N.J.

¹⁰HOE 490 8/USA/201/DM—Glimepiride Studies, Hoechst Marion Roussel Pharmaceuticals, Somerville, N.J.

¹¹United Kingdom Prospective Diabetes Study Group: United Kingdom Prospective Diabetes Study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin-dependent diabetes followed for three years. Br Med J 310:83-88, 1995.

¹²Hermann LS, Schersten B, Bitzen P, Kjellstrom T, Lindgarde F, Melander A: Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. Diabetes Care 17:1100-1109, 1994.

¹³Coniff RF, Shapior JA, Seaton TB, Bray G: Multicenter, placebo-controlled trial comparing acarbose (BAY g5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 98:443-51, 1995.

¹⁴Vinambres C, Villanueva-Penacarrillo ML, Valverde I, Malaisse WJ: Repaglinide preserves nutrient-stimulated biosynthetic activity in rat pancreatic islets. Pharmacol Res 34:83-85, 1996.

¹⁵Gromada J, Dissing S, Kofod H, Frokjaer-Jensen J: Effects of hypoglycemic drugs repaglinide and glibenclamide on ATP-sensitive potassium channels and cytosolic calcium levels in beta TC3 cells and rat pancreatic beta cells. Diabetologia 38:1025-32, 1995.

¹⁶PrandinTM package insert (proposed but not accepted), Novo Nordisk, Princeton, N.J.

¹⁷Damsbo P, Anderson PH, Lund S, Porksen N: Improved glycaemic control with repaglinide in NIDDM with 3 times daily meal related dosing (Abstract). Diabetes 46 (Suppl. 1):34A, 1997.

¹⁸Landgraf R, Bilo H: Repaglinide vs. glibenclamide: a 14-week efficacy and safety comparison (Abstract). Diabetes 46 (Suppl. 1):162A, 1997.

¹⁹Santeusanio F, Compagnucci P: A risk-benefit appraisal of acarbose in the management of non-insulin-dependent diabetes mellitus. Drug Safety 11:432-44, 1994.

²⁰Precose package insert, Bayer Pharmaceuticals, West Haven, Conn.

²¹Conniff RF, Shapiro JA, Seaton TB: Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med 154:2442-48, 1994.

²²Hanefeld M, Fischer S, Schulze J, Spengler M, Wargenau M, Schollberg K, Fücker K: Therapeutic potentials of acarbose as a first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 14:732-37, 1991.

²³Saltiel AR, Olefsky JM: Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45:1661-69, 1996.

²⁴Rezulin package insert, Parke-Davis, Morris Plains, N.J.

²⁵Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T: Effects of troglitazone. Diabetes Care 19:151-56, 1996.

²⁶Kumar S, Boulton AJM, Beck-Nielsen H, Berthezene F, Meggeo M, Persson B, Spines GA, Donoghue S, Lettis S, Stewart-Long P: Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 39:701-709, 1996.

²⁷Purnell JQ, Hirsch IB: New oral therapies for type 2 diabetes. Am Fam Phys 56:1835-42, 1997.

²⁸White J: The pharmacologic management of patients with type II diabetes mellitus in the era of new oral agents and insulin analogs. Diabetes Spectrum 9:227-34, 1996.

²⁹Dagogo-Jack S, Santiago JV: Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions. Arch Intern Med 157:1802-17, 1997.

³⁰Bailey CJ: Metformin, an update. Gen Pharmacol 24:1299-1309, 1993.

³¹DeFronzo RA, Barzilai N, Simonson DC: Mechanism of metformin action in obese and lean NIDDM subjects. J Clin Endocrinol Metab 73:1294-1301, 1993.

³²Stumvall M, Nurjhan N, Perriello G, Dailey G, Gerich J: Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 333:550-54, 1995.

³³DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group: Efficacy of metformin in patients with NIDDM. N Engl J Med 333:541-49, 1995.

³⁴Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL: Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 102:491-97, 1997.

³⁵Glucophage package insert, Bristol-Meyers Squibb, Wilton, Conn.

³⁶Genuth S: Insulin use in NIDDM. Diabetes Care 13:1240-64, 1990.

³⁷Davis SN, Granner DK: Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, ninth edition. Hardman JG, Limbird LE, Eds. New York, McGraw-Hill 1996, p. 1487-1518.

³⁸Skyler J: Insulin treatment. In Therapy for Diabetes Mellitus and Related Disorders, second edition. Lebovitz H, Ed. Alexandria, Va., American Diabetes Association, 1994, p. 131-41.

³⁹Seigler DE, Olsson GM, Skyler J: Morning versus bedtime isophane insulin in type 2 (non-insulin-dependent) diabetes mellitus. Diabetic Med 8:826-33, 1992.

⁴⁰Galloway JA: Treatment of NIDDM with insulin agonists or substitutes. Diabetes Care 13:1209-39, 1990.

⁴¹Turner RC, Holman RR: The UK Prospective Diabetes Study. Ann Med 28:439-44, 1996.

⁴²American Diabetes Association: Consensus Statement: The pharmacologic treatment of hyperglycemia in NIDDM. Diabetes Care 19 (Suppl. 1):S54-61, 1996.

⁴³Chiasson J-L, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryen EA, Tan MH, Wolevert MS: The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med 121:928-35, 1994.

⁴⁴Pugh JA, Wagner ML, Sawyer J, Ramirez G, Tuley M, Friedberg SJ: Is combination sulfonylurea and insulin therapy useful in NIDDM patients? A meta-analysis. Diabetes Care 15:953-59, 1992.

⁴⁵Johnson JL, Wolf SL, Kabadi UM: Efficacy of insulin and sulfonylurea combination therapy in type II diabetes: a meta-analysis of randomized, placebo-controlled studies. Arch Intern Med 156:259-64, 1996.

⁴⁶Gugliano D, Quatraro A, Consoli G, Minei A, Ceriello A, DeRosa N, Onofrio ED: Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 44:107-12, 1993.

⁴⁷Bell D, Mayo M: Outcome of metformin facilitated reinitiation of oral diabetic therapy in the insulin-requiring non-insulin-dependent diabetic patient. Endocrine Pract 3:73-76, 1997.

 John R. White, Jr., PharmD, is an associate professor of pharmacy practice at the College of Pharmacy at Washington State University in Spokane.

Note of disclosure: Dr. White has received honoraria for speaking engagements from Novo Nordisk, Eli Lilly and Company, Lifescan, BMS, Parke-Davis, and Bayer Corporation, all of which manufacture pharmaceutical products for the treatment of diabetes. 

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