Achieving glycemic control in type 2 diabetes: a practical guide for clinicians on oral hypoglycemics.

Abstract: Type 2 diabetes mellitus has reached epidemic proportions in the United States. Cardiovascular morbidity and mortality are particularly high in this patient population. Improved glucose control, especially early in the course of diabetes, can slow or prevent complications, preserve [beta]-cell function, and improve long-term outcomes. Within the last decade, new treatments and glycemic goals have created an opportunity to better manage this prevalent, chronic disease. Defects of insulin resistance and deficiency leading to type 2 diabetes can now be directly targeted with available therapies. In addition to diet and exercise, oral treatment options have been broadened, with both insulin secretagogues and insulin sensitizers. These advances in treatment options make glycemic control an obtainable target, and therefore should improve overall morbidity and mortality for patients. This paper will review currently available oral therapies, with a focus on the unique attributes of the insulin sensitizers for patients with type 2 diabetes.

Key Words: acarbose, meglitinides, metformin, oral treatment, sulfonylureas, thiazolidinediones, type 2 diabetes mellitus

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Diabetes mellitus type 2 (DM2) has reached epidemic proportions in the United States, with over 16 million persons diagnosed with the disease, and a likely additional 16 million who have prediabetes or undiagnosed DM2. (1) This number is expected to double by the year 2030, (2) and the trend shows disproportionately more African-Americans and Hispanics are affected by the disease. (3) The manifestation of DM2 is an elevated fasting blood sugar secondary to insufficient insulin action. The insufficient insulin action is two-fold: the presence of insulin resistance, and the reduction in endogenous insulin. The United Kingdom Prospective Diabetes Study (UKPDS) (4) demonstrated a progressive decline of endogenous insulin release, and demonstrated [beta]-cell function at less than 60% at baseline for patients with DM2.

The initial defect in insulin secretion is the loss of the first-phase insulin release seen in response to a rapid rise in glucose. This results in elevated postprandial glucoses. Over time the insulin deficiency progresses, causing elevated fasting blood glucoses. Exogenous insulin becomes necessary in the management of diabetes as pancreatic [beta]-cell function declines and defective endogenous insulin secretion occurs. Improving overall glucose control, especially early in the course of diabetes, can slow or prevent complications, preserve [beta]-cell function, and improve long-term glycemic control. (5,6)

The insulin-resistance syndrome, or metabolic syndrome, has been shown to be a major risk factor for the development of DM2. A recent study of over 8,000 US men and women projected an estimated prevalence of the metabolic syndrome approaching 47 million or approximately 22% of the US population. (7) Criteria for the diagnosis of the syndrome has recently been defined as the presence of three or more of the following: 1. Abdominal obesity: waist circumference > 102 cm in men and > 88 cm in women; 2. Hypertriglyceridemia: [greater than or equal to] 150 mg/dL (1.69 mmol/L); 3. High-density lipoprotein (HDL) cholesterol: < 40 mg/dL (1.04 mmol/L) in men and < 50 mg/dL (1.29 mmol/L) in women; 4. Blood pressure: [greater than or equal to] 130/85 mm Hg; 5. Fasting glucose: [greater than or equal to] 110 mg/dL (6.1 mmol/L). (8)

The culmination of the metabolic syndrome is an elevation of the fasting glucose and thus, DM2. The greatest risk for cardiovascular events is during the prediabetes phase of the metabolic syndrome. (7,9) These risk factors include impaired glucose tolerance, hyperinsulinemia, hypertension, dyslipidemia, and visceral adiposity. (10,11) Ischemic cardiac mortality is up to four times higher in patients with diabetes, and nearly 80% of patients with diabetes are expected to die from cardiovascular-related complications. (5,12) Identification and treatment of known cardiovascular risk factors are essential at the time the metabolic syndrome is diagnosed, and should not be delayed until DM2 is diagnosed. (5)

The UKPDS was a 20-year prospective study of over 5,000 DM2 patients conducted to identify risks factors for microvascular and macrovascular disease. In addition, the UKPDS identified optimal treatments and treatment targets for glycemic control. Patients were primarily treated with either a sulfonylurea, insulin, or a combination, depending upon the primary goals of the intervention, for a median follow-up of 10.7 years. (4,13) A small cohort of obese patients received metformin therapy. (14) All the interventions were compared with current conventional treatment plus diet. The incidence of clinical complications from diabetes was directly associated with the level of glycemia. The lower the glycosylated hemoglobin, or hemoglobin [A1.sub.c] (AIc), the greater the risk reduction. (13) Other interventional studies with both type 1 and type 2 diabetes mellitus have demonstrated that tight glycemic control significantly reduced the onset and progression of microvascular complications from hyperglycemia. (15,16) Although the UKPDS demonstrated no threshold for glycemic control, (13) the American Diabetes Association recommends a goal AIc of < 7%. (17) The American Association of Clinical Endocrinologists recommends a target AIc of < 6.5%. (18)

Insulin Secretagogues

The insulin secretagogues include the sulfonylureas (glipizide, glyburide, and glimepiride) and meglitinides (repaglinide and nateglinide). The sulfonylureas have been available for use since 1942 and were the mainstay of oral therapy for DM2 for decades. They selectively target the [K.sub.ATP] channel in the plasma membrane of the beta cell of the pancreas to stimulate endogenous insulin secretion. (19) Through endogenous hyperinsulinemia, sulfonylurea therapy has been shown to lower fasting blood sugar, but may result in weight gain and hypoglycemia. The sulfonylureas are excreted renally, and should be used with caution in patients with renal insufficiency, and among the elderly. The latest generation sulfonylurea, glimepiride, was developed for a more rapid onset of action and a consequently lower risk of hypoglycemia. (19-21) The average AIc reduction with sulfonylureas is 0.8 to 2.0%. (22)

Questions regarding increased cardiac mortality with use of sulfonylureas remain unanswered. An epidemiologic association between hyperinsulinemia and cardiovascular disease has raised concerns about the safety of sulfonylureas. However, the UKPDS did not show increased mortality in patients treated with sulfonylureas. Other concerns regarding the exhaustion of [beta] cell function with sulfonylurea therapy have also not been proven. (20,21)

Repaglinide and nateglinide are nonsulfonylurea insulin secretagogues. They are differentiated from the sulfonylureas by their receptor binding location and short metabolic half-lives. They were developed to improve early meal-mediated insulin secretion. Their rapid effects and limited duration of action have decreased hypoglycemia and improved glycemic excursion after meals. Because they are short-acting, they are administered at the start of meals. Repaglinide has sufficient duration of action to improve fasting hyperglycemia as well as postprandial hyperglycemia, whereas nateglinide has little to no effect on fasting hyperglycemia. (19) The efficacy of repaglinide is similar to that of the sulfonylureas, whereas nateglinide appears to be a less potent secretagogue. The average AIc reduction seems to be equivalent to the sulfonylureas at 0.5 to 2.0%, but the cost is substantially higher (Table). (21,22) The adverse effects of hypoglycemia and weight gain are probably less pronounced than with the sulfonylureas. The long-term effectiveness of repaglinide and nateglinide in decreasing microvascular or macrovascular risk has not been assessed. (21)

[alpha]-glucosidase Inhibitors

The [alpha]-glucosidase inhibitors (acarbose [Precose] and miglitol [Glyset]) were introduced in 1996. They act at the brush border of the proximal small intestinal epithelium, and interfere with complex carbohydrate digestion. The competitive inhibition of [alpha]-glucosidase delays carbohydrate absorption, and decreases postprandial glucose excursion. They must be taken at every meal. Their efficacy is less than that of the sulfonylureas or metformin, with an average AIc reduction of 0.7 to 1.0%, (22) and side effects of flatulence, abdominal pain, and diarrhea often lead to patient intolerance and cessation of therapy. (21,19) One study demonstrated the safety and acceptable side effect profile of the [alpha]-glucosidase inhibitor miglitol as compared with sulfonylurea therapy in elderly patients with mild diabetes. (23)

Insulin Sensitizers

Biguanide 

Metformin (Glucophage, Glucophage XR) is an insulin sensitizing biguanide, available in the United States since 1995, although used internationally for decades. (21) Its primary mechanism of action is to suppress gluconeogenesis at the level of the hepatocyte mitochondria, thereby reducing fasting glucose. It also increases peripheral insulin sensitivity, mainly at the skeletal muscle. Metformin is not protein bound and has maximal accumulation in the small intestinal wall. It has been shown in multiple studies to be effective as mono-therapy and in combination therapy with sulfonylureas, thiazolidinediones, and insulin. (10) In the Diabetes Control and Prevention Trial, (24) metformin therapy in the prediabetic patient reduced the onset of DM2 by 31%.

Metformin has particular benefit in obese patients with diabetes, and has been associated with visceral fat reduction. Visceral fat is more metabolically active, and produces adipocytokines which contribute to insulin resistance. (25) Metformin also has an independent beneficial effect on cardiovascular morbidity and mortality. In the UKPDS, metformin reduced rates of diabetic complications and all-cause mortality compared with sulfonylureas and insulin, despite similar changes in the AIc. A significant reduction in coronary atherosclerotic disease events was noted in obese patients treated with metformin which did not appear to be present among patients with similar AIc reduction on other therapies. (14) Metformin has favorable effects on both dyslipidemia and hyper-coagulability by way of decreased plasminogen activator inhibitor-1 (PAI-1) levels. (26) Animal models demonstrate that metformin improves diastolic cardiac abnormalities and lowers blood pressure, both of which would be beneficial in this high-risk patient population. One of the most significant benefits of metformin is the promotion of weight loss and appetite suppression when used as a single agent or in combination therapy. (10) The average AIc reduction is 1.5 to 2.0%. (22)

As with all medications, the side effect profile of metformin must be considered before therapy is initiated. Metformin is generally well tolerated and rarely causes hypoglycemia. Up to 50% of patients will experience gastrointestinal side effects including diarrhea, flatulence, nausea and vomiting, or abdominal discomfort. These usually abate in the first few weeks, and can be minimized by starting with a single dose of 500 mg after the evening meal, titrating up slowly, and taking after meals. (27) Metformin's maximum glucose-lowering effect is at a dose of 2 g daily (divided). Higher doses show reduced effects on glucose, and place the patient at greater risk for side effects. (28)

Lactic acidosis is a rare but potentially fatal side effect of metformin. The incidence is 0.03 cases per 1,000 patient-years. (29) Almost all cases of metformin-induced lactic acidosis have occurred in patients with known contraindications. Despite the risk, many patients are continued on metformin while hospitalized. (29,30) Absolute contraindications to metformin therapy include elevated creatinine (Cr [greater than or equal to] 1.5 mg/mL in males or [greater than or equal to] 1.4 mg/mL in females), congestive heart failure, metabolic acidosis, intravenous contrast, and hypoxia. Age > 80 years is not an absolute contraindication to metformin therapy, but should be used cautiously, with close monitoring and verification of creatinine clearance. (27) Hepatotoxicity from metformin has not been reported, however patients with chronic liver disease or patients at risk for acute hepatic toxicity (such as acute alcohol intoxication or excessive acetaminophen use) should not be prescribed metformin because of the potential for reduced hepatic metabolism of lactic acid. (31)

A less well-known side effect of metformin is its association with vitamin [B.sub.12] deficiency. Although rarely of clinical consequence, it is estimated to occur in 10 to 30% of patients taking metformin. It usually develops within 10 to 15 years of therapy. (10,32) This remains a rare finding, as metformin has only been available in the United States since 1995. However, it is likely to increase in prevalence over time. Calcium supplementation may reverse the [B.sub.12] malabsorption, (33) but is not currently recommended as prophylaxis.

The thiazolidinediones

The thiazolidinediones or TZDs (rosiglitazone [Avandia] and pioglitazone [Actos]) have joined metformin as effective insulin sensitizers, targeting different key organs to decrease insulin resistance. The TZDs, also referred to as the glitazones, have been available for clinical use in the United States since 1997, and are approved for both monotherapy and combination therapy with other oral hypoglycemic agents and insulin. (34) They are insulin sensitizing agents that increase peripheral utilization of insulin by acting as ligands of the gamma isoform of the peroxisome proliferator-activated receptor (PPARy). This receptor is found in high concentrations in adipose tissue, hepatocytes, and skeletal muscle, and is involved with the regulation of genes that control glucose homeostasis, lipid metabolism, and adipose tissue. The mechanisms by which they improve insulin sensitivity are via phosphorylation of the insulin receptor, and activation of transcription factors which increase insulin sensitivity at the tissue level. TZDs have demonstrated [beta]-cell preservation, delaying or preventing endogenous insulin deficiency which would otherwise have resulted in insulin therapy. This has not been seen in patients treated with sulfonylureas or metformin. Since TZDs directly improve insulin resistance and reduce hyperinsulinemia, there is hope that these agents may confer a cardiovascular benefit independent of improved glycemic control. TZDs have other beneficial effects, which include favorable modification of the lipoproteins, leading to an increase in high-density lipoprotein, and a less dense, less atherogenic low-density lipoprotein. Recent studies have also shown a significant reduction in PAI-1 levels, improved endothelial function, and a mild reduction in diastolic blood pressure. (34-36) These nonhypoglycemic effects are of particular benefit in patients with DM2 because of the high incidence of coronary atherosclerotic disease in this patient population.

The first TZD licensed in the United States was troglitazone (Rezulin). It was associated with severe hepatic dysfunction, and was removed from the market in March 2000. This led to concerns about the safety of the newer TZDs, rosiglitazone and pioglitazone. The theorized mechanism behind troglitazone's toxicity was dependent on both the dose and the half-life of the drug and its metabolites. Clinical trials involving 4,500 patients have demonstrated no increase in hepatotoxicity with either rosiglitazone or pioglitazone compared with placebo, (37) but a few case reports exist. (38-41) Because of the history of severe hepatic dysfunction with troglitazone, the Food and Drug Administration recommends monitoring liver function tests every 2 months during the first year, and periodically thereafter. (37)

When comparing the efficacy of rosiglitazone and pioglitazone, it is important to note that no head-to-head trials have been conducted to date. Overall, their effect on hyperglycemia appears similar, with average AIc reductions of 0.5 to 1.5% for both. (22,42) Efficacy trials that have been done involve different patient populations with varying degrees of glycemic control. With both of the TZDs, the duration of diabetes appears to be an important variable in the degree of improvement of AIc. The TZDs become less effective as diabetes progresses and endogenous insulin production wanes. In many studies, high baseline glucoses generated a robust initial response to therapy. (43)

Apart from the concerns of hepatoxicity, rosiglitazone and pioglitazone are very well tolerated. Side effects that are common to both include peripheral edema, anemia, and weight gain. (34,36) Mild to moderate edema will be experienced by approximately 5% of patients, and is rarely a cause for discontinuation of therapy. Due to the increase in plasma volume, a dilutional anemia can be seen, but rarely results in a fall of the hematocrit level of greater than 3%. Weight gain with the TZDs can occur, and appears to be due to increased fluid retention as well as an increase in body fat. (37) TZD therapy transforms the adipose cell into a more efficient cell, which increases the adipose mass and, in addition, leads to a translocation of fat from the visceral compartment (metabolically active) to the subcutaneous space (not metabolically active). (44) Like metformin, the TZDs rarely cause hypoglycemia.

The most distinguishable difference between rosiglitazone and pioglitazone is the pathway utilized for oxidative metabolism. Pioglitazone, in part, shares a cytochrome pathway with over 150 other commonly used drugs, including macrolide antibiotics, protease inhibitors, cyclosporine, steroids, estrogens, and calcium channel blockers. This raises the possibility of drug interactions and toxicity. However, placebo-controlled trials have shown no altered metabolism of these drugs, and the risk therefore remains theoretical. Myalgias and asymptomatic rises in creatine phosphokinase (CPK) concentrations have been seen infrequently in patients on pioglitazone, but have not led to withdrawal of the medication. (37)

Overall, both drugs are safe and effective sensitizing agents when used in the appropriate patient. There is no contraindication for patients with impaired renal function, but they should not be used in patients with known hepatic failure, advanced congestive heart failure (New York Heart Association class [greater than or equal to] III), or in patients with significant edema. (34) The data for [beta]-cell preservation is compelling, and makes the TZDs a favorable choice early in the course of DM2.

Conclusion

Diabetes is a highly prevalent disease with significant associated morbidity and mortality. Microvascular and macrovascular complications are directly related to the level of glycemic control, and although a goal AIc of 7.0% has been set, no threshold exists. Advances in pharmacotherapy have enabled physicians to target both defects of DM2. Insulin secretagogues, sulfonylureas, and nonsulfonylureas have been joined by metformin and the TZDs to improve insulin sensitivity. Both metformin and TZDs have beneficial effects on lipid metabolism and coagulation factors, reducing the risk of cardiovascular events in this high-risk population. Better options for achieving glycemic control exist with these agents when used either as monotherapy or in a combination therapy. Overall, these therapies are safe, well-tolerated, and effective. A course of close follow-up, continued titration of medications, and monitoring for side effects is the only way to reach treatment goals and improve outcomes for diabetic patients.

Table. Dose and cost of sulfonylureas and meglitinides

                                      Generic name cost
Generic name            Brand name    mg/day (cost) (a,b)

           Sulfonylureas
Glyburide               Diabeta       1.25 ($7.99) to 5.0 ($12.00)
Glyburide               Micronase     1.25 ($7.99) to 5.0 ($12.00)
Glyburide (micronized)  Glynase       1.50 ($8.00) to 6.0 ($14.00)
Glipizide               Glucotrol     5.0 ($5.00) to 10 ($6.50)
Glipizide               Glucotrol XL  2.5 ($10.99) to 10 ($19.99)
Glimepiride             Amaryl                   N/A (c)

           Meglitinides
Repaglinide             Prandin                  N/A (c)
Nateglinide             Starlix                  N/A (c)

                                      Brand name cost mg/
Generic name            Brand name    day (cost) (a,b)

           Sulfonylureas
Glyburide               Diabeta        1.25 ($7.99) to 5.0 ($24.19)
Glyburide               Micronase      1.25 ($13.51) to 5.0 ($33.27)
Glyburide (micronized)  Glynase        1.5 ($18.50) to 6.0 ($42.50)
Glipizide               Glucotrol      5.0 ($13.50) to 10 ($26.20)
Glipizide               Glucotrol XL   2.5 ($17.16) to 10 ($25.99)
Glimepiride             Amaryl         1.0 ($13.06) to 4.0 ($32.99)

           Meglitinides
Repaglinide             Prandin        0.5 ($31.80) to 2.0 ($31.80)
Nateglinide             Starlix       60 ($33.94) to 120 ($32.99)

(a) Estimated cost based on average self-pay prices, www.drugstore.com.
(b) Prices are for 30 pill supply.
(c) Generic formulation not available.

Accepted June 4, 2004.

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RELATED ARTICLE: Key Points

* Type 2 diabetes mellitus is an epidemic with significant cardiovascular morbidity and mortality.

* New treatments and glycemic goals have allowed better therapeutic options for patients.

* Insulin sensitizers are safe, effective, and have benefits beyond glycemic control.

Lisa L. Willett, MD, and Eric S. Albright, MD

From the Divisions of General Internal Medicine and Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.

The authors received no financial support, and have no financial or proprietary interest in any product mentioned in this article.

Reprint requests to Lisa L. Willett, MD, University of Alabama at Birmingham, Boshell Diabetes Building 339, 1530 Third Avenue South, Birmingham, AL 35294-0012. Email: [e-mail]