Antidiabetic Drugs

Archive for the ‘Diabetes’ Category

Prokinetic agents are the mainstay of pharmacological treatment in these patients. The main agents that are available for management of diabetic gastropathy are metoclopramide, domperidone, erythromycin and cisapride. These agents differ with respect to mechanism of action, dosing and efficacy, side-effect profile, drug interactions, and current FDA approval status, as noted in TABLE 6.

Metoclopramide

Metoclopramide accelerates gastric emptying and intestinal transit through a variety of mechanisms peripherally: cholinergic enhancement through cholinesterase inhibition, antagonism of dopaminergic (D2) receptors, and direct effect on the GI smooth muscle. Metoclopramide also acts centrally, in the area postrema, as an antagonist at D2 receptors and 5-HT3 receptors, which may contribute to the anti-emetic action of the drug, and may be vital to the drug’s ability to relieve the symptoms of gastropathy. With metoclopramide therapy, the symptoms of gastropathy appear to improve at different time intervals. Relief of nausea, vomiting, and anorexia may occur within the first three weeks with metoclopramide therapy, than the feelings of persistent postprandial fullness and abdominal pain and distention, which may only resolve with one more week or longer of therapy. The major limiting factor of therapy with metoclopramide is the central nervous system side effects, which include extrapyramidal symptoms.

Erythromycin

Erythromycin increases gastrointestinal motility by binding and stimulating the gastrointestinal peptide motilin. The affinity for the motilin receptor is due to the 14-member macrolide lactone ring that is part of the erythromycin structure. This effect is not related to its antibiotic mechanism of action. In a study by Janssens et al., the effect of erythromycin on gastric emptying in 10 patients with insulin-dependent diabetes mellitus and gastroparesis was studied. The emptying of liquids and solids was studied with intravenous erythromycin versus a placebo. Erythromycin shortened the gastric emptying time of both liquids and solids to normal. Oral erythromycin was also evaluated in studies at doses of 250-500 mg three times a day and four times a day. Though the improvement in gastric emptying rate is not as good as with the intravenous product, the overall improvement in total symptom scores are reported as significant. The major side effect of oral erythromycin therapy is dose-dependent cramps and abdominal pain, which is a major limiting factor to the use of this drug in many patients.

Domperidone

Domperidone is a peripheral D2-receptor antagonist that does not readily enter the blood-brain barrier and therefore exhibits very low incidence of central nervous system side effects. It improves gastrointestinal motility by inhibiting fundic receptive relaxation and enhancing antral contractions. There is also some action on the D2 receptors in the area postrema, leading to anti-emetic activity.

In a study by Silvers et al., 208 patients were enrolled in double-blind fashion to either domperidone or placebo, after a single-blind run in phase. More patients experienced a deterioration of symptoms on the placebo than on domperidone, by both investigator assessment and by patient diary scores (p = 0.025). Of the domperidone-treated patients, 51% had continued symptom improvement compared to 41% of the placebo-treated patients during the double-blind phase (p = 0.038). The associated health-related quality of life (HRQOL) scores for these patients were also evaluated. During the double-blind phase, the domperidone group maintained their high HRQOL scores, while the placebo group showed a significant decline in the physical component summary of the survey (p = 0.05).

The major problem associated with this drug has to do with the fact that domperidone enters the pituitary and prolactin is released, leading to hyperprolactinemia. Currently, the oral dosage of domperidone is not yet approved for use in the United States. It is available through a compassionate use protocol from Janssen Research Foundation, as it awaits FDA approval. The intravenous form of domperidone is no longer available. It was discontinued in the U.S. and worldwide markets due to adverse reports of cardiovascular events.

Cisapride

Cisapride stimulates gastrointestinal motility by facilitating acetylcholine release at the myenteric plexus via stimulation of the 5-HT-4 receptors. It does not penetrate the blood-brain barrier and thus does not exhibit the central nervous system or prolactin related side effects. In a study by Horowitz et al., the effects of cisapride on gastric emptying and gastrointestinal symptoms were studied in 20 insulin-dependent diabetic patients. After four weeks of therapy of either 10 mg four times a day of cisapride or placebo, gastric emptying of solid and liquid was faster in the cisapride group (p < 0.001). Upper gastrointestinal symptoms were also less after cisapride therapy (p < 0.05) versus no change with the placebo (p > 0.2). The major common side effects were abdominal cramping, diarrhea, and headache. Cisapride does not have any anti-emetic property, however it is indicated for gastroesophageal reflux, which is also a symptom of diabetic gastropathy. Overall, cisapride was a viable option for the management of diabetic gastropathy.

However, the manufacturer of cisapride, Janssen Pharmaceutica, stopped marketing cisapride as of July 2000 in the U.S. This decision was based on reports of serious cardiovascular toxicity associated with this drug. The cardiovascular side effects mainly were arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. The coadministration of this drug with azole antifungal agents, macrolide antibiotics, anti-HIV protease inhibitors, and some antidepressants were all contraindicated, since these drugs increased cisapride levels due to CYP3A4 drug interactions, leading to increased risk of QT prolongation and subsequent arrhythmias. Currently, the drug is available on an investigational limited access program from the pharmaceutical company. For the patients to receive cisapride, the following criteria must be met: 1) patients must have failed all standard therapeutic modalities; 2) undergo appropriate diagnostic evaluation, including radiologic examination or endoscopy; 3) baseline screening tests must be performed to screen for contraindicated risk factors; 4) the patient must be under the care of a gastroenterologist by consultation, if the prescribing physician is not a gastroenterologist; and 5) institutional review board approval, completion of a Form FDA 1572, and signed informed consent are necessary.

Combination Therapy

Combination therapy with two prokinetic agents is indicated if monotherapy fails. If combination therapy is indicated, it is best to combine drugs with different mechanisms of action. Metoclopramide and erythromycin may currently be the best option for dual therapy, since the other two agents are difficult to obtain. Also, the prokinetic and anti-emetic properties are combination in this dual therapy. Other options for dual therapy are metoclopramide and cisapride, and cisapride and domperidone. The combination of cisapride and erythromycin is contraindicated due to an interaction through CYP3A4 that potentiates cardiovascular side effects.

New Drugs in Research

Several new drugs are being investigated for the management of diabetic gastropathy. An uncontrolled non-randomized study by Koshiyama, et al. evaluated 21 patients with type 2 diabetics on mosapride therapy, a new prokinetic 5-HT4 receptor agonist. Patients were treated for a mean of 100.7 days at 15 mg per day of mosapride, which resulted in the disappearance of gastrointestinal symptoms in all subjects. Another study by Watkins et al. studied the effects of sildenafil on diabetic gastropathy in animal models. The effects of inhibiting the guanosine 3′,5′-cyclic monophosphate- (GMP-) specific phosphodiesterase 5 (PDE5) with sildenafil were tested on gastric emptying. Sildenafil reversed delays in gastric emptying in the diabetic mice, suggesting that increases in cGMP resulting from PDE5 inhibition produce pyloric relaxation and reduce outflow obstruction.

Other agents being studied include tegaserod,a 5-HT4 receptor partial agonist, and botulinum toxin. As further controlled human studies are conducted with these agents, new drugs may become available as treatment options.

Pharmacological Management of Nausea and Vomiting

Nausea and vomiting related to gastropathy can be managed with anti-emetics, in addition to prokinetic therapy. Traditional anti-emetics, such as phenothiazines, and newer, more potent agents, such as the 5-HT3 receptor antagonists (e.g., ondansetron), are available in various modes of administration. Parenteral routes are available for inpatient use, while suppositories are available for outpatient use when oral use is impaired. TABLE 7 lists the various agents that are available for treatment of nausea and vomiting.

Nonpharmacological Therapy of Gastropathy

There are very limited options available to patients whose condition does not improve with medical therapy. In patients who lose weight due to the severity of gastropathy, a jejunostomy tube is placed for feedings. Jejunostomy tube feeding has been shown to improve symptoms of gastropathy, glucose control, and gastric emptying rates.

A new technique available for these refractory patients is gastric pacing. In a study by McCallum et al., nine refractory patients were enrolled in a study in which four pairs of cardiac pacing wires were implanted on the serosa of the stomach and electric stimulation was performed for up to one hour before the meal and for up to three hours after the meal. After a mean period of 49 days, gastric emptying significantly improved to the extent that eight of the nine patients did not need to rely on jejunostomy tube feeds. Further studies are necessary to determine the exact role of this technique in the management of these patients. In patients with refractory nausea and vomiting, a study evaluating the effect of Chinese acupuncture has been reported. Acustimulation at P6, a traditional acupuncture point, reduced idiopathic nausea by approximately 40% in patients whose symptoms were refractory to drug therapy. The mechanism of action of this method is unknown, and more studies are required in this area.

Treatment goals in patients with diabetic gastropathy mainly focus on improving symptoms and quality of life and ensuring adequate nutritional intake. A stepwise approach, as outlined in TABLE 4, can be followed, depending on the specific symptoms and severity of the disease. Treatment initially focuses on glycemic control and dietary modifications before instituting pharmacological modalities.

Glucose Control: Adequate glucose control is vital but very difficult to maintain in this population. The goal of insulin therapy or the oral antidiabetic agents should be to maintain the plasma glucose level less than 200 mg/dL. Plasma levels less than 200 mg/dL have been associated with improved gastric myoelectrical activity and autonomic function. However, improved glycemic control does not always correlate well with improvement in the severity of symptoms.

Dietary Modification: Dietary changes are required in the management of these patients in many instances, due to the fact they are not able to tolerate the standard American Diabetes Association diets. Patients with diabetic gastropathy should have a diet that is low in fiber and digestible roughage, because there is an increased incidence of bezoar formation with these foods. They should also have a low-fat diet (<40 grams/day), since lipids slow gastric emptying rates. Small frequent meals, usually four to six times daily, should replace the regular three meals per day. The smaller meals will reduce the neuromuscular work of gastric emptying and will also result in a slower but steadier rate of delivery of nutrients into the small bowel for absorption. Replacing solid food with a liquid diet or even supplementing with a liquid diet will also assist in improving the symptoms in these patients.

For patients experiencing severe nausea and vomiting, Koch et al. describe a stepwise diet as a treatment approach. TABLE 5 lists various foods and the caloric requirements for patients who are experiencing nausea and vomiting due to diabetic gastropathy.

The term diabetic gastropathy refers to a number of neuromuscular dysfunctions of the stomach in patients with diabetes mellitus, including contractile and electrical abnormalities. These abnormalities may consist of gastric dysrhythmias, gastroparesis, antral hypomotility and dilation, antroduodenal coordination, and gastric tone dysfunction.

Pathophysiology and Mechanism of Diabetic Gastropathy

The mechanism of diabetic gastropathies is unknown. However, like other long-term complications associated with diabetes mellitus (nephropathy, retinopathy, and peripheral neuropathy), there are several proposed mechanisms that may be responsible, such as autonomic neuropathies, postprandial release of hormones, and glucose toxicity.

Vagal nerve impairment has been detected in patients with diabetes, and most likely plays a role in the development of diabetic gastropathy. Sympathetic vagal innervations inhibit vagal excitation. Vagal inhibition results in relaxation in the fundus, inhibition followed by contraction of the body, and relaxation of the pyloric sphincter and of the duodenum. Damage to inhibitory nerves may be the cause of increased gastric emptying of liquids, as well as the occasional pylorospasm. Loss of vagal tone and increased sympathetic nervous system activity have also been attributed to gastric dysrhythmias in some diabetic patients.

Postprandial hormone release of glucagon and pancreatic polypeptides, as well as the release of neurotransmitters, may be altered in diabetic patients. These responses can become complex issues, due to the variety of gastric responses stimulated by different foods.

Glucose toxicity may be a cause of end-organ neuromuscular dysfunctions. Hyperglycemia affects both intracellular metabolic pathways and membrane function in neural cells. After studying the effects of hyperglycemia in normal and diabetes patients, it was found that antral contractions in the postprandial state were significantly decreased during induced hyperglycemia.

The most severe neuromuscular abnormality associated with diabetic gastropathy is gastroparesis. Gastroparesis is often diagnosed when delayed emptying of food from the stomach has been documented. Gastroparesis is believed to result from gastric hypomotility or antroduodenal incoordination; however, autonomic nervous system dysfunction is not an absolute predictor of gastroparesis.

Epidemiology

Upper gastrointestinal symptoms such as nausea, vomiting, bloating, and abdominal discomfort are common occurrences in both type 1 and type 2 diabetes mellitus patients. It is estimated that these symptoms occur in approximately 50% of patients with type 1 diabetes and in 30% of patients with type 2 diabetes. One survey of diabetic patients revealed that 76% experienced chronic or recurrent gastrointestinal symptoms. Early satiety, fullness, and bloating are also common symptoms. As many as 50% of patients with type 1 diabetes have delayed gastric emptying.

Clinical Presentation and Diagnosis

Signs and Symptoms

Nausea and vomiting are among the most severe symptoms in patients who are diagnosed with diabetic gastropathy. Other symptoms include bloating, postprandial fullness and abdominal discomfort. Symptoms are often increased after the ingestion of solid foods. Slight dietary changes can often provide relief to patients who have meal-related symptoms. Some patients with delayed gastric emptying may be asymptomatic. The only clue that gastric neuromuscular dysfunction may be present is poor glucose control. Patients may experience episodes of hypoglycemia as a result of delayed gastric emptying. It should be noted, however, that all diabetes patients who experience upper gastrointestinal symptoms may not necessarily have gastroparesis. Therefore, other causes not related to diabetes (e.g., adverse drug reactions, pregnancy, central nervous system disorders) should be ruled out.

Diagnosis

Evaluations of diabetes patients presenting with any of the above symptoms should include a complete physical examination and medical history. Insulin and medication doses should be adjusted as needed to obtain optimal blood glucose control. Because certain medications can delay gastric emptying (TABLE 1), a medication history should be performed in order to rule out adverse drug reactions. Laboratory tests and evaluations of other organs that may cause gastrointestinal symptoms should also be performed before diagnosing a patient with gastroparesis. If these tests are found to be normal and blood glucose levels remain uncontrolled, then tests used to evaluate neuromuscular dysfunction should be considered (TABLE 2). Various tests are used to evaluate gastric emptying rate (TABLE 3), and there are advantages and disadvantages to each.

The most common technique is gastric scintigraphy. This noninvasive procedure involves the consumption of a radioisotope-labeled meal (usually scrambled eggs). The test is performed in the morning after an evening fast. Any pharmacotherapeutic agents that can accelerate or delay gastric emptying must be discontinued 48-72 hours before the procedure. Because hyperglycemia can cause a delay in gastric emptying, patients using insulin are advised to take only one half of their morning dose. Counts of the radioisotope are taken at intervals to evaluate the rate of gastric emptying. Both solid phase and liquid phase gastric emptying studies should be performed because some diabetic patients have an abnormally rapid rate of liquid phase emptying. Gastric emptying is reported as a percentage of the meal emptied, or the time to empty 50% of the meal. The normal range of solid phase gastric emptying is variable, and results can sometimes be affected by age, obesity, or even menstrual cycles.

Electrogastrography is a noninvasive test that measures fasting and postprandial gastric myoelectrical activity by placing electrodes on the skin in the epigastrium. Care must be taken to keep the patient still, since some artifacts in the electrogastrography signal are created by movement.

Breath tests are new techniques used to measure gastric emptying using C-labeled foods that estimate the rate of emptying of food from the C values in the expired breath. Ultrasonography is a noninvasive technique that measures the gastric emptying of liquids. Due to the complexity of the interpretation of the results, expertise is generally required for this test. Magnetic resonance imaging can also measure gastric emptying; however, this technique is often expensive and time-consuming. Antroduodenal tests are invasive and can be stressful to patients, and are often difficult to interpret.

Gestational Diabetes Mellitus: Risks, Complications, and Therapeutic Outcomes

Glucose is the principal nutrient that a mother supplies to her fetus through the placenta. This occurs by way of concentration-dependent mechanisms. What are the implications when those mechanisms go awry? Any degree of glucose intolerance with onset or first recognition during pregnancy is considered gestational diabetes mellitus (GDM). Whether diet alone or insulin is used for treatment and whether or not the condition persists after pregnancy, the definition still applies.

Prevalence

Approximately 135,000 cases of gestational diabetes mellitus are diagnosed annually, arising from ~4% of all pregnancies. The rate may be much higher in certain populations (e.g., Asians, Native Americans, Mexican-Americans, Pacific Islanders, Indians). Depending on the diagnostic tests and the population studied, prevalence may range from 1%–14% of all pregnancies.

Risks to Patient and Offspring

Women with GDM are at increased risk of developing diabetes, usually type 2, after pregnancy. An increased risk of type 1 diabetes is associated with markers of islet cell-directed autoimmunity. Factors, including obesity, that promote insulin resistance appear to contribute to the risk of type 2 diabetes. Because the prevalence of obesity is currently rising in developed countries (making pregravid overweight one of the most common high-risk obstetric situations), it is not surprising that even moderate overweight is a risk factor for gestational diabetes mellitus and hypertensive disorders of pregnancy. A recent study sought to determine the association between pregnancy-induced hypertension (PIH) and carbohydrate intolerance in pregnancy. After adjusting for maternal age, body mass index (BMI), parity, and ethnic origin, results showed a significant residual risk of PIH among individuals with gestational diabetes mellitus. The effects of GDM also may affect the patient’s offspring, resulting in an increased risk of obesity, glucose intolerance, and diabetes in late adolescence and young adulthood. Another recent study compared the pregnancy complications, obstetric outcomes, and perinatal outcomes between women with early-onset and late-onset gestational diabetes mellitus. Researchers concluded that women with an early diagnosis of gestational diabetes mellitus represent a high-risk subgroup. The likelihood of hypertension, higher glycemic values and the need for insulin, neonatal hypoglycemia, and perinatal deaths were greater in the women diagnosed with GDM during early pregnancy. Smoking in pregnancy also has been shown to direct parameters of glucose homeostasis toward gestational diabetes mellitus. During the last 4–8 weeks of gestation, an increased risk of fetal death may be associated with fasting hyperglycemia(>105 mg/dL). An increased frequency of the need for cesarean delivery has been documented and may result from changes in obstetric management and/or fetal growth disorders.

Risk Assessment

At the first prenatal visit, patients should undergo a risk assessment. Glucose testing should be done on those women with a high risk of gestational diabetes mellitus (a family history of diabetes, marked obesity, glycosuria, and personal history of GDM). Even if initial testing is negative for gestational diabetes mellitus, high-risk individuals should be retested between 24 and 28 weeks of gestation, the timeframe at which women of average risk are initially tested. A low-risk patient requires no glucose testing; however, she must meet all low-risk characteristics (TABLE 1) outlined in the Clinical Practice Recommendations 2000 of the American Diabetes Association (ADA). Due to infant macrosomia and a lifelong risk of developing diabetes associated with uncontrolled GDM, some researchers and clinicians recommend that all pregnant women be screened for carbohydrate intolerance.

Testing

When a fasting plasma glucose level >126 mg/dL or a casual plasma glucose level >200 mg/dL is confirmed on a subsequent day, the need for glucose challenge is unnecessary because these values meet the threshold for the diagnosis of diabetes. If this is not the case, one of two approaches should be followed to evaluate for gestational diabetes mellitus in women with average- or high-risk characteristics. The one-step approach may be cost-effective in high-risk patients/populations and consists of an oral glucose tolerance test (OGTT) without prior plasma or serum glucose screening. The two-step approach first measures the plasma or serum glucose concentration 1 h after a 50-g oral glucose load (glucose challenge test [GCT]). Then, on that subset of women exceeding the glucose threshold on the GCT, a diagnostic OGTT is performed. If a glucose threshold cutoff of >140 mg/dL is employed, approximately 80% of women with GDM may be identified. The yield increases to 90% by using a cutoff of >130 mg/dL. The diagnosis of GDM is based on an OGTT with either approach (a 100-g OGTT being better validated than a 75-g OGTT). A preparatory diet, thought to reduce false-positive diagnosis of GDM, does not significantly alter results of an OGTT and unnecessarily delays the diagnosis of gestational diabetes mellitus.

Monitoring

It appears that daily self-monitoring of blood glucose (SMBG) is superior to plasma glucose monitoring at periodic office visits. For those on insulin therapy, postprandial monitoring is superior to preprandial monitoring. Urine ketone monitoring may be helpful in determining sufficient caloric or carbohydrate intake, but urine glucose monitoring is not useful in gestational diabetes mellitus. Blood pressure and urine protein monitoring are useful in detecting hypertensive disorders. Techniques used to assess fetal demise depend on cumulative risk from GDM and other conditions, but are particularly appropriate when fasting glucose levels exceed 105 mg/dL or the pregnancy continues past term.

Management

When possible, individualized medical nutrition therapy (MNT) by a registered dietitian is recommended to all women with gestational diabetes mellitus. Balancing adequate calories and nutrients with maternal blood glucose goals is the key. For obese women (BMI >30), an intake of ~1,800 kcal/day can reduce hyperglycemia and plasma triglycerides with no increase in ketonuria. Concentrated sweets and excessive prenatal weight gain (>9 kg) should be avoided. Oral glucose-lowering agents are not recommended during pregnancy. The only pharmacological therapy known to reduce fetal morbidities when added to MNT is insulin. Human insulin is recommended to minimize antibody formation. At this time, the use of insulin analogs in GDM has not been adequately tested. Candidates for insulin therapy are identified based on maternal glucose levels (with or without an assessment of fetal growth characteristics) when MNT alone cannot maintain fasting whole blood glucose levels < or = 95 mg/dL or 2-h postprandial levels < or =120 mg/dL. A HbA1c concentration of <8% reflects good control in pregnancy. Exercise is beneficial and has been shown to lower maternal glucose concentrations. Gestation >42 weeks should be avoided, and ADA guidelines recommend delivery during the 38th week to decrease risk of fetal macrosomia. All patients and their families should be instructed in the subcutaneous administration of glucagon in case of severe hypoglycemia (plasma glucose <40 mg/dL, confusion, unconsciousness).

Postpartum Issues

Breast-feeding should be encouraged in women with GDM but may be associated with hypoglycemia in women with type 1. Patients with type 2 diabetes should be maintained on insulin (vs. oral hypoglycemics) while breast-feeding.

Uncontrolled gestational diabetes mellitus is associated with infant macrosomia and a lifelong risk of developing diabetes for both mother and offspring.

Conclusion

Gestational diabetes mellitus, when uncontrolled, is associated with infant macrosomia and a lifelong risk of developing diabetes for both mother and offspring. Obese women should be referred to a dietitian as part of preconception counseling (when possible) and followed dietetically and medically during gestation. The maintenance of normal body weight through MNT and exercise, avoidance of medications that increase insulin resistance (glucocorticoids, nicotinic acid), and reassessment of glycemia are important for long-term management. Offspring of women with gestational diabetes mellitus should be followed closely for the development of obesity and/or abnormalities of glucose tolerance. To reduce the risk of negative outcomes for patient and offspring, prompt diagnosis and aggressive management of GDM is critical. The pharmacist’s knowledge, monitoring capabilities, and counseling skills may be integrated at every stage of this illness to produce beneficial outcomes.

Immunobiology researchers from Yale University have identified an antigen that triggers development of Type I diabetes. Though Type 1 diabetes is classified as an autoimmune disease, the agent that stimulates the immune system to attack the pancreas hasn’t been identified until now.

Researchers used NOD (non-obese diabetic) mice for their studies, because mice have a version of Type I diabetes that’s extremely similar to the human version of this disease. For both mice and humans, the major contributing factor for the disease is genetic and involves a defect in an area called the major histocompatibility complex (MHC).

Through an unknown mechanism, the beta cells of the pancreas, which are responsible for making insulin, are attacked by the body as if they are foreign tissue. Defensive cells of the immune system, called CD8 T lymphocytes react to an antigen on the beta cells. The reaction takes the form of an attack, eventually destroying the beta cells, and thereby eliminating the body’s ability to make insulin.

Type I diabetes accounts for approximately 10 percent of all cases of diabetes and usually begins in childhood. Type II diabetes, which is much more common, is not an autoimmune disease but a dysfunction in the metabolism of glucose (sugar). Those with Type I need to take replacement insulin, whereas those with Type II diabetes may or may not need insulin.

While the cells that carry out the destruction had been identified previously, the antigen that sets off the reaction had not. Previous researchers proposed that the offending agent is insulin itself or one of its chemical precursors.

Now that the antigen has been identified, researchers hope to investigate the possibility of using it to desensitize the body, similar to the way allergy shots work. If this can be achieved, it may become possible to prevent Type I diabetes.

Patient-Specific Considerations

New antidiabetic agents were approved for the U.S. market. They are metformin, acarbose and glimepiride. Precautions associated with their use in the patient with renal insufficiency will now be described.

Metformin (Glucophage): The biguanide hypoglycemic agent metformin (Glucophage) is approved for use in the treatment of diabetes mellitus. Metformin is indicated for use as an adjunct to diet and/or a sulfonylurea agent when either of these treatment regimens does not control hyperglycemia. The mechanism of action for metformin differs from the sulfonylureas. Metformin decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and use and by decreasing hepatic glucose production. The primary concern with metformin is the development of lactic acidosis, especially in patients with renal insufficiency.

Metformin is a congener of phenformin, also a biguanide hypoglycemic agent, which was pulled off the market in the U.S. in 1977 due to concerns with phenformin causing lactic acidosis. Metformin has also been associated with causing lactic acidosis; however, the rate of metformin-associated lactic acidosis is one-tenth that of phenformin (one in 4,000 vs. one in 40,000 – 80,000). Cases of metformin-induced lactic acidosis have occurred primarily in patients with renal insufficiency and increased age.

The biguanides can induce lactic acidosis through an increase in cellular lactate production and a decrease in the hepatic metabolism of lactate. Diabetic patients are particularly at high risk for metformin-induced lactic acidosis due to their predisposition to renal dysfunction and impaired clearance of the drug, as well as their abnormal lactate metabolism. Due to the high risk of lactic acidosis in patients with renal dysfunction, metformin is contraindicated in patients with serum creatinine levels >1.5 mg/dL for males and >1.4 mg/dL for females.

The signs and symptoms of biguanide-induced lactic acidosis are nonspecific and include (in decreasing order of frequency) vomiting, somnolence, nausea, epigastric pain, anorexia, hyperpnea, lethargy, diarrhea and thirst. The hallmark of biguanide-associated lactic acidosis is severe lactic acidosis without evidence of hypoperfusion or hypoxia. The treatment of biguanide-induced lactic acidosis is support of the circulation and removal of the drug from the body.

Acarbose (Precose): Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. In patients with renal impairment, plasma concentrations of acarbose have been shown to be proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine >2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.

Glimepiride (Amaryl): Glimepiride is a new sulfonylurea blood glucose-lowering agent. Patients with renal impairment may be more sensitive to the glucose-lowering effect of glimepiride. Thus, in patients who have renal dysfunction, a starting dose of 1 mg once daily followed by appropriate dose titration is recommended. Pharmacist’s Involvement

With the provision of pharmaceutical care, the pharmacist should be closely involved with the diabetic patient in renal failure and can offer the patient assistance in several health-care areas, including the management of his/her diabetes. The pharmacist can educate the patient about diabetes, its complications and the importance of controlling blood glucose levels through proper diet, exercise and use of medications. The proper use of a blood glucose machine to monitor home blood glucose levels can also be taught by the pharmacist, as well as frequently measuring and monitoring the patient’s blood glucose. Since hypertension can worsen renal function, the pharmacist should also periodically monitor the patient’s blood pressure and teach the patient how to measure his or her blood pressure at home. In monitoring blood glucose and blood pressure, the pharmacist also needs to assess the patient’s diet, activity level and health status.

In addition, the pharmacist should evaluate the patient’s drug therapy — assessing not only the medication’s efficacy, but also the medication’s effect on blood glucose, blood pressure, electrolytes, lipids and renal function. The patient’s optimal drug therapy, lifestyle, blood glucose, blood pressure and renal function must be monitored to prevent further complications.Summary

Renal failure seriously impacts the quality of life and management of the diabetic patient. There are numerous patient considerations that the pharmacist must evaluate. Additionally, an understanding of the effect renal failure has on insulin greatly assists the pharmacist who is providing pharmaceutical care to the diabetic patient with renal insufficiency.

Patient-Specific Considerations

Acute Renal Failure: Although reported infrequently, the diabetic patient in acute renal failure may also experience changes in insulin requirements and should be carefully monitored. In 1978 Weinrauch et al. described the development of acute renal failure in 12 insulin-dependent diabetes mellitus (IDDM) patients who received radiographic contrast material for a cardiac catherization. All of these patients had chronic renal insufficiency at baseline. Eleven of these patients demonstrated a need for less insulin during their acute renal failure. Eight of the 12 patients experienced a hypoglycemic reaction. In a case report described by Naschitz et al., a diabetic patient went into acute renal failure secondary to post – streptococcal glomerulonephritis. While in acute renal failure, the authors noted that the patient’s insulin requirements decreased from 56 to eight units daily. Subsequently, as the patient’s renal function improved, his insulin requirements increased. Although not relevant to this patient, other considerations to keep in mind when monitoring the diabetic patient with acute renal failure would include the patient’s daily caloric intake and the occurrence of emesis.

Pharmaceutical Care Decision Making Pharmacologic Agents: As described earlier, uremia may affect insulin activity and the ability of a patient to maintain optimal glucose control. The selection of the oral pharmacologic agents used to control blood glucose must also be evaluated. Prolonged half-lives of the agents or their metabolites and the potential for adverse drug events with the accumulation of these agents in renal failure are two key issues to consider. Chlorpropamide is a first-generation sulfonylurea. However, its use in patients with renal insufficiency should be avoided. It has a half-life of 24 – 48 hours, which is significantly increased with renal failure. This leads to the potential for a severe hypoglycemic reaction. Also, chlorpropamide use has been associated with hyponatremia and water retention.

Glyburide is a second-generation sulfonylurea that has a relatively long half-life. Approximately 50% of glyburide is excreted unchanged in the urine. It also has metabolites with hypoglycemic activity. It too has been associated with causing hypoglycemic reactions in patients with renal failure and its use should be avoided in patients with renal insufficiency.

Glipizide is another second-generation sulfonylurea. However, unlike glyburide, glipizide is cleared more quickly and its metabolites are inactive. The dose does not have to be decreased in renal insufficiency and thus is safe to use in diabetic patients with renal failure. Concerns associated with the use of the other oral sulfonylureas are described in Table 3.

Patient-Specific Considerations

Barbosa et al. described a prospective randomized study that evaluated over five years the effect of tight glycemic control in insulin-dependent diabetes mellitus (IDDM) patients to prevent diabetic nephropathy in the transplanted kidneys of recipients who were transplanted secondary to diabetic nephropathy. Patients were randomly assigned to receive either standardized or maximized insulin treatment. Results indicated that the patients who were given the maximized insulin therapy demonstrated significantly less renal pathology closely associated with the diabetic nephropathy. As with the DCCT trial, the results of this study also noted a higher incidence of hypoglycemia in the group with tighter glucose control.

Patient-Specific Considerations

There are many factors that influence the clinical management of the diabetic patient with renal insufficiency. Several common patient considerations that the pharmacy practitioner should evaluate are described in this section.

Hypertension: Hypertension is frequently seen in diabetic patients, especially in those with decreased renal function. In addition, the progression of renal dysfunction is closely related to the elevation in blood pressure. Consequently, it is important that the effects of antihypertensive medications be considered before selecting the most appropriate agent.

Christlieb proposed a step approach to antihypertensive therapy in diabetics with or without concurrent diabetic complications. Recommended step 1 agents include angiotensin-converting enzyme inhibitors (ACE) or calcium channel blockers. The angiotensin-converting enzyme inhibitors are preferred antihypertensive agents in diabetic patients for several reasons. Recent studies have shown that the ACE inhibitors in combination with captopril and enalapril decrease the amount of microalbuminuria in both hypertensive and normotensive diabetics with microalbuminuria or persistent proteinuria. These results suggest that angiotensin-converting enzyme inhibition may be beneficial, even at the earliest stage of diabetic nephropathy. In addition, Ravid et al. concluded that ACE inhibition offers long-term protection against the development of nephropathy in NIDDM patients who have microalbuminuria, and it stabilizes renal function in previously untreated patients with impaired renal function. Other beneficial qualities of the angiotensin-converting enzyme inhibitors include no adverse effects on glucose metabolism or lipid levels and a reduction in the occurrence of impotence.

Calcium channel blockers are also efficacious for the hypertensive diabetic patient and have no inherent adverse metabolic effects. If hypoaldosteronism is present or if the patient is hyporeninemic, a calcium channel blocker may be preferred as step 1 therapy. If an ACE inhibitor or a calcium channel blocker does not sufficiently decrease the blood pressure, a diuretic can be added as step 2 therapy. If edema is present, a diuretic should be included in step 1 therapy. Thiazide diuretics are effective until the patient’s creatinine clearance declines to 40 – 50 mL/min, at which time a loop diuretic may be more effective.

In addition to beneficial effects, adverse effects of antihypertensive medications must also be considered when evaluating the diabetic patient’s drug therapy. Adverse effects of angiotensin-converting enzyme inhibitors in patients with renal failure include hyperkalemia and further compromise of renal function. Hypertensive patients with renal disease, specifically severe renal artery stenosis, have developed increases in serum creatinine and BUN after reduction of blood pressure with ACE inhibitors. Therefore, renal function and potassium levels should be monitored during the first few weeks of ACE-inhibitor therapy. Impaired renal function can also decrease elimination of certain ACE inhibitors. Dosage reduction may be necessary for quinapril, benazepril, ramipril and lisinopril in patients with declining renal function.

Diuretics have been shown to adversely affect electrolyte, cholesterol and glucose levels. Thus, serum electrolyte, glucose and lipid levels should be monitored frequently in diabetic patients with renal dysfunction. In patients with renal dysfunction, potassium-sparing diuretics can cause severe hyperkalemia and should be avoided. Beta-blockers may adversely affect glucose and lipid metabolism. Blockade of beta receptors can cause diminished symptoms of hypoglycemia — primarily palpitations, anxiety and tremors — as well as delays in recovery from hypoglycemia. However, cardioselective beta-blockers (e.g., metoprolol, atenolol) may have fewer adverse effects than do noncardioselective beta-blockers (e.g., propranolol) for most hypertensive patients.

Increases in triglyceride levels and decreases in high-density lipoprotein cholesterol levels are also associated with beta-blockade. However, beta-blockers with intrinsic sympathomimetic activity or alpha-blocking activity do not adversely affect lipids. In addition, beta-blockade may also aggravate peripheral vascular disease, which is a diabetic complication.

Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) in the United States. The relationship between kidney function and insulin activity has important implications to the pharmacist providing pharmaceutical care to the diabetic patient with renal disease. Approximately one third of the body’s insulin is removed by the kidneys. Insulin is filtered at the glomerulus and largely resorbed in the proximal tubules. Additionally, the extraction of insulin by the kidneys is greater than the glomerular filtration rate, suggesting that much of the insulin is degraded in the renal cells. As a result, the patient in renal failure may require less insulin secondary to a decreased metabolism of insulin by the kidney. Additionally, in a state of uremia, the patient may exhibit insulin resistance. Hypoglycemia and hyperglycemia have also been observed in previously non-diabetic patients. This pathophysiology, as well as patient-specific considerations, make the management of the diabetic patient with renal disease complicated. Such patients often require intense pharmacologic management, as well as routine monitoring and follow-up.

Pathophysiology of Uremia and Insulin

As a patient’s renal function deteriorates, it is often clinically observed that blood glucose control becomes more challenging. Once a patient’s creatinine clearance declines to less than 15 mL/min, the clearance of insulin diminishes and the half-life is prolonged. As a result, the insulin requirements for the patient may decrease.

The uremic patient may exhibit insulin resistance. This is partially the result of an impaired glucose uptake by the muscle. The diminished insulin sensitivity and glucose metabolism appear to be associated with uremic toxins and have been shown to be reversible with dialysis. These abnormalities also appear to be improved with a low-protein diet. Gin et al. studied the impact of a low-protein diet on insulin sensitivity of tissue in insulin-dependent diabetes mellitus (IDDM) patients with chronic renal failure. The results of this study indicate that when uremic toxin production is decreased with a low-protein diet, tissue sensitivity to insulin improves. Interestingly, the number of insulin receptors and the affinity of insulin to the receptors do not appear to change as a result of uremia.

There appear to be two types of alterations in insulin secretion that are observed in the uremic patient. The first type of patient presents elevated insulin levels and normal glucose levels. The second type of patient presents normal or low insulin levels and elevated glucose levels. It is thought that the patient with normal glucose levels has beta cells in the pancreas that are able to secrete enough insulin to overcome the insulin resistance. The second type of patient does not have this capability. This may explain why some uremic patients become glucose intolerant and some remain normal.

Hyperparathyroidism and vitamin D deficiency have been postulated to affect insulin secretion. Hyperparathyroidism is a common complication observed in patients with renal failure. Mak reviewed the management of hyperparathyroidism in the ESRD patient by studying the results of animal and human studies that evaluated the effects of parathyroid hormone and vitamin D deficiency on insulin secretion. In his review, Mak wrote that elevated parathyroid hormone causes an inhibition of the beta cells of the pancreas to secrete insulin. This results in the clinical observation of glucose intolerance. Additionally, vitamin D deficiency may alter insulin secretion in the ESRD patient. Mak noted that the results of human studies have shown that when active vitamin D is administered, glucose intolerance is normalized. Allegra et al. studied the effect of active vitamin D, calcitriol, in 17 uremic patients. The results of their study showed that when calcitriol was given, the early phase of insulin secretion was improved. Their results also showed that glucose-induced insulin secretion may be inhibited by calcitriol deficiency. The beta cells of the pancreas appeared to be directly affected by the calcitrol. Clinical conditions influenced by an altered insulin metabolism are described in Table 1.