sign in sign up
<<
Home , Acarbose

A New Era in Diabetic Agents: Hope for Diabetics

By

Janice M. Sherer, RN, BSN

A manuscript submitted in partial fulfillment of the requirements for the degree of

MASTER IN NURSING

Washington State University Vancouver College of Nursing Intercollegiate Center for Nursing Education January 1999 A New era in Diabetic Agents: Hope for diabetics

By Janice M. Sherer BSN Washington State University Vancollver Novelnber 1998

ABSTRACT

In 1997, there were an estimated 15.7 million Diabetics in the United States alone, with an additional 798,000 new cases diagnosed each year. Mellitus is characterized by abnormal homeostasis, resulting in chronic . Prolonged hyperglycemia has been associated with retinopathy, peripheral neuropathy, autonomic neuropathy, coronary artery disease, peripheral vascular disease, and nephropathy. As

Primary care providers, we need to seek out better and more effective treattnents for this devastating disease. This paper will discuss: pharmacodynamics, , current research, adverse effects, and possible treatment options of diabetic agents lispro, , glilnepiride, , and acarbose.

,. TABLE OF CONTENTS

Abstract . 2 Man.uscript . 4 Table 1 . 14 Figu.re 1 . 15 Reference List . 16 Introduction

In the United States alone, there were an estimated 15.7 lnillion cases of diabetes in

1997, with an additional 798,000 new cases diagnosed each year (National Institute of

Health, 1998). Diabetes Mellitus, one of the most COlnmon and devastating diseases known to man, is characterized by abnormal glucose homeostasis, resulting in chronic hyperglycemia. Prolonged hyperglycemia has been associated with retinopathy, peripheral neuropathy, autonomic neuropathy, coronary artery disease, peripheral vascular disease, and nephropathy (McPhee, Lingappa, Ganong, and Lange, 1995). These ailments can lead to further complications ofrenal failllfe, infection, blindness, stroke, Inyocardial infarction and amputation. A consistent reduction in blood glucose levels has been shown to directly reduce the incidence ofthese devastating complications (Riddle and Karl, 1995). The American

Diabetes Association has estitnated tllat for every one dollar spent on preventing hyperglycemia, seven dollars are saved in the long term treatment ofthe complications of diabetes (Manley, 1997).

In addition to the problem of chronic hyperglycemia, there is also the problem of secondary failure. It is estimated that once diagnosis has taken place in type II diabetes, all mono treatments tend to succeed at first, and then tend to lose efficacy over time. This process is known as secondary failure (Riddle et al., 1995). The advent of new drug options have given far more clloices for combinations to llelp combat secondary failtlfe, and increase our ability to keep tighter blood glucose control for diabetics, and therefor, reduce complications. This article will discuss: phannacodynamics, phannacokinetics, current research, adverse effects, and the possible treatment options of lispro, troglitazone, , metformin, and acarbose. Lispro

PhannacodynaInics

Insulin lispro (Humalog) is an analog ofrecombinant DNA origin. Lispro stimulates insulin receptors, which leads to phosphorylation of multiple intracellular signaling molecules. Intracellular signals cause translocation of glucose transporters from the endosomal compartment to the plasma membrane where they increase glucose uptake (Page,

Curtis, Sutter, Walker and Hoffman, 1997). Lispro differs from human insulin in having lysine at the B28 position and proline at the B29 position.

Pharmacokinetics

Lispro is more rapidly absorbed, produces higher peak concentrations and lowered postprandial gllicose levels. Lispro peaks in 30 to 90 minlltes (Grimley, 1997). Lispro's half­ life is one hour (as shown in table 1). Compared with , the peak serum insulin concentration of is three times higher, time to peak is 4.2 times faster, the absorption rate constant is double, and the duration of action is half as long (Campbell, R.

Campbell, L., and White, 1996).

Current research

p'flutzner et.al, (1996) evaluated overall long-term glucose reduction by measuring

HbA1c and found no significant difference between regular human insulin and lispro. The same study noted that there were significant decreases in 1 and 2 hour postprandial glucose excursions in patients treated with lispro. However, Zinman, Tildesley, Chiasson, Tsui, and

Strack (1997) found a significant decrease in HbA1c after their subjects changed from regular human insulin to lispro for three months. Researchers found consistently that HbA1c was equal or reduced with use of lispro. Jehle et aI., (1996) found lispro increases the number and affinity of insulin receptors on circulating monocytes to a level similar to that observed in healthy subjects. Jehle et at,

(1996) concluded that the above phenomenon is related to lispro's more physiological pharmacokinetic profile. Additionally it was detennined that lispro decreased overall insulin dosage (P'flutzner, et aI., 1996). Pampanelli, et aI., (1995) detennined that IDDM subjects with some residual pancreatic beta cell function are ideal candidates for prandial use oflispro because they can maintain near normoglycemia longer after the subcutaneous analog injection related to their residual endogenous insulin secretion. Until the release oflispro, no preparations were available to provide the high concentrations needed to stimulate postprandial glucose disposal (White, 1996). Schemthaner, et ale (1998), concluded that using insulin lispro immediately postprandial is as effective as regular insulin 40 minutes before meals, which gives diabetics anotller treatment option.

Campbell et aI., (1996) concluded that indeed lispro does reduce the incidence of hypoglycemic events, particularly nighttime episodes because of it's increased elimination time. Garg et aI., (1996) detennined type I diabetics .had a lower number ofhypoglycemic events and better postprandial controls.

Lispro also has a diminished tendency to self-associate (Fineburg et al.,1996). In a year long randomized trial the immunogenicity of insulin lispro and regular human insulin were compared. Lispro was shown to be less likely to create antibodies than regular human insulin (Fineburg et al.,1996). Lispro was detennined to be an excellent alternative to regular human insulin in diabetics with substantially increased human insulin antibodies. Apparently, the structural difference between lispro and human insulin molecules prevented ljspro from binding to the human insulin antibodies (Lahtela, Knip, Paul, Antonen, and Salmi, 1997).

Kumar et.al, (1996) also found that lispro would be useful in managing patients with an allergy to human insulin. Lispro's onset of action is not changed by injection sites which allows more potential sites for subcutaneous injection with assllfed rapid response (Braak et al., 1996). Patient satisfaction seems to be improved in patients receiving lispro because injections can be given immediately before mealtime, with no need to wait before eating tllereby increasing flexibility for patients (P' flutzner et al., 1996). In quality oflife studies conducted on subjects using lispro, the subjects (N=942) listed: the ability to eat immediately after injection, better control, more freedom, and feeling better were all advantages when using lispro

(Grimley,1997). Some treatment options oflispro are noted in figure 1.

Adverse effects

Campbell et ala (1996), noted that lispro is very similar to hwnan insulin with reference to dose, toxicity, adverse effects, and drug interactions. The major side effect of both human insulin and lispro is (as shown in table 1), which appears to be reduced with lispro use. Weight gain is a possible side effect of regular human insulin; it is unclear at this time if lispro has the same effect.

Troglitazone

Phannacodynamics

Troglitazone (Rezulin) is a derivative that lowers insulin resistance by improving the action ofendogenous insulin in the liver, skeletal muscle, adipose tissue and peripheral tissue. It increases the activity of hepatic enzymes, which catalyze glycogenosis and suppress gluconeogenesis, and increases the activity of enzymes that catalyze muscle glycogenosis (parke-Davis, 1997). Troglitazone's unique mechanism is dependent on insulin for activity.

Phannacokinetics

Troglitazone's peak plasma levels are reached within 2-3 hours following oral administration. Troglitazone's plasma half-life ranges from 16-34 hours (as shown in table

7 1). Troglitazone is absorbed rapidly by oral route and food enhances absorption by 30-85%, thus it is imperative that tlus drug be administered witll food. Troglitazone is extensively metabolized into inactive metabolites (Parke-Davis,1997).

Current research

The patient population to most benefit from this dnlg are type II diabetics who are using> 30 units ofinsulin a day with a HbAlc >8.5. These figures represent insulin resistance which is this drug's primary target (Parke-Davis, 1997). Unlike , troglitazone does not increase insulin secretion, and is not active in insulin deficient patients

(Parke-Davis, 1997). Therefore this drug is not appropriate for type 1 diabetics. This same quality also makes hypoglycemic episodes with this drug in mono therapy very unlikely.

Graf, Xi, Hsuell, & Law (1997) demonstrated that troglitazone decreased the development of neointimal hyperplasia and atherosclerosis. Troglitazone partially restored the basal heart rate and cardiac work in diabetic subjects to nearly control values.

Troglitazone treatment had cardioprotective effects on basal post ischemic cardiac function

(Shimabukuro et at 1996). Troglitazone exerts multiple effects on cardiomyocytes. It was suggested that an increased glucose supply may be beneficial for the diabetic heart and that troglitazone improves insulin action on cardiac tissue (Bahr et aI., 1996). Ghazzi et at

(1997), demonstrated that patients (N=154) treated with troglitazolle did not show an increase in cardiac mass or an increase in cardiac function impairment.

Troglitazone also seems to have positive effects on lipid profiles of patients receiving the drug. Reductions in total cholesterol and total triglycerides were noted. Additionally, there was an increase in high-density lipids (Dunaif et a1. 1997). Kumar et at (1996), also found reductions in cllolesterol and total triglycerides in clinically significant numbers. Dose adjustment for patients with renal dysfunction is not necessary (Parke-Davis, 1997). Elderly patients tolerate this drug well, provided they have good liver function (Parke-Davis, 1997).

Troglitazone was found to have positive benefits for women with polycystic ovary disease (Dunaif, Scott, Finegood, Quintana, and Whitcomb, 1996). Polycystic ovary disease is believed to be linked to insulin resistance (Dunaif et al.,1996).Troglitazone resulted in the resumption of ovulation in some premenopausal anovulatory women with insulin resistance

(parke- Davis, 1997).

Adverse effects

Troglitazone Dletabolite concentrations with chronic liver disease were increased from 30 % to 400%, compared to healthy subjects without hepatic dysfunction. Therefore, it is recommended that this drug be used cautiously in patients with hepatic diseases (parke­

Davis, 1997) (see table 1). Additionally, elevated liver function tests have been observed in

2.2% ofpatients on troglitazone (parke-Davis, 1997).

This drug is not recommended in breast feeding women, as it is excreted in breast milk in animal studies (parke-Davis, 1997). There is a tendency for neutrophil COlmts to drop at very high dosing ofthe drug (over 800 mg) (Grimley, 1997). A slight decrease in white blood cells, hemoglobin, and hematocrit were observed in clinical trials, yet these changes were not associated with clinical effects (Parke-Davis, 1997).

Glimepiride

Pharmacodynamics

Glimepiride (Amaryl) is a second-generation similar to

(Glyburide). Glimepiride blocks adenosine triphosphate and potassium channels in the pancreatic beta cells. This causes depolarization and sllbsequent activation of voltage sensitive calcium channels and increased insulin release (page et al.,1997). Glimepiride may also increase insulin sensitivity in peripheral tissues (Grimley, 1997).

Q Phannacokinetics

Glimepiride's approaches 100%. It is highly protein bound at 99.5%.

Peak time is 2-3 hours. The serum half-life is about 5-9.2 hours (Table 1). Glimepiride is metabolized into two Inajor metabolites, Ml and M2. These metabolites are excreted in the urine and feces (Grimley, 1997).

Current Research

Many of the studies done on glimepiride compare and contrast it with it's popillar predecessor glibenclamide. Glimepiride has some significant advantages in cardiovascular effects over glibenclamide according to Pogatsa (1996). Patients taking glimepiride are reported to have a decreased incidence of fatal myocardial infarct and the development of ventricular fibrillation than glibenclamide (pogatsa, 1995).

Glimepiride produced fewer hypertensive events, better coronary blood flow, lower coronary resistance, increased mechanical activity, and more stable potassium levels than glibenclamide the same glucose lowering levels (Geisen, Vlegh, Krause, & Papp, 1996).

Glimepiride also has a more potent hypoglycemic action than glibenclamide

(Wolffenbuttel &Graal, 1996). This has been speculated to be related to an extrapancreatic effect in the fonn of hepatic glucose uptake. Dills& Schneider, (1996) fOlmd that although there were similar decreases in fasting plasma glucose with both drugs, there was a lower incidence of hypoglycemia with glimepiride than glibenclamide. Cheta, Lim, Chan,

Kunakom, and Charles (1995), detennined that glimepiride has preventive effects against the onset of diabetes in animal studies, even in treatment periods of as short as forty days, and decreases the severity of islet intlamlnation. Some treatment options for glimepiride are shown in figure 1.

10 Adverse effects

Rosenkranz (1996) demonstrated that patients with significant renal impairment

(N=31) were more likely to experience hypoglycemic effects from glimepiride as the elimination ofthe metabolites was impaired. These metabolites have similar phannacological activity as the parent drug. Phannacokinetic data on sulfonylureas are generally inconsistent in cirrhotic patients (Rosenkranz, 1996). These studies imply that the phannacokinetics of glimepiride are altered in renal disease, but not seriously affected in patients with liver diseases (Rosenkranz, 1996). Qi, et al.(1995), suggests that glimepiride has a direct inhibitory effect on platelet aggregation.

Glimepiride is not without it's adverse effects (Table 1). These include: hypoglycemia, dizziness, asthenia, headache, and nausea, although these occur in less than

2% ofrecipients (Grimley, 1997).

Metfonnin

Pharmacodynamics

Metfonnin is an oral antihyperglycemic agent and not a hypoglycemic agent.

Metfonnin. enhances the effects ofinsulin on liver, muscle, and adipose tissue (Riddle et a!.,

1995). Metfonnin lowers blood glucose by er.thancing insulin stimulated glucose transport in skeletal muscle. It also reduces hepatic glucose production in type II diabetics that may be secondary to a reduction in glllconeogenesis (Riddle et aI., 1995).

Phannacokinetics

The peak time ofmetfonnin is 2-3 hours, and the half-life is 17.6 hours (Table 1).

Bioavailability is 50 to 60%. Metfonnin is excreted llnchanged in the urine and does not undergo hepatic metabolism or biliary excretion (Drug facts and comparisons, 1996) Current Research

Metfonnin (Glucophage) is a drug related to phenfonnin, a drug introduced in 1957 which can calIse fatal lactic acidosis and was removed from the market (White, 1996). The mechanism of action differs frOID sulfonylureas because it does not increase insulin secretion, does not cause hypoglycemia, and does not induce weight gain (White, 1996).

Metfonnin reduced fasting glucose levels an average of 58 mg! dl and HbAlc an average of

1.8 % compared to diet plus placebo (Defranzo and Goodman, 1995). Metfonnin is associated with a reduction in triglyceride levels, low-density lipids and cholesterol.

Metfonnin is associated with increased high-density lipids, and modest weight loss (Riddle et al., 1995). Some treatment options for metfonnin are shown in figure 1.

Adverse effects

Metfonnin does have adverse effects, which are relatively common. Patients treated with metfonnin llad 30% more reports of abdominal bloating, nausea, cramping, a feeling of fullness and (Table 1) than did patients receiving a placebo (Bristol-Meyers Squibb,

1996). These side effects are usually self-limiting, transient and can be mitigated by starting with a low dose and titrating up slowly, as well as taking the medication with food (White,

1996).

Metfonnin is contraindicated ill patients with renal dysfunction (senun creatinine

>1.5 mg /dl in males or>1.4 mg/dl in females). Hepatic dysfunction is also a contraindication relating to the association of hepatic dysfunction with acidosis. Metfonnin is also contraindicated for patients with alcoholism or binge drinking (White, 1996). Metfonnin should be withheld from patients that are at risk for renal failure or acute acidosis. Conditions

SUCll as acute myocardial infarction, exacerbation ofcongestive heart failure, or major

1'. surgery can predispose a patient to renal failure or acute acidosis. (Bristol-Meyers Squibb,

1996).

Naivaiz, Cleveland, Gaines, and Chan (1998) suggested that metformin also be withheld for at least 48 hours prior to the test if the patient is undergoing procedures using iodinated contrast and has renal impairment as indicated by an abnonnally high creatinine.

The same study group suggested that metfonnin need not be withheld ifrenal function is normal. However, Rasuli and Hammond (1998) found that it is commonly the contrast media that causes renal failure, and ifmetfonnin is continued in the presence ofrenal failure, lactic acidosis will occur. It is their recommendation that metfonnin be withheld for 48 hours post procedure, and renal function studies done to rule out renal failure before the metfonnin is resumed. It would seem reasonable in light ofthese studies to do renal function tests both pre and post procedure to ensure renal function is not ilnpaired.

Acarbose

Pharmacodynamics

Acarbose (Precose) is a competitive reversible inhibitor ofpancreatic alpha amylase, which hydrolyses complex to . In the small intestine, alpha and the brush border membrane are responsible for the digestion of complex to glucose or . By inhibiting these enzymes, acarbose is capable of delaying digestion of complex and subsequent absorption of glucose, which results in a smaller rise in postprandial blood glucose concentrations.

Acarbose inhibits the metabolism of to glucose and . Acarbose is a competitive inhibitor ofthe alpha glucosjdases ( Corporatlon, 1995). Ranganath,

Norris, Morgan, Wright & Marks, (1998) noted that there is a significant delay in gastric emptying which also contribute s to the therapeutic affect ofacarbose.

1':l Pharmacokinetics

The peak time of acarbose is 2-3 hours, and half-life is 8-9 hours (Table 1). The primary route for elimination of unchanged acarbose (51 %) is in the feces. Systemic bioavailability is 1-2%. The relnainder of acarbose appears to be degraded by digestive enzymes or microorganisms in the (Ahr,1989).

Current Research

Further effects of acarbose are a decreased beta pancreatic response to meals, and influences on gut hormone secretion and plasma lipid levels (Salvatore & Giugliano, 1996).

A reduction in very-low-density lipids, triglycerides and low-density lipids have also been noted (Bayer Corporation, 1995). However, Chiasson et aI., (1994) found no changes in lipid levels, so it is unclear if decreasing lipid levels is a consistent effect of this drug. An efficacy study by Spengler & Cagatay, (1995) cited therapelltic benefit and good tolerability.

HbAlc and capillary glucose were found to be consistently lower than t.he control group

(Colomer, Cotaia, & Baena, 1995).

Acarbose would appear to be helpful for type I and type II diabetics. Fasting, postprandial glllcose and HbAl c levels were all decreased for both type I and type II diabetics (Spengler & Cagatay, 1995). Reduction in flllctuations of glucose levels throughout the day, may llelp control type 1 diabetics with "brittle diabetes" (Salvatore & Giugliano,

1996). Acarbose was found useful as a fust line drug in type II diabetics who did not get. good glucose control with diet alone (Hanefeld, 1991). Additionally, 50% of subjects

(N=316) were shown to respond to acarbose regardless of their concurrent antidiabetic medication (Chiasson et a1., 1994). Acarbose is not assoc1ated w1th weight ga1n or hypoglycemic effects (Yee & Fong, 1996). Acarbose does not appear to be contraindicated for patients with decreased renal function. Hepatic deficiency has not been documented as a contraindication.

14 Acarbose may prevent dumping syndrome. Dumping is a result of gastric resection when the physiological regulatory system has been physically altered. This change restllts in a hyperosmolar chyme entering the intestine, drawing vascular fluids into the gastric lumen causing hypotension. Acarbose decreases the oSlnolarity by decreasing the breakdown of carbohydrates, leading to improvement of symptoms (Mimura, Tsukakubo, Tsujiguchi, &

Hoshikawa, 1996). Some treatment options for acarbose are shown in figure 1.

Adverse effects

Adverse effects ofacarbose include , borborygmus, abdominal distention, abdominal pain, and loose stools (Table 1). Most of these side effects decrease with time or may be alleviated by a reduction in dose (Bayer Corporation,1995). Rachman & Turner,

(1995) published one case study where acarbose was thought to have reduced digoxin levels, but more infonnation on tIlat possible side effect has not been noted. An elevation in senun transaminase levels has been reported in 15% ofpatients being treated with acarbose. This appears to be dose related, more common in females, and were generally asymptomatic and reversible (Bayer Corporation, 1995). Patients with GI disturbances such as Crohn's disease, or with a history of abdominal obstruction should avoid acarbose usage (Bayer Corporation,

1995).

Conclusion

Until recently, tile treatment of diabetes had changed little in almost 45 years (White,

1996). We are now entering a new frontier in the history of diabetic treatment, which provides us with many options and dilemmas. Primary care providers can look forward to more infonnation regarding the new diabetic agents, and look with hope to the future for even better and more effective treatments for this devastating disease.

loC\ Treatment Strategies With so many new agents available, where shall treatment begin? White (1996) suggested a proposed treatment plan for type 11 diabetics. Ifinadequate response after 2...3 months have passed; move on to the next step Figure 1

Step 1: Evaluation and nonpharmacological approaches: diet, exercise and education. This step should be continued throughout the other phases.

Step 2 : Oral monotherapy

Obese patients Non-Obese patients Consider Metformin Consider Glimepiride or Acarbose

Step 3: Obese patients Step 3: Non-Obese patients combination oral therapy who have failed Acarbose therapy: Metfonnin and glimepiride or Glilnepiride or other sulfonurea other sulfonylurea For those patients should be considered. For patients that are within 20 mgldl of fasting who have failed sulfonurea monotherapy: plasma glucose goal with Metformin consider adding Metformin or Acarbose monotherapy, Acarbose rather than a sulfonylurea should be considered.

Step 4: Two options; 1 a single or evening bedtime injection ofNPH or lente, while continuing oral therapy, sulfonylureas have been most widely studied. 2 initiate three times a day dosing ofLispro with a single oral agent. This form of therapy should offer good postprandial glycemic control without the insulin meal...tirning issues.

Obese patients with inadequate Non-Obese patients with response to Metfonnin IAcarbose inadequate response to Acarbosel therapy, the Acarbose should be sulfonylurea combination, the Acarbose dropped and insulin added. should be stopped and insulin started Non-Obese patients on Metformin/ Sulfonylurea conlbinations, the Metformin Should be removed and insulin started

Step 5: Insulin therapy Lispro should be considered in place ofregular insulin.

11\ SiU1l1lll8lY Ta ble 1 Agent I Halflifel Mechanism of action Adverse effects! Comments Total daily dose Peak time Contraindications (Mg) Lispro Halflife An used as a Adverse effects Use for type I and IT diabetics (Humalog) 1 hour replacement for endogenous Hypoglycemia Rapid absorption Peak time insulin, increasing glucose Possible Lower post prandial glucose Variable 30-90 min transport across fat and Weight gain Reduction in insulin dosage muscle cell membranes Contraindications Reduced hypoglycemic events None reported Less immunogenicity More injection sites

Troglitazone Halflife Improves the action of Adverse effects Use for type IT diabetics only (Rezulin) 200- 16-34 endogenous insulin in the Neutrophil COWlts drop 99010 boWld to plasma 600 lug/Day hours liver) skeletal muscle, and with high dosing Administer with food Peak time adipose tissue. Increases (800mg) Useful for insulin resistance 2-3 ho1,1fs hepatic enzymes that Elevated liver ftmction tests May decrease insulin usc catalyze glycogenosis and Cardioprotective effects suppresses gluconeogenesis, Contraindications Decreased lipid profiles and increases l11uscle Hepatic dysfunction Useful in patients with renal glycogenosis Breast feeding itnpainnent May result in resumption of ovulation

Glimepiride Halflife Stimulates secretion of Adverse effects Use for type 11 diabetics only (Amaryl) 5-9 ~ insulin trom functional beta Hypoglycemia 990/0 protein bolUld Single therapy Hours cells in the , may Dizziness Asthenia Less cardiovascular activity 1-4 mg/Day Peak also increase insulin Headache, Nausea Less hypoglycemia Adjooct to insulin 8 time sensitivity in the peripheral Inhibits platelet aggregation May have preventive effects mg/Day 2-3 hours tissues Decreases inflammation of islet cells COlltraindications Renal impainnent

Mctfonnin Halflife Enhances the effects of Adverse effects Usc for type II diabetics only (Glucophage) 17.6 Hours insulin on the liver, muscles Alxlominal bloating, nause~ Does not cause hypoglycemia 1000-2500 Peak time and adipose tissue, and cramping) diarrhea Does not cause weight gain Decreased (mg)/Day 2-3 hours reduces hepatic glucose Lipid profiles production Contraindications Renal dysfullction, Hepatic dysfunction Alcoholism Major surgery Cardiac dysfunction Hold for iodinated cOlltra~ procedures

Acarbose IIalflife Acarbose is a competitive Adverse effects Use for type I and type IT diabetics (Precose) 8 -9 hours reversible inhibitor of Flatulence Lowers lipid profiles 150-300 (mg) I Peak tinle pancreatic alpha amylase Borborygnlus May improve dumping syndrome Day 2-3 hours which hydrolyses conlplex Alxlominal di&1ention, Does not cause weight gain or slurches to oligosttCClUtride. abdomiIutl pain, loose stools hypoglycemic events Acarbose delays digestion of Elevations in serwn conlplex carbohydrates and transaminase snbsequent absorption of glucose. Contraindications Crohn's disease GI disturbances, or prone to obstruction

17 References

Ahr, H.J. (1989). Pharmacokinetics ofacarbose: Part 1: Absorption, concentration in plasma, metabolism and excretion after a single administration in of [14C]acarbose to rats, dogs and man.

Arzneim Forsch Drug Res, 39 1254 -1265.

Bahr, M., Spelleken, M., Boch, M., von- Holtey, M., Kiehn, R, & Eckel, 1. (1996). Acute and chronic effects oftrog1itazone (C8-045) on isolated rat ventricular cardiomyocytes. Diabetologia 39 (7) 766-74. [On­ line]. Medline Unique identifier 96414040.

Bayer Corporation ( 1995). Package literature for Precose.

Braak, E. W., Woodworht, 1. R., Bianch~ R, Cerimele, B., Erkelens, D. W., Thijssen, 1. H., & Kurtz,

D. (1996). Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.

Diabetes care, 19 (12) 1437-40. [On-line] Accession number 1997009234.

Bristol-Meyers Squibb.(1996). [Package literature for Metformin].

Campbell, R. K., Campbell, L. K., & White, J. R. (1996). Insulin Lispro : It's role in the treatment of diabetes Inellitus. ArulalS ofPhannacothera,py, 30 (11) 1263-71. [On-line] Medline . Unique identifier 97070483

Cheta, D. M., Lim, 1., Chan, E. K., Kunakom, T., & Charles, M. A. (1995). Glimepiride-induced prevention ofdiabetes and autoimmune events in the BB rat. Life Science ,57 (24). 2281-90. [On-line] Medline.

Unique identifier 96080984.

Chiasson, 1., Josse, R. G., Hunt, 1. A., Palrnason, C., Rodger, W., Ross, S. A., Ryan, E.A., Tan, M. H.,

& Wolever, T. (1994). The efficacy ofAcarbose in the treatment ofpatients with non-insulin-dependent Diabetes

Mellitus. Annals ofIntemal Medicine ,121 (12) 928-34.

Colomer M. 1., Cotain~ T. M. D., & Baen~ M. 1. (1995). Acarbose in the metabolic control of infanto-juvenile onset diabetes mellitus. Annals of Internal Medicine, 12 (8). 382-7. [On-line] Med.line. Unique identifier 96397080.

Defranzo, R.A., Goodman, A.M., and the muJti-center Metformin study group (1995). Efficacy of metformin in NIDDM patients. The New England Journal ofmedicine,333 541-49.

Dills, D. G., & Schneider, 1. (1996) . Clinical evaluation ofGlimepiride versus glyburide in NIDDM in a double-blind comparative study. Hormone and Metabolic Research, 28 (9) 426-9.[On-line]. Medline . Unique identifier 97068789.

Drug facts and comparisons ( 50th ed.). (1996) S1. Louis, MO : Wolters Kluwer .

lR Dunai£: A., Scott, D., Finegood, D., Quintanna, B., & Whitcomb, R (1996) . The insulin sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolim, 81 (9) 3299-306. [On-line] Medline . Unique identifier 96378524.

Fineberg, N. S., Fineberg, S. E., Anderso~ 1. H., Birkett, M A., Gibso~ R G., & Hufferd, S. (1996).

Immunologic effects of insulin lispro Lys (B28) pro (B29) human insulin in IDDM and NIDDM patients previously treated with insulin. Diabetes, 45 (12) 1750-4 . [On-line] Medline. Unique identifier 97081079.

Garg, S. K., Carmain, 1. A., Braddy, K. C., Anderson, 1. H., Vignati, L., Jennings, M. K., & Chase, H

P. (1996). Pre-meal insulin analog insulin lispro verses humulin R insulin treatment in young subjects with type I diabetes. Diabetic Medicine, 13 (1) 47-52 . [On-line] Medline. Unique identifier 96352128 .

Geisen, K., Viegh, A., Krause, E. & Papp 1. G. (1996) . Cardiovascular effects of conventional sulfonylureas and Glimepiride. Hormone and Metabolic Research, 28 (9) 496-507 [On-line] Medline. Unique identifier 97068799.

Geis~ovel, F., Frorath, B., & Brabant, G. (1996). Acarbose reduces elevated testosterone serum concentrations in hyperinsulinaemic premenopausal women: A pilot study. Human Reproduction, 11 (11).

2377- 81 . [On-line] Medline. Unique identifier 97135577 .

Ghazzi, M. N., Perez, 1. E., Antonucci, T. K., Driscoll, 1. H., Huang, S. M., Faja, B. W., & Whitcomb,

R. W. (1997). Cardiac and glycemic benefits oftroglitazone treatment in NIDDM. Diabetes, 46 (3) 433-9. [On­ line] Medline . unique identifier 97184297.

Glucophage package insert, Bristol-Meyers Squibb, Princeton, NJ.

Graf, K., Xi, X. P., Hsueh, W. A., & Law, R. E. (1997) . Troglitazone inhibits angiotensin I and induces

DNA synthesis and migration in vascular smooth muscle cells. FEBS Lett, 400 (1) 119-21. [Online] Medline.

Unique identifier 97153235.

Grirrdey, G. (1997) . Formulary review: Glimepiride. Unpublished review.

Grimley, G. (1997) . Formulary review: Insulin Lispro. Unpublished review.

Grimley, G. (1997). Formulary review: Troglitazone. Unpublished review.

Hanefeld, M. (1991). Therapeutic potentials of Acarbose as a first-line drug in NIDDM insufficiently treated with diet alone. Diabetes care, 14 732-737.

Jehle, P. M., Fussgaenger, R D., Kunze, D., Dolder, M., Warchol, W., & Koop, I. (1996). The human insulin analog insulin lispro improves insulin binding on circulating monocytes ofintensively treated insulin­

lQ dependent diabetes mellitus patients. Journal of Clinical Endocrinology & Metabolism, 81 (6) 2319-27 . [On­ line] Medline. Unique identifier 96241800 .

Kumar, S., Boulton, A. 1., Beck-Nielsen, H., Berthezene, F., Muggeo, M., Persson, B., Spinas, C. A.,

Donoghue, S., Lettis, S., & Stewart- Long, P. (1996). Troglitazone an insulin action enhancer improves metabolic control in NIDDM patients. Diabetologia 39 (6) 701-9. Unique identifier 96375455 .

Lahtela, J. T., Knip, M., Paul, R., Antonen, J., & Salmi, J. (1997) . Severe antibody- mediated human insulin resistance: successful treatment with the insulin analog lispro : A case report . Diabetes care, 20 (1) 71-3

. [On-line] Accession number 1997009252 .

Manley, A. (1997) . Combination therapy for NIDDM. Unpublished article.

McPhee, S. 1., Lingappa V. R ., Ganong, W. F., & Lang (1995). Pathophysiology ofdisease: An introduction to clinical medicine Norwalk, Connecticut :Appleton & Lange.

Mimura, M., Tsukakubo, T., Tsujiguchi, N., & Hoshikawa, T. (1996) The effect of alpha- glucosidase inhibitors on burning epigastralgia in dumping syndrome: A case report . Masill, 45 (3) 337-9. [On-line]

Medline. Unique identifier 96308433.

National Institute ofHealth. (1998). Publication NO. 98-3926.

Navias, S., Cleveland, T., Gaines, P., & Chan, P. (1998). Clinical risk associated with contrast angiography in metfonnin treated patients: a clinical review. Clinical Radiology, 53 (5) 342-4.

Page, C., Curtis, M., Sutter, M., Walker, M. & Hoffman, B. (1997). Integrated Pharmacology. London:

Mosby.

Pampanelli, S., Torlone, E., lalli, C., Del Sindaco, P., Ciofetta, M., Lepore, M., Bartocci, L., Brunettti,

P., & Bolli, G. B. (1995) . Improved postprandial metabolic control after subcutaneous injection of short acting insulin analog in 100Mofshort duration with residual pancreatic beta cell function. Diabetes Care,18 (11) 1452­

9. [On-line] Medline. Unique identifier 96352404.

Parke-Davis. (1997). [package literature for Rezulin].

P'flutzner, A., Klustner, E., Forst, T., Schulze-Schleppinghof( B., Trautmann, M. E., Haslbeck, M.,

Schatz, H., & Beyer, 1. (1996). Intensive insulin therapy with insulin lispro in patients with type I diabetes reduces the frequency of hypoglycemic episodes. Experiments in Clinical Endocrinology & Diabetes, 104 (1)

25-30. [On-line] Medline . Unique identifier 96351120.

Pogatsa G. (1995). Potassiwn channels in the cardiovascular system. Diabetes Results in Clinical

Practice, 28 . S91-8. [On-line] Medline. Unique identifier 6791700

?O Pogasta G. (1996). What kind ofcardiovascular alterations could be influenced positively by oral antidiabetic agents. Diabetes Results in Clinical Practice, 31.827-31. [On-line]. Medline. Unique identifier

97018021.

QI, R, Ozaki, Y., Satoh, K., Kurot~ K., Asazum~ N., Yatomi, Y., & Kume, S. (1995). Sulfonylurea agents inhibit platelet aggregation and [Ca2+]i elevation induced by arachidonic acid. Biochemical

Pharmacology, 49, (12) 1735-9. [On-line] Medline. Unique identifier 953211971.

Rachman 1., Turner RC., (1995). Drugs on the horizon for treatment oftype n diabetes. Diabetes

Medicine~ (6) 467-78. [On-line]. Medline. Unique identifier 95376921.

Ranganath, L., Norris, F., Morgan, L., Wright, 1., & Marks, V. (1998). Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its anti-hyperglycemic effect Diabetic

Medicine,15 (2): 120-4.

Rasuli , P., & Hammond, D.I., (1998) Metformin and contrast media: Where is the conflict? Canadian

Association ofRadiology Journal, 49 (3) 161-6.

Riddle, M. C. (1996) . Conlbined therapy with a sulfonylurea plus evening insulin~ Safe, reliable, and becoming routine. Hormone and Metabolic Research, 28 (9) 430-3 . [On-line] Medline. Unique identifier

97068790.

Riddle, M. C., & Karl, D. M. (1995). Systematically combining treatments for type II diabetes.

Practical Diabetology, (Sept) 2-5 .

Rosenkranz, B. (1996) . Pharmacokinetic basis for safety ofglimepiride in risk groups ofNIDDM patients. Hormone and Metabolic Research, 28 (9) . 434-9. [On-line] Medline. Unique identifier 97068791.

Salvatore, T., & Giugliano, D. (1996). Pharmacokinetic-pharmacodynamic relationships ofAcarbose.

Clinical Pharmacokinetics, 30 (2) 94-106. [On-line} Medline . Unique identifier 97063026 .

Schemthaner, G., Wein, W., Sandholzer, K., Equiluz-Bruck, S., Bates, P., & Birkett, M. (1998).

Postprandial insulin lispro: A new therapeutic option for type one diabetic patients. Diabetes Care, 21 (4) 570-3.

Serrano, 1. S., Jimenez C. M., Serrano, M. 1., Balboa, B. (1996) A possible interaction ofpotential clinical interest between digoxin and Acarbose. Clinical Pharmacology & Therapeutics, 60 (5) 589-92 . [On line] unique identifier 97096009.

Shimabukuro, M., Higa, S., Shinzato, T., Nagamine, F., Komiya, 1, & Takausu, N. (1996).

Cardioprotective effects ofTroglitazone in streptozotocin-induced diabetic rats. Metabolism, 45 (9) 1168-73).

[On-line] Medline. Unique identifier 96374924.

1.1 Spengler, M. & Cagatay, M. (1995). The use of Acarbose in the primary- care setting: Evaluation of efficacy and tolerability ofAcarbose by postmarketing surveillance study. Clinicallnvestigative Medicine, 18 (4)

325-31.

White, 1. R (1996). The pharmacologic managelnent of patients with type IT diabetes mellitus in the era ofnew oral agents and insulin analog. Diabetes spectrum, 9 (4) 227-234 .

Wolffenbuttel, B. H., & Graal, M. B., (1996) . New treatments for patients with type II diabetes melitis.

Postgraduate Medical JournaL 72 (853). [On-line]. Medline . Unique identifier 97099637.

Vee, H. S., & Fong, N. T. (1996). A review ofthe safety and efficacy ofacarbose in diabetes mellitus .

Pharmacotherapy.. 16 (5) 792-805 . [On-line] Medline. Unique identifier 97042877.

Zinman, B., Tildesley, H., Chiasson, 1. L., Tsui, E., & Strack, T. (1997). Insulin lispro in CSll: Results ofa double-blind crossover study. Diabetes, 46 (3) 440-3. [On-line] Medline. Unique identifier 97184298 .

"