Prior to that time, the diagnosis of diabetes was an Insulin treatment had transformed diabetes from an in Type 2 diabetes patients, the University …
Pharmacotherapy Perspectives
by Lorna Goshman, RPh, CSPI
Column Editor: Lee Vermeulen, MS, RPh, Director, Center for Drug Policy, University of Wisconsin Hospital and Clinics
Diabetes:
New oral medications, new attitudes
n 1998, we celebrated the 75th anniversary of the presentation of the Nobel Prize in Medicine to Dr Frederick Banting and Professor JRR Macleod for their discovery of insulin They, along with Professor JC Collip and Charles Best, then a medical student, treated their first diabetic patient, a 14-yearold boy weighing 64 pounds, in January of 1922 1 Continuing on insulin therapy, the young man went on to gain weight, recover, and live until the age of 27, when he died of pneumonia Prior to that time, the diagnosis of diabetes was an automatic death sentence, so that the prolongation of life and the possibility of pregnancy and childbirth in diabetic women seemed miraculous The vision of a disease conquered began to fade as diabetic patients lived longer, but developed complications like blindness, end-stage kidney disease, neuropathies and early atherosclerosis Insulin treatment had transformed diabetes from an acute illness to a chronic illness that gradually
produced lifedisrupting long-term debility see Table 1
Table 1
Clinical Complications of Type 1 Diabetes 2 Complication Visual impairment Blindness Renal failure Amputation Stroke Myocardial infarction Cumulative Prevalence in Patients 14 16 35 12 10 25
Clinical studies
Practitioners through the years have considered the most probable cause of long-term problems to be prolonged hyperglycemia and have debated whether improved glycemic control could lead to improved outcomes The debate was difficult to resolve while glucose testing was done with urine, because until home blood glucose monitoring became available in the late 1970s, tight control of blood glucose could not be attempted without risking hypoglycemic episodes 3 Nonetheless, the first large-scale trial to examine the importance of glycemic control in Type 2 diabetes patients, the University Group Diabetes Program UGDP, was completed by 19704 Five treatment arms compared diet plus placebo to standard and variable insulin doses and to two oral medications, tolbutamide Orinase and the biguanide phenformin, later removed from the US market Although glucose control was better in the insulin group where doses were titrated
according to fasting glucose levels, no treatment group had a clear advantage in microvascular or cardiovascular outcomes After a mean follow-up of 55 years, the trial was prematurely terminated because of unexpected excess cardiovascular mortality in the tolbutamide group5,6 Two implications followed from UGPD: that improved glucose control alone did not improve health,
and there was a possibility that sulfonylureas produced direct cardiovascular damage As a consequence, practitioners had no good evidence for many years that strict glucose control was clinically beneficial, and patients were not encouraged to work toward well-defined metabolic goals Evidence that intensive therapy does improve health finally came from the DCCT, the Diabetes Control and Complications Trial7 Beginning in 1983, almost 1500 Type 1 diabetes patients between the ages of 13 and 39 were recruited and followed for an average of 65 years Two cohorts were studied: patients with early disease and no retinopathy, and those with the disease for 1 to 15 years with mild-to-moderate retinopathy Patients were randomized to conventional twicedaily insulin injections versus three or more daily injections or insulin
administered by pump, with glucose monitoring at least four times daily Intensive therapy lowered hemoglobin A 1c to 7, compared to 9 in the conventional groups In the first group with early disease, the risk of retinopathy was decreased by 76 by intensive treatment, and in the second group, the progression of retinopathy was decreased by 54 In addition, the incidence of nephropathy and neuropathy was much lower in the intensive treatment groups see Table 2 Because Type 2 patients develop the same complications and disabilities, it is logical to believe that improved glucose control in Type 2 patients would also produce similar benefits
Lorna Goshman is a Clinical Pharmacist in the Center for Drug Policy and Clinical Economics, Department of Pharmacy, University of Wisconsin Hospital and Clinics, and is a Certified Specialist in Poison Information in the UW Hospital Poison Control Center
The information given and views expressed herein do not necessarily reflect the opinions of PSW, its Board or members
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Pharmacotherapy Perspectives
Table 2
Decrease In Diabetic Complications with Intensive Therapy in DCCT 7
Complication Retinopathy Cumulative incidence early disease Sustained progression later disease Severe or proliferative Laser treatment Nephropathy Microalbuminuria Proteinuria Neuropathy Reduction in Incidence 76 54 47 56 39 54 60
Confirmation of this hypothesis first came from a six-year study at Kumamoto University of 110 Japanese patients with Type 2 diabetes 8 In a trial design based on DCCT, two groups of subjects, those with no retinopathy or microalbuminuria and those with discernible retinopathy and urinary albumin less than 30 mg/24 hours, were randomized to conventional twice daily insulin vs multiple daily injections with the goal of normalizing glucose levels throughout each day At the baseline, patients with an average age of 50, already on twice-daily intermediate-acting insulin, had hemoglobin A 1c values hovering around 90 Those who continued on conventional therapy maintained a hemoglobin A1c of 94 during the study, compared to 71 for the patients in the intensively-treated groups As in the DCCT, intensive therapy decreased the incidence and progression of retinopathy, nephropathy and neuropathy From the study results, the authors defined appropriate metabolic
goals as hemoglobin A1c less than 65, fasting blood glucose below 110 mg/dl and two-hour postprandial blood glucose below 180 mg/dl Patients within these parameters showed no microvascular disease progression Meanwhile, a much larger multi-center study was in progress in Great Britain The UKPDS, the United Kingdom Prospective Diabetes Study, began recruiting patients in 1977 to find out if tight glucose control in Type 2 patients over a protracted observation period could lead to better long-term outcomes 9 Between 1977 and 1991, over 5000 newly-diagnosed patients, with an average age of 54 years, entered the study They were randomized to intensive vs conventional management, defined by glycemic goals of maintaining fasting blood sugar below 6 mmol/L 107 mg/dl or below 15 mmol/L 270 mg/dl respectively Conventional patients all began with diet therapy, while the intensively treated patients were randomized to therapy with insulin or oral sulfonylureas chlorpropamide or glyburide, or later, glipizide
If patients in either group at regular check-ups exceeded glycemic targets, they received stepped therapy until goals were attained Those on diet alone were randomized to insulin,
sulfonylureas, or if markedly overweight, to metformin Those already on sulfonylureas added metformin or insulin, and those on insulin titrated their dosage to goals Median daily insulin doses at 3, 6, 9, and 12 years in fact increased from 22 units up through 28, 34, and 36 units Earlier publications from the UKPDS study had documented that in Type 2 patients, after diagnosis, pancreatic beta-cell function declines over the years, so that patients can expect periodic revisions in their therapy9 Conventionally managed patients in the study maintained a hemoglobin A1c of 79, while intensively managed patients lowered theirs to 70 Because hypertension is commonly associated with Type 2 diabetes, a hypertension study was embedded into the ongoing glucose control study beginning in 198711,12 Over 1100 hypertensive patients already enrolled in UKPDS were randomly assigned to antihypertensive drug treatment with atenolol or captopril vs less strict blood pressure control without the help of either beta-blockers or ACE inhibitors In the tight management group, target blood pressure was less than 150/85 mm Hg, and other agents were added if captopril 50 mg po twice daily BID or atenolol
100 mg po daily QD proved to be insufficient Unlike DCCT, which focused on microvascular complications, UKPDS also set out to look at macrovascular consequences like atherosclerosis and true end-points like cardiovascular death9 After statistical analysis of the study groups, made even more complex by therapeutic overlap between groups, the investigators concluded that the intensively treated patients stayed well longer Microvascular end-points were reduced 25, any diabetes-related end-point was reduced by 12, diabetes-related death by 10, and all-cause mortality by 6 The risk of macrovascular death was not reduced Weight gain at the ten-year point was 3 kg for conventional patients and 6 kg for intensively treated patients Those on insulin gained 7 kg Neither insulin nor sulfonylureas increased cardiovascular mortality see Table 3 In the nested study where tight blood pressure management was studied in the UKPDS patients, patients on atenolol or captopril achieved a mean blood pressure of 144/82 mm Hg compared to 154/87 mm Hg in the controls11,12 The reduction in blood pressure was accompanied by a reduced risk of complications and death due to diabetes The risk reduction was 37
in microvascular end-points, 24 in diabetes-related end-points, 32 in diabetes-related death, with a non-significant reduction in all-cause mortality Strokes declined by a remarkable 44 and risk of heart failure dropped by 56 There was also a 34 decrease in two-step progression of retinopathy and a 47 reduced risk of visual loss see Table 3
Journal of the Pharmacy Society of Wisconsin Jan/Feb 1999 23
Pharmacotherapy Perspectives
Treatment of hyperglycemia alone may not reverse all disease complications This study illustrates the importance of direct treatment of hypertension in addition Similarly, aggressive treatment of hyperlipidemias will probably result in better long-term health in Type 2 patients
Guidelines
Ever since DCCT, both patients and practitioners have used the evidence from the trial to regain control of disease management Increasingly, every treatable complication has generated a management goal Diabetes educators have encouraged patients not only to carry out beneficial lifestyle changes, but
Table 3
to take ownership of their own treatment programs Table 4 presents a listing of major diabetic complications and their related disabilities, with selected
monitoring parameters In our own state, where over 300,000 people have diabetes, the Wisconsin Diabetes Advisory Group has published the Essential Diabetes Mellitus Care Guidelines, based on American Diabetes Association Guidelines and incorporating regional consensus13 The guidelines with supporting documents and references may be found on the Internet at http:// wwwdhfsstatewius/health/indexhtm A wallet card version is also available for patients through the Wisconsin Diabetes Control Program at 608-261-6871 See next page
Medications
Diabetes Complications in Type 2 Patients Treated Intensively vs Conventionally in UKPDS 9,11
Risk Reduction with Intensive Blood Glucose Control UKPDS 33 12 10 6 25 No reduction 7 9 Risk Reduction with Intensive Hypertension Control UKPDS 38 24 32 18 not significant 37 34 44 56
Endpoint Any Diabetes-Related Endpoint Diabetes-Related Death All-Cause Mortality Microvascular Endpoints Macrovascular Endpoints Stroke Heart Failure
Table 4
Management of Diabetes Complications
Complication Hyperglycemia Care and Monitoring Parameters Blood glucose Hemoglobin A1c Diet, Exercise, Medication Self-Management Training Dental Exams Blood Pressure Renal
Function Tests Urinalysis Lipid Panels Eye exams Foot and Skin Care Complication-Related Disabilities Myocardial Infarct Stroke Renal Failure Peripheral Vascular Disease Vision Problems Periodontal Disease Myocardial Infarct Stroke Renal Failure Myocardial Infarct Stroke Peripheral Vascular Disease Visual Impairment Blindness Peripheral Vascular Disease Non-Healing Tissue Ulcers Amputation Gastroparesis Impotence
Hypertension Hyperlipidemia Retinopathy Neuropathy
Since 1994, there has been an explosion of new oral medications in four new therapeutic categories for Type 2 diabetes in the US14 In addition to sulfonylurea hypoglycemics, we now have a non-sulfonylurea hypoglycemic, repaglinide Prandin,two alpha-glucosidase inhibitors GSIs, acarbose Precose and miglitol Glyset, a biguanide, metformin Glucophage, and the first thiazolidinedione TZD, troglitazone Rezulin15 In addition, insulin lispro Humalog, a new rapid-acting, recombinant insulin analog with a short duration has been introduced It can be injected immediately prior to meals and is physically compatible with isophane NPH and extended zinc ultralente insulins The new classes of agents have different sites of action so
that they can function not only as alternatives to sulfonylureas, but in combination with each other to delay the need for insulin therapy in Type 2 patients Because the GSIs, metformin, and troglitazone do not stimulate
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Pharmacotherapy Perspectives
Essential Diabetes Mellitus Care Guidelines - Wisconsin
Care is a partnership between the patient, family and the diabetes team: the primary care provider, diabetes educator, nurse, dietitian, pharmacist and other specialists Abnormal physical or lab findings should result in appropriate interventions For particular details and references for each specific area, please refer to the companion supporting documents
Concerns
General Recommendations Glycemic Control
Care/ Test
Diabetes focused visit Review management plan, problems and goals on control and complications Review meds and frequency of low blood sugar Self blood glucose monitoring, set review goals HbA1C - Goal: 70 or 1 above lab norms If HbA1c 80, action is recommended Weight/BMI/Growth Urinalysis Urine for microalbuminuria: If higher than 30 mcg/mg creatinine or 30 mg/24 hours, initiate ACE
inhibitor unless contraindicated Creatinine clearance protein Smoking Lipid profile Adult goals: Triglycerides 200 mg/dL HDL 35 mg/dL LDL 100 mg/dL optimal goal Blood pressure Adult goal: 130/85 Childrens goal: below 90 of ideal for age Aspirin prophylaxis unless contraindicated Exercise/Diet/Weight Goals Dilated eye exam by ophthalmologist or optometrist Inspect feet, with shoes and socks off Comprehensive lower extremity sensory exam Assess contraception/discuss family planning Preconception consult Management
Frequency
Type 1: every 3 months Type 2: every 3 - 6 months or more often based Each focused visit; revise as needed Each focused visit 2 - 4 times/day or as recommended Every 3 - 6 months Each focused visit At diagnosis and yearly Type 1: Begin with puberty or after 5 years duration, then yearly Type 2: At diagnosis, then yearly Yearly, after microalbuminuria 300mg/24 hour Counsel to stop every visit Children: If 2 years, after diagnosis once glycemic control is established - repeat yearly if abnormal Follow National Cholesterol Education Program NCEP guidelines Adults: yearly If abnormal, follow NCEP guidelines Each focused visit Age 40
years Each focused visit Type 1: After 5 years duration; then yearly Type 2: At diagnosis, then yearly Each focused visit: stress need for daily self-exam Yearly At diagnosis and yearly during childbearing years 3 - 4 months prior to conception Some medications eg, oral antidiabetic agents, ACE inhibitors, angiotensin II blockers, etc are contraindicated during pregnancy At diagnosis, then every 6 - 12 months or more as indicated by the patients status At diagnosis; then Type 1if age 18 years, every 3 - 6 months or if age 18 years, every 6 -12 months Type 2every 6 - 12 months; or as indicated by the patients status Yearly for adults and children 6 months Once for adults and children 2 years
Kidney Function
Cardiovascular
Eye Care Foot Care Pregnancy
Self-Management Training Nutrition Therapy
By diabetes educator Curriculum to include the 15 key areas of the national standards for diabetes self-management education By a dietitian To include areas defined by the American Dietetic Associations Nutrition Practice Guidelines Influenza vaccine Pneumococcal vaccine
Immunizations
The entire guideline package, including supporting documents, references, quality improvement
guidelines, and tools, is available at http:/ /wwwdhfsstatewius/health/indexhtm or through the Wisconsin Diabetes Control Program, 608-261-6871
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Pharmacotherapy Perspectives
Figure 1 Sites of Action of Diabetes Medication
insulin secretion, they have a lower potential for causing hypoglycemia They are effective only in the presence of insulin, in patients with some beta-cell function With these agents, weight gain, and possibly hyperlipidemia and hypertension, are less likely Long-term use of metformin causes minimal weight gain, even in overweight patients16 In contrast, the UKPDS patients using insulin gained 15 pounds during the course of the study9 Figure 1 illustrates the sites of action of currently available antidiabetic agents
Repaglinide Prandin
Repaglinide is a meglitinide, the non-sulfonyl part of the glyburide molecule15 It stimulates insulin production in pancreatic beta cells at higher plasma glucose levels, like the sulfonylureas It is rapidly acting and is cleared quickly by hepatic metabolism to inactive metabolites When it is given 15 minutes prior to meals, one-hour postprandial glucose levels are
lowered, although fasting glucose may not change significantly It is indicated for treatment of Type 2 diabetes in patients whose glucose is not well controlled by diet and exercise If its effect is inadequate as monotherapy, repaglinide may be combined with metformin For dosing, administration, and monitoring information, see Table 5 Its most troublesome adverse effect is hypoglycemia
Acarbose Precose
Acarbose was the first alpha-glucosidase inhibitor GSI to
26 Jan/Feb 1999 Journal of the Pharmacy Society of Wisconsin
be approved in the US15 The GSIs are competitive inhibitors of intestinal alpha-glucosidases, enzymes that hydrolyze sucrose and dietary starches into absorbable subunits Inhibition of enzyme action significantly slows intestinal carbohydrate absorption and decreases postprandial plasma glucose peaks The GSIs do not affect lactose metabolism Acarbose as monotherapy usually has only a modest effect on hemoglobin A1c, but can increase the hypoglycemic effects of sulfonylureas or insulin Initial dosage is 25 mg TID three times daily with meals, with gradual increases to minimize adverse effects like flatulence, abdominal discomfort, and diarrhea As dosage is gradually
increased, periodic assessment of one-hour postprandial glucose can be used as a dosage guide Acarbose may be combined with any of the other oral agents In one recent study, 90 Chinese Type 2 patients whose blood sugar was inadequately controlled on maximal doses of sulfonylureas plus metformin were treated with acarbose 100 mg TID for 24 weeks17 Compared to placebo, acarbose produced significantly greater reductions in postprandial glucose, hemoglobin A1c, and body weight in this group, when added to the other two agents The nuisance side effects of acarbose abate over time Dose-related elevations of alanine amino transferase ALT and aspartate amino transferase AST have occurred in some patients, most frequently at doses greater than 100 mg TID Laboratory abnormalities have usually been asymptomatic and reversible on drug discontinuation, but the manufacturer
Pharmacotherapy Perspectives
Table 5
New Oral Diabetes Medications
Drug Repaglinide Prandin Acarbose Precose Dose 05-2mg TID-QID Max QD 16 mg 25mg TID to 50 TID if 60kg 100TID 60kg 25mg TID to 50-100 TID 500mg BID-TID; 850mg BID-TID Max QD 2500mg 400mg QD up to 600mg; in combos, 200mg QD Dose in Renal Dysfunction Use
caution in changing doses Not in patients with CrCl 25 or creatinine 2 Administration 15 min prior to meals Take with the first bite of the meal Pregnancy Risk Factor C Monitor FBG HGBA1c Adjust Q 7 days Periodic 1-hr postprandial glucose; ALT, AST Adjust Q 4-8 weeks HGBA1c Q 3 mo Adjust Q 4-8 weeks FBG HGBA1c Q 3mo Renal Function Adjust Q 7-14 days FBG HGBA1c Q 3mo ALT, AST Adjust Q 4 weeks Most Common Drug Combos Metformin
B
Sulfonylureas Insulin
Miglitol Glyset Metformin Glucophage
Not in patients with creatinine 2 Not in patients with creatinine 14 female or 15 male or liver problems No change
Take with the first bite of the meal With meals
B
Sulfonylureas Insulin Sulfonylureas
B
Troglitazone Rezulin
With meals
B
Insulin Sulfonylureas
FBG Fasting blood glucose
HGBA1c Hemoglobin A1c
CrCl creatinine clearance
recommends that transaminases be checked every 3 months during the first year of therapy and periodically after that
Miglitol Glyset
Miglitol, a second GSI, was approved by the FDA in 199715 It is structurally unrelated to acarbose Like acarbose, miglitol produces smaller decreases in hemoglobin A1c than glyburide, but studies typically have shown less
weight gain and hypoglycemia in patients than with sulfonamides18 It can also be used in stepwise combinations with other agents when glucose control deteriorates, to enable patients to delay insulin therapy Also, like acarbose, miglitol is associated with nuisance gastrointestinal effects early in therapy, probably due to gas formed by bacterial fermentation of increased quantities of carbohydrate in the intestine Unlike acarbose, it does not produce elevations of liver enzymes15
Metformin Glucophage
Metformin, approved by the FDA in late 1994, is a biguanide15 In 1977, the first biguanide used in the US, phenformin, was withdrawn from the US market because of reports
of fatal lactic acidosis14 Metformin has a much improved safety profile, but still can cause lactic acidosis in patients with renal dysfunction The biguanides lower plasma glucose by decreasing inappropriately high glucose output by the liver15 They also improve peripheral utilization of glucose Metformin has effectively reduced both fasting and postprandial glucose levels when used as a single agent, and has been combined successfully with other agents like sulfonylureas The UKPDS 34 has reported spectacular
results in long-term studies of obese 120 of ideal body weight patients placed on metformin as initial therapy16 Newly diagnosed patients allocated to intensive metformin therapy had risk reductions of 32 for any diabetes-related endpoint, 42 for diabetes-related death, and 36 for all-cause mortality There was little long-term weight gain Although the authors endorsed its use as first-line therapy, caution should be used in basing recommendations on any one study Early adverse effects can include nausea, anorexia, metallic taste, flatulence, and diarrhea, but these problems usually
Journal of the Pharmacy Society of Wisconsin Jan/Feb 1999 27
Pharmacotherapy Perspectives
Table 6
Oral Medications Used in Type 2 Diabetes
Drug Class Sulfonylureas First generation Drug Acetohexamide Dymelor Chlorpropamide Diabinese Tolazamide Tolinase Tolbutamide Orinase Glyburide Micronase, DiaBeta, Glynase Glipizide Glucotrol Glimepiride Amaryl Repaglinide Prandin Mechanism of Action stimulates increase in insulin secretion by beta cells stimulates increase in insulin secretion by beta cells stimulates increase in insulin secretion by beta cells decreases postprandial rate of carbohydrate
absorption decreases glucose output from the liver decreases insulin resistance Advantage least expensive Adverse Effects Disadvantages hypoglycemia; drug interactions; gradual loss of glucose control; weight gain same as first-generation hypoglycemia
HbA1c 15-2
Second generation
similar to first-generation short-acting, taken with meals; may be combined with metformin may be combined with other oral agents; no hypoglycemia may be combined with other agents; no weight gain; no hypoglycemia may be used with insulin or oral agents; no hypoglycemia
Non-sulfonylurea Hypoglycemic -Glucosidase Inhibitors Biguanide
Acarbose Precose Miglitol Glyset Metformin Glucophage
modest effect; intestinal gas diarrhea; rarely lactic acidosis; contraindicated in renal dysfunction rarely, serious liver injury; ineffective if no insulin
Thiazolidinedione
Troglitazone Rezulin
resolve with continued use15 Vitamin B12 supplementation may be necessary Lactic acidosis occurs very rarely, but patients who develop any conditions that can predispose to lactic acidosis should be taken off metformin14 These conditions include renal dysfunction or rapid decline in renal function, congestive heart failure,
hypoxia, or liver impairment, since lactic acid is cleared by the liver Metformin should be discontinued for 48 hours after administration of contrast media and not restarted until baseline renal function has been regained Preventive discontinuation of the medication is doubly important because the symptoms of lactic acidosis like anorexia, nausea, drowsiness and fatigue, are non-specific and occur in elderly people for more benign reasons Once the initial GI discomfort is over, gastrointestinal symptoms due to metformin are very rare, so that nausea or vomiting should be an alarm signal in a patient taking metformin Metformin may not be advisable in patient populations like prisoners, where such symptoms could escape notice until the patient became critically ill Type 2 diabetes is characterized by two primary metabolic defects: insulin deficiency and insulin resistance2 Insulin resistance precedes the development of hyperglycemia in Type 2 patients Normally, most plasma glucose is transported
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Troglitazone Rezulin
into muscle and adipose tissue, but insulin resistance prevents normal uptake Consequently, absorption of
glucose from the intestine into plasma after meals can cause prolonged elevation of glucose levels Increased insulin production can compensate for insulin resistance unless pancreatic beta cells become fatigued and pancreatic insulin output decreases Troglitazone, the first thiazolidinedione, decreases insulin resistance and improves glucose uptake in peripheral tissues, particularly muscle and adipose tissues15 Originally approved for use in Type 2 patients already taking insulin, the addition of troglitazone permits reduction in administered insulin doses Troglitazone has also been approved for use as monotherapy, and can be used in conjunction with other oral agents Trials are also in progress to determine if it can delay the development of Type 2 diabetes in patients at risk19 Troglitazone is remarkably free of nuisance side effects15 Now that it has been so widely prescribed, especially in Japan and the United States after its approval here in 1997, a very rare but sometimes fatal adverse reaction has been reported Hepatocellular injury has resulted in scattered cases of liver failure requiring liver transplant or resulting in death20 As a result, the prescribing information
now recommends checking transaminase levels at the time therapy is begun, every month for eight months, every two months at months 10 and 12, and then
Pharmacotherapy Perspectives
Figure 2 Pharmacologic Management of Type 2 Diabetes
Adapted from Diabetes Care 1996 suppl 1:S54-S61
periodically If levels are more than three times the upper limit of normal, or the patient has jaundice, troglitazone should be discontinued The major disadvantage of the drug is its cost The average wholesale price AWP for a 30-day supply ranges from 89 to 179 in 199821
Pharmacologic Management of Type 2 Diabetes
The American Diabetes Association has periodically updated guidelines for therapy of Type 2 diabetes22 see Table 6 and Figure 2 Although initial therapy is diet and exercise, with the exceptions noted in the diagram, only about 10 of Type 2 patients achieve acceptable long-term glucose control without
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Pharmacotherapy Perspectives
medication23 Now that sulfonylureas are not the only first-line oral medications, the patient in consultation with his care team, including the physician, the nurse-educator, the pharmacist, and the
dietitian, has wider choices Because the most important element in diabetes management is self-care, and informed, motivated patients can manage glucose control more effectively, patient choice is an important consideration The older sulfonylureas address the immediate problem of insulin deficiency and are the least expensive choice They differ from the second-generation sulfonylureas mainly in kinetic profiles, while safety and efficacy are comparable9 For patients unlikely to manage possible hypoglycemic events, metformin, acarbose, miglitol or troglitazone are all useful If glycemic control is not satisfactory with monotherapy at optimal dosing, other oral agents can be added in stepwise combinations, as indicated in Figure 2 Combinations of oral agents with insulin usually are used later in the course of therapy Because Type 2 diabetes is an evolving disease process with continuously declining pancreatic beta-cell function and constant upward creep of hemoglobin A1c, drug therapy needs periodic review and change Prior to oral drug combination use, about 65 of Type 2 patients started on oral medication, but after 15 years, only 25 remained solely on oral medication22 Over the
same time span the percentage of patients using insulin increased from 20 to 60 Overall, about 36 of Type 2 patients are insulin-dependent
References
Conclusion
Useful new pharmacologic tools to facilitate the management of Type 2 diabetes have become available just as the results of the Kumamoto study and UKPDS have confirmed and extended the conclusions from DCCT Tight glucose control can reverse the biochemical consequences of prolonged hyperglycemia and enable patients to stay well, avoid hospitalization and lead more productive lives Caregivers have focused more intensely not only on glycemic control, but also on concurrent control of blood pressure and hyperlipidemia Patient education is based on the premise that recruitment of each patient as his own pro-active care manager is the most effective way to achieve long-term control Guidelines are easily available for both caregivers and patients Type 2 patients have a life expectancy of at least twenty years after diagnosis They deserve a plan Successive stopgaps are no longer adequate for treatment of a lifelong condition As caregivers with patient medication profiles, pharmacists have an excellent opportunity to monitor
medication compliance and to provide information and advice on drugs, home glucose measurement, and practical ways for patients to become successful managers s
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1 Rafuse J Seventy-five years later, insulin remains Canadas major medicalresearch coup CMAJ 1996;155:1306-1309 2 Nathan DM VI Diabetes Mellitus, in Scientific American Medicine 1997;9 VI- 20 3 Tamborlane WV, Ahern J Implications and Results of the Diabetes Control and Complications Trial Pediatr Clin North Am 1997;44:285-300 4 University Group Diabetes Program A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes Diabetes 1970;19suppl 2:747-830 5 Goldner MG, Knatterud GL, Prout TE Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes 3 Clinical implications of UGDP results JAMA 1971;2118:1400-1410 6 Feinstein AR Clinical biostatistics 8 An analytical appraisal of the University Group Diabetes Program UGDP study Clin Pharmacol Ther 1971;12:167-191 7 The Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the
development and progression of longterm complications in insulin-dependent diabetes mellitus N Engl J Med 1993;329:977-986 8 Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S et al Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study Diabetes Res Clin Prac 1995;28:103-117 9 Turner R for the United Kingdom Prospective Diabetes Study Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS 33 Lancet 1998;352:837-853 10 United Kingdom Prospective Diabetes Study Group Overview of 6 years therapy of Type 2 diabetes: a progressive disease UKPDS 16 Diabetes 1995;44:1249-1258 11 UK Prospective Diabetes Study Group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 BMJ 1998;317:703-713 12 UK Prospective Diabetes Study Group Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39 BMJ
1998;317:713-720 13 Wisconsin Diabetes Advisory Group Essential Diabetes Mellitus Care Guidelines WMJ 1998;97:17-18 14 Pernell JQ, Hirsch IB New oral therapies for type 2 diabetes Am Fam Physician 1997;56:1835-1842 15 Antidiabetic agents in Drug Facts and Comparisons, St Louis, MO: Facts and Comparisons, updated October, 1998 16 UK Prospective Diabetes Study UKPDS Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS 34 Lancet 1998;352:854-865 17 Lam KS, Tiu SC, Tsang MW, Ip TP, and Tam SC Acarbose in NIDDM patients with poor control on conventional oral agents A 24-week placebocontrolled study Diabetes Care 1998;21:1154-1158 18 Johnston PS, Lebovitz HE, Coniff RF, Simonson DC, Raskin P, Munera CL Advantages of alpha-glucosidase inhibition as monotherapy in elderly type 2 diabetic patients J Clin Endocrinol Metab 1998;83:1515-1522 19 Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang A, Buchanan TA TRIPOD Troglitazone In the Prevention Of Diabetes: a randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus Controlled Clin Trials 1998;19:217-231 20 FDA Talk Paper:
patient testing and labeling strengthened for Rezulin Food and Drug Administration Rockville MD, 1997 Dec 1 http://wwwfdagov/ bbs/topics/ANSWERS/ANS00837html, accessed Dec 2, 1998 21 1998 Drug Topics Red Book, Medical Economics Co, Montvale NJ 07645, April 1998 22 The pharmacological treatment of hyperglycemia in NIDDM: consensus statement Diabetes Care 1996; 19 suppl 1:S54-S61
