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July 2003 Body.qxd 7/14/03 8:52 AM Page 189 Clinical Medicine & Research
Volume 1, Number 3: 189-200
2003 Clinical Medicine & Research Current Therapeutic Options in Type 2 Diabetes Mellitus:
A Practical Approach
Michael T. Sheehan, MD, Department of Endocrinology, Marshfield Clinic-Wausau Center, Wausau, Wisconsin [See related article 173 - 174] ABSTRACT
The incidence of type 2 diabetes mellitus (DM) in the United States continues to grow rapidly, paralleling the overweight and obesity
epidemic. For many years the only therapeutic options for type 2 DM were sulfonylureas and insulin. However, over the last 9
years there has been an explosion of new and exciting agents approved for the treatment of type 2 DM. Some of the treatments
target insulin deficiency and others insulin resistance, the hallmarks of the disease. Other drugs delay the intestinal absorption of
carbohydrate. Recently several combination agents have been released. With these new drugs has come an overwhelming
mountain of information, making it difficult for the busy clinician to know how best to manage the ever-increasing portion of
patients with type 2 DM.
New questions have arisen: Which agent to start as first line? How much of this drug to use before adding something else? Howlong for this drug to reach full effect? Which agent to add second? Should a patient uncontrolled on dual therapy begin insulin orstart a third oral agent? If insulin therapy is started, what should become of the patient's oral agents? How best to explain thepatient's weight gain on therapy? These are not easy questions and no review can fully detail all the therapeutic combinations possible. Instead, the practical approach of reviewing the agents in terms of their mechanism of action and critically comparingtheir dosing, effect and cost, is undertaken herein. Also addressed is the possible niche some newer classes of agents and combination drugs may or may not hold in the management of type 2 DM. The decision of using insulin versus a third oral agentwill be looked at from the standpoint of where the patient is on dual therapy in relation to the hemoglobin A1c goal. In this way it is hoped that some clarity will be brought to the dizzying array of information that both the physician and patient have to deal within regard to the management of this prevalent and serious disease.
MARCH 31, 2003
Michael T. Sheehan, MD Type 2 DM; Insulin secretagogues; Insulin sensitizers; Department of Endocrinology Diabetes therapy; Glucose absorption inhibitors Marshfield Clinic-Wausau Center2727 Plaza DriveWausau, WI 54401 Telephone: 715-847-3550 Dr. Sheehan serves on the Speaker Bureaus for the Fax: 715-847-3039 following pharmaceutical companies: Takeda, GlaxoSmithKline, Lilly, Aventis and Pfizer.
July 2003 Body.qxd 7/14/03 8:52 AM Page 190 tinue as even newer agents with completely different mecha-nisms of action are currently under investigation. Along with Vast amounts of literature have been written about the cur- this explosion of therapeutic options has come uncertainty rent and growing epidemic of diabetes mellitus (DM) and its over how to use these agents effectively. When thought of associated complications. The cost of diabetes to the United simply, there are but three ways in which these agents work States healthcare system is staggering, amounting to $100 toward improving glycemic control: (1) increasing insulin billion in direct and indirect expenditures annually.1 Currently secretion [insulin secretagogues], (2) increasing insulin 15 million Americans have diabetes, one third of whom have action [insulin sensitizers], and (3) decreasing insulin need yet to be diagnosed. Ninety percent of these cases represent [inhibitors of glucose absorption].
type 2 DM. The incidence of type 2 DM and its precursor(impaired glucose tolerance) continues to rise, paralleling that Increasing insulin secretion (secretagogues) of overweight and obesity.2 Frighteningly, this is occurring in children and adolescents, as well as adults.3 Over the last These agents were first introduced for the management of 9 years a growing number of oral medications and newer type 2 DM in the mid-1950s. These were the only oral agents insulin analogs have become available for use in type 2 DM.
available in the United States until 1994. These drugs work The optimal use of these agents has become more difficult by binding to a regulatory protein (commonly referred to as with the increased complexity a greater number of choices the SU receptor) on pancreatic β-cells, which in turn, results bring. This task is made more challenging with the pharma- in closure of ATP-dependent potassium (K ceutical industry spending large sums of money annually in leading to membrane depolarization and influx of calcium direct marketing toward physicians and patients.4 For better through voltage-dependent channels, which subsequently or worse, prescribing patterns are affected by this marketing, leads to insulin secretion.7 or obviously such amounts of money would not be so spent.5 It should be stressed that despite the vast literature available, As the second generation SUs are currently the most widely many patients and physicians alike still view type 2 DM as a used, this discussion will be limited to these agents. The "less severe" illness than type 1 DM. On the contrary, because dosing, and the cost and effect of the SUs on HbA1c are of the much greater prevalence of type 2 DM, the great summarized in table 1. As is apparent, their relative potency majority of microvascular complications occurs in these is similar. The most common side effect of the SUs is hypo- patients. The increased risk of cardiovascular disease (CVD) glycemia, the risk of which varies somewhat among the in type 2 DM has led to more stringent goals for the agents. It is generally accepted that glyburide has twice the management of cholesterol and blood pressure, in addition risk of hypoglycemia compared to the other second generation to the use of aspirin.6 Therefore, close attention should be SUs.8,9 This is due to increased duration of binding to the paid to the overall cardiovascular health of patients with SU receptor, resulting in fasting hyperinsulinemia with gly- type 2 DM, not just their hemoglobin A buride. This degree of fasting hyperinsulinemia is generally not seen with the other SUs, which are more glucose-sensi- The optimal management of type 2 DM cannot be discussed tive (and thus prandial) in their stimulation of insulin secre- by simply outlining what agents are available along with tion.9 An additional factor in this regard is glyburide's their doses, effectiveness and side effects. More difficult suppression of several counter-regulatory hormones. Weight management issues need to be explored as well. Also, as gain is variable, but tends to be greatest with glyburide, which CVD is so prevalent in patients with type 2 DM the relates to its greater propensity to induce hypoglycemia. There potential for non-glycemic benefits of some of the newer is some evidence that glipizide-gastrointestinal therapeutic agents deserves mention. This review will focus not only on system (glipizide-GITS) and glimepiride are more weight the oral agents per se, but also on their proper use over time neutral.10 Also, the potential for decreasing myocardial and in combination. The potential benefit of non-glycemic protective mechanisms via cross-reactivity of SUs with effects of some agents will be mentioned briefly. The use of myocardial KATP channels seems to be greater with glyburide insulin in combination with oral agents will also be described.
than other SUs.11 It is hoped that through a better understanding of these agentsproviders of care for patients with type 2 DM will be aided The clinical importance of this is not known, but the contro- in the most difficult task of preventing the complications of versy regarding increased risk of myocardial events with the disease.
SUs noted in the University Group Diabetes Program12,13has finally been put to rest by the United Kingdom Prospective ORAL AGENTS AVAILABLE FOR THE
Diabetes Study (UKPDS) where a decreased event rate fell TREATMENT OF TYPE 2 DM
just short of statistical significance.14 Another concern laidto rest by the UKPDS it that SUs may hasten the demise of Prior to 1994 selecting an oral agent for the treatment of the β-cell. On the contrary, by the end of the study those on type 2 DM was as simple as choosing which sulfonylurea SU therapy had higher β-cell function than those not on (SU) to use. Since then, a variety of newer agents with such therapy because of increased insulin secretion in the unique mechanisms of action and even some combination first year, the rate of decline thereafter paralleling that of the agents have been released for use as monotherapy or in any other groups (figure 1).15 These agents and their metabolites number of combination regimens. This trend is likely to con- CM&R 2003 : 1 (July)
July 2003 Body.qxd 7/14/03 8:52 AM Page 191 Table 1. Dosing, efficacy and cost of oral agents for treatment naïve type 2 diabetes mellitus patients.
Maximum dose
Doses (mg)
10 qd-bid49-51,54 1.25/250, 2.5/500, 5/500 1/500, 2/500, 4/500 2.5/250, 2.5/500, 5/500 a Approximate hemoglobin A (HbA ) reduction versus placebo at maximally effective dose, except where indicated.
b Cost of maximally effective dose, average wholesale price for brand name, or maximal allowable cost as set by a regional insurer for generic.
c Generic preparations. d 10 mg bid dosing.
e 10 mg qd dosing.
f 8 mg tablets, 1/2 bid (4 mg bid: $1,975/year).
g Represents equivalent maximally effective doses of components.
h Mean dose 4.1 mg/824 mg daily (Glucovance package insert).
i No clinical efficacy trials conducted.
j Mean dose 7.4 mg/1477 mg daily (Metaglip package insert).
* Glucophage-XR, Glucovance and Metaglip (Bristol-Myers Squibb Company, Princeton, NJ).
* Avandamet (GlaxoSmithKline, Research Triangle Park, NC).
* Glipizide gastrointestinal therapeutic system (glipizide-GITS).
are excreted by various degrees via the kidneys. Caution In terms of overall potency, repaglinide is equivalent to the should be used in the setting of renal insufficiency. Of the SUs, with nateglinide being less effective (table 1). As second-generation agents, glyburide may be of most concern they are metabolized and excreted by hepatic mechanisms in this regard with the others being generally safer in mild exclusively, these agents can be safely used in more renal insufficiency.16 Overall, the SUs are a potent, safe and advanced renal insufficiency (vs. glimepiride for example).
cost-effective management option in type 2 DM.
Much has been said in regard to the ability of these agents to control postprandial glucose (PPG) because of their faster Repaglinide and nateglinide were released in 1998 and 2001, onset of action. There is no doubt that control of PPG is respectively. These agents are not SUs. These agents are also important in the optimal control of type 2 DM. There is also a different class from each other, repaglinide being a mem- evidence that increased PPG levels may translate into a ber of the meglitinide family and nateglinide a derivative of greater risk of CVD.18 If PPG levels are targeted, the goal phenylalanine. The main difference between these agents should be <140 mg/dL at 2 hours, as documented by the and the SUs is the rapidity and duration of stimulation of American Diabetes Association position statement.19 The insulin secretion. The non-SUs differ from SUs in two unanswered question is how best to achieve this postprandial ways:17 (1) dosing at each meal, (2) potentially less risk of hypoglycemia, especially if a meal is missed.
Therapeutic options in type 2 DM CM&R 2003 : 1 (July)
July 2003 Body.qxd 7/14/03 8:52 AM Page 192 Despite the methods in which these newer insulin secreta- Increasing insulin action (insulin sensitizers) gogues have been marketed, there is little published evidence they control PPG better than the SUs. Indeed, Landgraf et al.
Metformin had been in widespread use overseas for many failed to show a significant difference in PPG between years before being approved in the United States in 1994.
repaglinide and glibenclamide (glyburide).20 However, This delay was due to the high risk of fatal lactic acidosis nateglinide did fare somewhat better than glyburide, with a with phenformin, which was removed from the United States PPG of <140 mg/dL achieved in 30% and 13%, respectively.21 market in the mid-1970s. The risk of this severe complica- Recently, data has emerged comparing glipizide to both tion is 10 to 20 times lower with metformin, and is limited repaglinide22 and nateglinide23 revealing little, if any, to those with renal insufficiency and other predispositions to difference in PPG control (figure 2). In fact, the conclusion acidosis, such as chronic pulmonary disease and congestive of Carroll et al. went as far as to say, heart failure.24 Metformin's actual mechanism of action isnot fully known, but its main effect is to decrease hepatic "The clinical decision to use glipizide versus nateglinide gluconeogenesis, thus improving fasting hyperglycemia.25 should be based on factors other than the control of post- There is also a peripheral effect of improved insulin action prandial hyperglycemia in type 2 diabetes."23 Although not in muscle tissue, which may be related to metformin's ability directly compared with the non-SU secretagogues, glimepiride to lower free fatty acids (FFA)26,27 and/or its induction of also has a significant effect on PPG control.11 The usefulness mild weight loss through decreased caloric intake.
of these agents remains to be seen and must take intoaccount their increased cost, and what differences there truly Metformin is likely the initial treatment of choice for most are versus the SUs in terms of PPG control.
patients with type 2 DM for a variety of reasons. By improving insulin sensitivity it also improves a variety ofother factors related to increased cardiovascular risk.28 Theseimprovements in surrogate markers do indeed translate intodecreased event rates. Although the exact mechanism wasunclear in the obese cohort of the UKPDS, metformin (vs.
conventional therapy) was shown to significantly reduce therate of myocardial infarction and all-cause mortality.29Metformin is also advantageous in that it is often weightneutral or induces slight weight loss through its appetite-suppressive action. This is true of monotherapy and in combination with other agents.
The main side effect of metformin is gastrointestinal intolerance (nausea, abdominal pain and diarrhea), whichoccurs in approximately 30% of patients.30 This problem isrelated to total dose and the rapidity with which the Figure 1. β-cell function in patients allocated to diet therapy
(❍), sulfonylurea (▲), or metformin (■)
medication is titrated upward. Much of this difficulty can be (adapted from reference 15).
avoided by administration with food and by increasing thedose by 500 mg per day, every 1 to 2 weeks (thus allowing 3 to 7 weeks before a full dose is reached). Very fewpatients need to discontinue metformin due to adverseevents when these guidelines are followed. As mentioned,the risk of lactic acidosis with metformin is minimal so longas its use is avoided in those at risk (serum creatinine ≥1.5mg/dL in men or ≥1.4 mg/dL in women). When uncertaintyarises as to the validity of serum creatinine, creatinine clearance should be measured or calculated (≥60 mL/minuteis considered safe). Metformin should also be avoided inpatients with liver disease or habits that put them at risk ofsuch (alcohol abuse and/or binge drinking) and other conditions that may predispose to acidosis (congestive heartfailure and/or pulmonary disease). Its use in patients over 80 years of age also carries greater risk. Lastly, metforminshould be held for 48 hours prior to and after surgery and/or Figure 2. Mean postprandial plasma glucose excursions
administration of radiocontrast materials.
from baseline with glipizide () or nateglinide (❍) after astandardized breakfast in 20 subjects with type 2 diabetes(adapted from reference 23). G, glipizide; M, meal; N, nateglinide.
CM&R 2003 : 1 (July)
July 2003 Body.qxd 7/14/03 8:52 AM Page 193 It deserves mention that an extended-release metformin, responders are looked at separately, the potency is comparable Glucophage XR (Bristol-Myers Squibb Company, Princeton, to other agents (see later).44 Their effect on glucose control NJ), is now available allowing once daily administration.
may be more sustained over time than that of other Although priced less than brand name Glucophage (Bristol- agents.37,38 The durability of glucose control over time with Myers Squibb Company, Princeton, NJ), it is significantly glyburide, metformin, or rosiglitazone in newly diagnosed more expensive than generic metformin (table 1). While type 2 diabetics will be definitively addressed in A Diabetes studies showed only a 9.5% incidence of diarrhea, it should Outcome Progression Trial (ADOPT).45 be recognized that this low rate might have stemmed fromthe much lower incidence of diarrhea in the entire study. In Like metformin, the TZDs have widespread beneficial fact, the risk of diarrhea with Glucophage XR was 3 to 4.5 effects on a variety of surrogate markers of cardiovascular times that of placebo, a similar degree of increase over risk; extensive study is ongoing in this area. Perhaps the placebo seen in trials of metformin (Glucophage XR package most noticeable of these non-glycemic effects is the ability insert). Also, in these same trials there was an unexplained of the TZDs to raise high-density lipoprotein (HDL) increase in triglyceride levels with Glucophage XR that was cholesterol by up to 13%.32,39-43,46 Furthermore, there may not seen in trials of metformin. Thus, there seems to be no be a differential effect on HDL subtypes with rosiglitazone, benefit of Glucophage XR beyond that of once daily dosing, preferentially effecting HDL-2 (the most protective HDL which is unlikely to be worth the increased cost versus subfraction).46 The effects on triglycerides and low-density generic metformin.
lipoprotein (LDL) levels tend to be more variable and thereis mounting evidence that pioglitazone performs consistently better in these regards than rosiglitazone.39-43 A double- With the introduction of troglitazone in 1997, an exciting blind, placebo-controlled, parallel design, phase IV study new era in the management of type 2 DM dawned. Despite directly comparing the effects of these two agents on the the removal of troglitazone from the market in 2000 because lipoprotein profile is currently underway. Despite their of liver toxicity, two newer agents, rosiglitazone and tendency to increase total LDL cholesterol, the TZDs shift pioglitazone (approved in 1999), continue in widespread use the LDL particle size to larger, less atherogenic molecules, without evidence of similar problems.31 However, the edema although it is uncertain what this means to overall cardio- and weight gain seen with the TZDs can be limiting in some patients. These agents bind to peroxisome proliferator activator receptor-gamma nuclear receptors affecting gene In addition to these effects on lipid parameters, the TZDs regulation in target cells. Interestingly, this alteration of gene beneficially affect plasminogen activator inhibitor, C-reactive transcription takes place in adipocytes and the genes concerned protein, endothelial function, smooth muscle proliferation primarily regulate fatty acid metabolism, the net result of and carotid intimal media thickness. Extensive reviews on which is to decrease serum FFA by approximately 20% to this subject can be found.47,48 Despite this growing body of 40%.32-34 This reduction in FFA, in turn, improves insulin circumstantial evidence, the most crucial question remains action in muscle tissue, thus implicating elevated FFA as a unanswered; will the use of TZDs translate into a reduction major contributor to insulin resistance. Further-more, this in cardiovascular events? The answer will be known the reduction in FFA improves β-cell function by decreasing latter part of this decade. The following trials will definitely lipotoxicity, a process whereby increased FFA eventually settle these issues: leads to β-cell death.35 In various trials the TZDs have - Rosiglitazone Evaluated for Cardiac Outcomes and increased β-cell function by up to 60%.33,35,36 Unlike the Regulation of glycemia in Diabetes (RECORD); increase in β-cell function seen with SUs in the first year of - Action to Control CardiOvascular Risk in Diabetes the UKPDS, the increased functional capacity induced by TZDs is maintained for at least 2 years.37,38 - Bypass Angioplasty Revasculization Investigation Type 2 Diabetes (BARI-2D); Both agents have been approved for use as monotherapy - PROspective Actos Clinical Trial In macroVascular Events and in combination with other oral agents. They are not (PROactive [Actos, Takeda Pharmaceuticals North approved for use in most triple therapy regimens, except for America, Inc., Lincolnshire, IL]). the combination of Glucovance (Bristol-Myers Squibb Company, Princeton, NJ) and rosiglitazone. Pioglitazone These issues of durable control over time and cardiovascular and rosiglitazone have been approved in combination with outcomes are of great importance not only to physicians insulin. TZDs are contraindicated in patients with liver caring for patients, but also to help healthcare systems determine disease and those with New York Heart Association class III whether these slightly less potent agents are worth their cost.
or IV cardiac status. From a therapeutic standpoint, there islikely no significant difference between these agents in Decreasing insulin need (inhibitors of glucose absorption) terms of glucose-lowering effect39-43 and they may be ALPHA-GLUCOSIDASE INHIBITORS (AGIs)
slightly less potent than the SUs or biguanides (table 1).
The two agents in this class currently available, acarbose and This apparent decreased potency may be related to a miglitol, were released in 1996. These drugs only affect PPG significant rate of non-responders; however, as when levels and do so by competitively inhibiting the binding of Therapeutic options in type 2 DM CM&R 2003 : 1 (July)
July 2003 Body.qxd 7/14/03 8:52 AM Page 194 oligosaccharides to the alpha-glucosidase enzyme in the Several points regarding the insulin sensitizers warrant brush border of the small intestine. This enzyme cleaves mention here as well. First, metformin dosages beyond oligosaccharides to monosaccharides, which can then be 1,000 mg twice daily will unlikely offer further benefit and absorbed. Thus, when taken with the first bite of food, these may increase the risk of gastrointestinal side effects that agents delay the absorption of carbohydrate. These drugs do could potentially result in the discontinuation of this extremely not cause hypoglycemia or weight gain. However, because useful agent.30 The effect of metformin on glucose control is they only affect PPG levels the potency of the AGIs is also seen fairly quickly, on the order of one to two weeks.
significantly less than most other agents (table 1). For this The TZDs are somewhat less confusing in this regard in that reason and for the often significantly troublesome side the maximal prescribable dose is the same as the maximally effects of flatulence, abdominal pain and diarrhea, these effective dose. However, with rosiglitazone it should be agents are used sparingly in the United States.
noted that 4 mg twice daily may be more potent than 8 mgonce daily.32 Lastly, it should be realized that it takes more IMPORTANT MANAGEMENT ISSUES IN
time for the TZDs to demonstrate full effect than the other oral agents (3 to 4 months vs. several weeks).32,33,36 Maximal prescribable dose vs. maximally effective doseAs mentioned previously, the cost of diabetes on the United States healthcare system is staggering. As newer, more Within the last 2 years several combination agents have been costly treatment modalities become available, physicians released for use in the management of type 2 DM. The need to be increasingly aware not only of the agents patient-friendly nature of these agents is a frequently sited themselves, but also of how to use them cost-effectively. benefit. "By prescribing these agents physicians can The maximal prescribable doses and maximally effective decrease cost (one co-pay) and increase compliance (fewer doses are listed in table 1. There is some debate as to the tablets)." The issue of cost certainly is important. However, validity of describing a "maximally effective" dose because the number of co-pays is but one factor in medication of the high degree of variability in response to SUs.49-51 expenditures. Increased use of more expensive combination While the author uses the listed maximally effective doses as agents could increase overall drug cost indirectly by such for glyburide and glimepiride, clinical experience has increasing insurance premiums. In regard to compliance, led to utilizing up to 10 mg bid for glipizide and 10 mg qd there is published evidence–and it makes intuitive sense–that for glipizide-GITS.
compliance is higher with one drug versus two.55 Compliancehowever, is more complex than pill number or frequency, Significant cost savings can be achieved by a better under- and in the author's opinion, is more strongly affected by standing of the maximally effective dosage of medications physician-patient discussions that occur (or do not occur) and how quickly to expect to reach that full effect. Savings in regard to combination therapy. An informed patient is can then be achieved on several fronts: more likely to comply with therapy than an uninformed or - Avoidance of prolonged therapy that is unlikely to work.
confused patient.
- Use of only as much of a given agent as is needed.
For a combination agent to be useful it should be comparable, - More timely addition of other treatment modalities. if not less, in cost to its components and should involve An all too common scenario is when an uncontrolled patient, fewer tablets daily (and/or decreased frequency of dosing).
for example with a HbA1c of 10.5% on glyburide 10 mg With this in mind, it is interesting to see that the various daily, is told to increase to 10 mg twice daily and follow-up combination agents available do not fare well (table 2).
in several months. A more appropriate sequence of events Indeed, none offer fewer tablets daily than the components might start with the realization that the effect of glyburide is taken separately. In reference to cost, only Avandamet close to full at 10 mg daily and any increase will certainly (GlaxoSmithKline, Research Triangle Park, NC) offers not get this patient to goal. Secondly, even if a dose increase savings over its components separately (approximately $400 was attempted, the full effect of an SU would be seen within per year less). There is some unpublished, retrospective data 1 to 2 weeks, with follow-up planned accordingly.52 Delayed suggesting that Glucovance lowers HbA1c to a greater degree follow-up only allows for continued poor control of diabetes, than similar doses of metformin and glyburide separately.
further raising the risk of costly complications. How many These results suggest a benefit of 0.13% to 0.6% with patients are being treated with an SU dose beyond what Glucovance. Until these results can be confirmed by a they need and at what extra cost? Generally, increasing an prospective, randomized trial, they should be interpreted SU from the maximally effective to maximum dose leads to with caution. Even if confirmed, the cost-effectiveness of an additional HbA1c lowering effect of ≤0.4% while this benefit (an additional $700 annually) is unclear.
doubling cost.49,50,53,54 Granted these medications areamong the least expensive, but they are also the most widely Dual therapy options prescribed. Thus, the savings of optimal dosing would likely As was shown in the UKPDS, most patients with type 2 DM be substantial.
will eventually require multiple oral agents to maintain optimal glycemic control. With the availability of newer CM&R 2003 : 1 (July)
July 2003 Body.qxd 7/14/03 8:53 AM Page 195 agents that target not only the defect in insulin secretion, but First, how far from goal is the patient? This is important in also insulin action, a variety of combination strategies are terms of both whether to add a TZD or start insulin, also now possible. A full discussion of these options is beyond how intense an insulin program to start, if need be. The the scope of this review, but several excellent summaries are addition of a TZD as a third agent is beneficial in about available.56,57 In general, the combination of an insulin 60% of patients.44 In those who respond the effect can be secretagogue and sensitizer is most often used and makes substantial with a mean HbA1c reduction of approximately intuitive sense given the two major pathogenic mechanisms 2.5% seen in a troglitazone trial.44 When taken as a whole of type 2 DM (insulin resistance and insulin deficiency).
(responders and non-responders alike), the mean reduction Most often this involves the use of metformin and an SU, as in HbA1c by adding troglitazone third line was only 1.4%.58 this combination brings together high potency, low cost and In the only published trial (in letter form) of the currently a low potential for weight gain. Certainly, a TZD should be available TZDs, rosiglitazone added to glimepiride and met- substituted for metformin in the case of contraindications to formin therapy,59 led to a 1.4% reduction in HbA1c. Patients the latter. The use of non-SU secretagogues and/or AGIs whose HbA1c is above 9.5% on dual therapy are unlikely to brings increased cost, decreased potency, and more potential get to goal by the addition of a TZD. A trial can be given to for side effects (with AGIs).
these patients (especially those particularly averse to insulintherapy), but follow-up for consideration of other options The potential utility of metformin plus a TZD as dual therapy should be scheduled after 3 months at maximal dose. The is interesting. From the standpoint of annual cost, this com- TZD should be discontinued if the patient does not respond.
bination ($2,500) is certainly more expensive than metformin If the decision to start insulin is made it should be stressed plus SU ( $800). Metformin plus TZD is also slightly less that adding bedtime insulin to daytime oral agent therapy potent than metformin or TZD plus SU.56,57 However, will only lower HbA1c by 2% to 2.5%.60 Therefore, if the despite both being insulin sensitizers, this combination still HbA1c is above 9.5% on dual therapy, the patient is likely to makes good pharmacologic sense, as each improves insulin need a more intensive insulin program. Also, there is no evi- resistance primarily in a different tissue. Also, there may be dence that bedtime glargine insulin results in better glycemic some potential for limiting weight gain with TZDs when control than bedtime neutral protamine Hagedorn (NPH) used with metformin. Furthermore, with the data on preser- insulin, although there is certainly less hypoglycemia with vation of β-cell function, a TZD may help preserve insulin the former.61 Use of glargine insulin increases costs by 65% secretory capacity and thus delay secondary failure of oral versus NPH insulin. As is noted in table 3, triple oral agent agent therapy.35,37,38 As well, this combination may allow therapy costs over twice as much as SU and metformin plus for tighter glycemic control without the risk of severe bedtime NPH insulin for a similar reduction in HbA1c.
hypoglycemia that using an SU might bring. Lastly, the beneficial effects on surrogate markers of CVD cannot help Second, if insulin is started, which oral agent(s) should be but make one think of the potential benefit of TZDs beyond stopped? This will depend on the type of insulin program lowering glucose. What might be the potential cost-benefit contemplated. If bedtime insulin is chosen, then daytime oral of early use of TZD therapy, if they are shown to prevent agents should be continued. However, if a more intensive cardiovascular events and/or deaths? insulin program is started, then three options should be con-sidered: (1) continue both the SU and metformin, (2) stop Triple oral therapy or insulin initiation? the SU and continue metformin, (3) discontinue both oral Perhaps one of the most difficult decisions in the management agents. Provided appropriate adjustments in insulin are made, of type 2 DM has become whether to add a third oral agent each of these three options will likely result in a similar or to start insulin therapy in an uncontrolled patient. This improvement in HbA1c. The cost is surprisingly similar as has only become an issue since the release of the TZDs well, owing to the differences in total insulin dose that will several years ago. As mentioned previously, there may be be needed to achieve control (i.e., continuing oral agents several reasons why these agents should be used earlier in will result in less insulin being needed) (table 3).62,63 the course of treatment than is typically the case. TZDs have Continuation of metformin makes intuitive sense, as its now been primarily used as third line agents and they will be mechanism compliments that of insulin and tends to lessen discussed as such in this setting. There are three key issues any weight gain that might occur. On the contrary, an SU that need considering when facing this decision.
works in relatively the same manner as insulin and thus is Table 2. Cost comparison of combination agents versus component agents separately.
Cost/year ($
cost/year ($
a Average wholesale price for brand name and maximal allowable cost for generic preparations.
*Glucophage-XR, Glucovance and Metaglip (Bristol-Myers Squibb Company, Princeton, NJ); Avandamet (GlaxoSmithKline, Research Triangle Park, NC).
Therapeutic options in type 2 DM CM&R 2003 : 1 (July)
July 2003 Body.qxd 7/14/03 8:53 AM Page 196 Table 3. Cost comparison of triple oral therapy (adding thiazolidinediones) versus institution of various insulin programs in patients uncontrolled on
sulfonylureas (SU) and metformin combination therapy.
Cost/year ($
Cost/year ($)b
HbA1c reduction (%
HbA1c reduction (%)
SU maximal dosec + metformin 1000 bid SU maximal dose + metformin 1000 bid + TZD maximal dosed 2.5 for responders44 60% response rate44 SU maximal dose + metformin 1000 bid + NPH and regular bid or 120 units/daye (70% NPH; 30% short-acting insulin) NPH and Humalog/NovoLog bid g metformin 1000 bid + NPH and regular bid or 82 units/day62,63 (70% NPH: 30% short-acting insulin) NPH and Humalog/NovoLog bid SU maximal dose + metformin 1000 bid + NPH and regular bid or 46 units/day62,63 (70% NPH; 30% short-acting insulin) NPH and Humalog/NovoLog bid a Insulin doses for oral agents plus insulin regimens represent "insulin-sparing" effects of oral agents as described in references noted.
b Average wholesale price for brand name and maximal allowable cost for generic (oral agents ± insulin vials) (syringes included).
c SU (sulfonylurea), Glipizide-GITS 10 mg qd or glimepiride 4 mg qd.
d TZD (thiazolidinediones), pioglitazone 45 qd or rosiglitazone 4 bid.
e Insulin dosage assumes a 100 kg patient requiring 1.2 units/kg/day.
f NPH, neutral protamine Hagedorn.
g Humalog (Eli Lilly and Company, Indianapolis, IN ); NovoLog (Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ).
often discontinued. It should be remembered, that the SU is common strategies is to employ a twice-daily regimen of an often still having some, albeit an inadequate, effect on glucose intermediately-acting insulin mixed with a short-acting control. If discontinued, the SU effect will dissipate quickly, insulin (figure 3). Whether self-mixing of insulin or premixed allowing glucose levels to sometimes rise dramatically. The formulations are used is a matter of preference, but the physician should relay this possibility to the patient so as to author prefers the former for its greater flexibility, which not mislead them into believing that the insulin is not working allows tighter control with less hypoglycemia. However, and they were "better off on pills." This may be particularly self-mixing of insulin may result in less accuracy. The choice important in patients who have been very resistant to insulin of regular insulin versus an insulin analog can be debated.
and in those who are less likely to be compliant with scheduled Most often this debate centers on cost-benefit issues as each follow-up. Continuation of both the SU and metformin may vial of an insulin analog is priced approximately $34 more be best in these patients. Interestingly, the incremental cost than regular insulin. As previously mentioned, this incremental of using fast-acting insulin analogs versus regular insulin cost becomes less of an issue as oral agents are used with becomes less as one or more oral agents are continued with insulin. There is good evidence that both insulin analogs insulin initiation due to an "insulin-sparing" effect of oral result in improvements in HbA1c (Humalog, 0.3% to 0.4% agents (table 3). As β-cell failure progresses, an increase [Eli Lilly and Company, Indianapolis, IN] and NovoLog, in exogenous insulin will be required, thus rendering the 0.12% to 0.16% [Novo Nordisk Pharmaceuticals Inc., continued use of the SU less cost-neutral.
Princeton, NJ]) when compared to regular insulin.64 Bothanalogs have also been shown to reduce hypoglycemic risk Lastly, what type of insulin program should be started? (especially nocturnal hypoglycemia) when compared with While a complete discussion of insulin options beyond regular insulin.64 For these reasons the author prefers to use bedtime dosing only is impossible here, one of the most insulin analogs.
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July 2003 Body.qxd 7/14/03 8:53 AM Page 197 Weight gain associated with the treatment of type 2 DM events. The greater a drug's propensity to cause hypo- Excess body weight and obesity play a large role in the glycemia, the larger an issue this becomes. Therefore, gly- development of type 2 DM. Many patients have struggled buride and insulin are the agents for which this component unsuccessfully for years to lose weight. Depending on a of weight gain can be substantial. The weight gain associated variety of factors patients might be gaining, maintaining, or with TZDs is a mixture of increased fat mass and fluid even losing weight when they are diagnosed with type 2 retention.57 Both the incidence of edema and amount of DM. The weight gain that often occurs in the first year of total weight gain with TZDs increases from monotherapy treatment can thus be especially frustrating. The propensity (4%, 1 to 3 kg) to combination with SU (6%, 2 to 2.5 kg) to for weight gain differs significantly between treatment options combination with insulin (15%, 4 to 5.4 kg) (rosiglitazone with metformin generally being the most weight-neutral.
package insert).
Insulin and the TZDs are at the other end of the spectrum, being prone to cause the greatest weight gain. The causes ofweight gain associated with treatment of type 2 DM are The optimal care for the growing number of patients with listed in table 4. The distribution of weight gain shows type 2 DM has been and will remain a complex and difficult two-thirds representing increased fat mass and one-third lean task. The importance of optimal control has become clear body mass.65 The weight-neutral characteristic of metformin with the results of the UKPDS. The cost of type 2 DM to the may be due to its ability to decrease energy intake.66 United States healthcare system is enormous. With neweragents now available treatment costs will continue to rise as The contribution of decreased glycosuria to weight gain can well. Physicians must critically appraise the true benefits of be substantial and will be greatest in those with the poorest newer drugs (including combination agents) from the stand- baseline control. However, those with the poorest baseline point of glucose control, side effects, potential non-glycemic control will improve the most with therapy. For every 100 g effects and cost. This difficult task is made even more per day decrease in glycosuria, there is a positive energy difficult by the endless barrage of information provided by balance of 400 kcal per day.57 With 1 kg of adipose tissue pharmaceutical companies to physicians and patients alike.
representing approximately 7,700 kcal, it can take just 3 weeks It is not acceptable to allow the optimal care of patients with to gain 1 kg once glycosuria ceases. Data from the UKPDS type 2 DM to be so confusing as to be impossible for the busy demonstrated a 2.5 kg weight gain in the intensively treated clinician to implement. When looked at from the standpoint group versus the conventional group. The HbA1c difference of its component parts–insulin resistance and insulin was 0.9%.14 Thus, one might expect a 2.8 kg (6.16 pound) deficiency–the management of type 2 DM becomes some- weight gain for every 1% decline in HbA1c. The increased what clearer. Furthermore, if one is allowed the opportunity food intake associated with hypoglycemia may be related to to truly compare the cost and effectiveness of the newer the treatment of overt events, stimulation of appetite by mild agents and combination drugs with more tried agents, the hypoglycemia and attempts by the patient to prevent future appropriate choice of therapy becomes more obvious. Thepotential benefits of some newer agents on the cardio-vascular system and on β-cell rejuvenation need to be con-sidered, as well, with the significant burden that CVD andsecondary failure to oral agents represent in the managementof type 2 DM. This review hopes to demystify the managementof type 2 DM from the initiation of oral agents through dual(potentially triple) therapy onto insulin initiation. The morewe can understand about the agents available to us, the betteroff our patients will be.
Thanks to Gary S. Plank, Ph.D., former Manager, SecurityHealth Plan Pharmacy, and Eric Paulsen, Manager, Clinic Figure 3. Characteristic action profiles of a twice-daily regi-
Pharmacy of Wausau, for helping with drug costs. Thanks men of an intermediately acting insulin (black line) mixed also to Marshfield Clinic Research Foundation for providing with a short acting insulin (gray line).
assistance in the preparation of this manuscript through theservices of Graig Eldred and Alice Stargardt.
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© The Authors Journal compilation © 2009 Biochemical SocietyEssays Biochem. (2009) 46, 95–110; doi:10.1042/BSE0460007 Polyamine analogues targeting epigenetic gene regulation Yi Huang*, Laurence J. Marton†, Patrick M. Woster¶ and Robert A. Casero, Jr*1*The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Bunting ◊ Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, U.S.A., †Progen Pharmaceuticals, Redwood City, CA 94065, U.S.A., and ¶Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, U.S.A.

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