Diabetes challenging cases

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Diabetes challenging cases

  1. 1. Challenging Cases 2012: in the Treatment of Type 2 Diabetes Faculty Rattan Juneja, MD Associate Professor of Clinical Medicine Indiana University School of Medicine Medical Director, Indiana University Diabetes CenterCase #1: Joan Sullivan: 52-year-old woman, Chief of Endocrinology, Wishard Memorial Hospitalmaternal history of type 2 diabetes Indianapolis, IN Learning ObjectivesVital signs and clinical and laboratory findings This activity is designed for specialists in primary care and endocrinology. Initial presentation One year later, after counseling, There are no prerequisites for this activity. At the conclusion of this diet, and exercise activity, participants should be able to: Age, years 52 53 • Preserve beta cell function, delay disease progression, and minimize the risk of diabetes-related complications by formulating Body weight, kg (lb.) 77.6 (171) 78.5 (173) an individualized treatment plan that addresses the multiple Hb A1c 7.0% 7.5% pathophysiologic mechanisms of diabetes. Blood pressure, mm Hg 118/78 122/82 • Recognize the fundamental features, benefits, and risks underlying Fasting plasma glucose, mg/dL 122 140 (retest: 145) current treatment recommendations when developing individualized treatment plans. Total cholesterol, mg/dL 195 212 • Employ multiple strategies to identify and reduce clinical inertia to LDL cholesterol, mg/dL 119 136 achieve optimal patient outcomes. HDL cholesterol, mg/dL 35 34 • Foster good patient self-management by establishing a Triglycerides, mg/dL 205 212 collaborative relationship with patients based on respect for Proteinuria Negative Negative individual patient preferences, needs, and values. • Establish a comprehensive conceptual framework for disease management of diabetes, hypertension, and hypercholesterolemiaAt her initial presentation, Mrs Sullivan There may also be biological reasons for so as to provide effective primary care based on current standards.was prescribed a program of counseling, the difficulty in losing weight, such as adiet, and exercise based on her laboratory mismatch between insulin production and CME Informationresults and weight. However, despite blood glucose peaks. This mismatch is due Release Date: June 25, 2012. Valid for credit through June 24, 2013.counseling for diet and exercise, she has to a reduction or loss of first-phase insulin This activity has been planned and implemented in accordance with thebeen unsuccessful in her attempts to lose production. The diminution of first-phase Essential Areas and Policies of the Accreditation Council for Continuingweight, her weight has increased, and her insulin release occurs because: (1) the Medical Education (ACCME) through the joint sponsorship of Indianaglycemic control has worsened. On her patient is producing maximal quantities University School of Medicine and Heath Focus, Inc. Indiana University School of Medicine is accredited by the ACCME to provide continuingreturn visit 1 year later, her fasting plasma of insulin to take care of the glucose the medical education for physicians. Indiana University School of Medicineglucose value was 140 mg/dL. On repeat, it body is producing from gluconeogenesis designates this enduring activity for a maximum of 4 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate withwas 145 mg/dL. She therefore satisfies the (basal glucose production); and (2) there the extent of their participation in the activity.criteria for type 2 diabetes.1 Most likely, her is a loss of meal-stimulated insulin release To receive credit, participants must review the slides and audio components of this website, and submit the activity evaluation formbeta cell function has continued to decline. (loss of the incretin effect) (see Figure 1). and posttest (passing score = 75% or higher). As a result, insulin release in response Length of time to complete the activity: 4 hoursThis scenario is common in patients to food ingestion is delayed, which in Disclosure Informationwith insulin resistance. Regardless of some instances may even precipitate late Commercial Supporttheir sincerity and intent to carry out postprandial hypoglycemia, which in turn Indiana University School of Medicine and Health Focus, Inc. gratefully acknowledge the unrestricted educational grant provided bythe required lifestyle modifications, could precipitate hunger. This loss of first- Eli Lilly & Company, Merck, Novo Nordisk, Sanofi.patients’ efforts often produce little phase insulin release is considered to besuccess. There are many reasons for this, the earliest detectable evidence of impaired Faculty Disclosure In accordance with the Accreditation Council for Continuing Medicalincluding social and environmental beta cell function. Education (ACCME) Standards for Commercial Support, educationalfactors, such as the time required for programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. Allexercise, familial and social patterns What is the best therapeutic approach faculty, authors, editors, and planning committee members participatingof overeating and underactivity, to improve Mrs Sullivan’s glycemic in an IUSM-sponsored activity are required to disclose any relevantlack of access to skilled counseling control in the short term AND to financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services thatand support, unhealthy nutritional maintain or improve her beta cell are discussed in an educational activity. Dr. Juneja reported that he hasenvironments (eg, the higher cost function in the long term? received consulting fees and/or honoraria from Alere, Amylin, Boehringer Ingelheim, Merck, Eli Lilly & Company, and Sanofi.of healthy foods and the ubiquitous Staff: Hassan Danesh, PhD, Monica Armin, and Dr. Deborah Teplow havepresence of cheap fast foods and junk According to current guidelines from disclosed that they have no potential or actual conflicts of interest.foods), and other barriers that challenge the American Diabetes Association CME Reviewer: Statements of disclosure of relevant financialpatients’ achievement of their goals. (ADA; Figure 2), initiation of metformin relationships have been obtained from Charles Clark Jr, MD. Dr. Clark has disclosed that he has no potential or actual conflicts of interest. Note: Although it offers CME credits, this activity is not intended to1 C M E c a se st u di es av ai l abl e at: w w w. 2012chall e n g i n g c a s e s i n d i a b e te s . c o m provide extensive training or certification in the field.
  2. 2. monotherapy is the recommendedapproach.2,3 Metformin monotherapy The Incretin Effect in Subjects Without andis usually successful in lowering With Type 2 Diabeteshemoglobin A1c (Hb A1c) levels to lessthan 7.0% in patients whose initial Hb Control Subjects Patients with Type 2 DiabetesA1c levels are equal to or greater than (n=8) (n=14)7.5%. However, it may not be the mostadvantageous approach because it is 0.6 0.6 80 80 Incretin The incretin effectnot likely to achieve the dual goals of Effect 0.5 is diminished 0.5therapy: improve glycemic control and in type 2 diabetes. IR Insulin, mU/L IR Insulin, mU/L 60 60preserve beta cell function. 0.4 0.4 nmol/L nmol / L 40 0.3 40 0.3Figure 3 shows beta cell function overtime, estimated using Homeostasis 0.2 0.2Model Assessment (HOMA), in patients 20 0.1 20 0.1who participated in the United KingdomProspective Diabetes Study (UKPDS).4 0 0 0 0Time zero represents the time at which 0 60 120 180 0 60 120 180patients were given the diagnosis of Time, min Time, mintype 2 diabetes and started treatment. Oral glucose loadIt was estimated that beta cell function Intravenous (IV) glucose infusionhad already declined by approximately50% in these patients, but treatment with Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.metformin, a sulfonylurea, or insulindid not prevent further decline in beta Figure 1. Demonstration of the Incretin Effect.cell function. The graphic on the left is from patients without diabetes. As can be seen, insulin production is much greater in response to oral glucose than IV glucose, because the incretin hormones GLP-1 and GIP are producedFigure 4 illustrates the implications of when glucose stimulates the intestine. In contrast, in patients with type 2 diabetes the incretin effect isdeclining beta cell function on Hb A1c diminished, either due to deficiency or decreased action, or both, of GLP-1.levels among patients in A Diabetes Position StatementOutcome Progression Trial (ADOPT).5These patients had mean initial Hb A1cvalues of approximately 7.3%, and theintroduction of metformin, glyburide,or rosiglitazone rapidly reduced Hb A1cvalues to acceptable levels. However,during the subsequent years, Hb A1clevels progressively worsened, so thatmost patients had Hb A1c levels ofgreater than 7.0% again within 3 yearsto 5 years, despite continued treatment.All 3 monotherapies tested reducedmean Hb A1c levels soon after initiationin patients with newly diagnosed type2 diabetes. However, Hb A1c levelsprogressively worsened during theensuing years, so that mean levels weregreater than 7.0% within 4 to 5 years oftreatment initiation.Using metformin monotherapy, wewould expect Mrs Sullivan’s Hb A1c levelto decline to less than 7.0% soon afterinitiation of treatment. But it is likely a Consider beginning at this stage in patients with very high HbA1c (e.g., $9%). bConsider rapid-acting, nonsulfonylurea secreta- Figure 2dAntihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potential gogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas.that it would return to a level above sequences of antihyperglycemic therapy. In most patients,glargine, detemir) in combination with noninsulin agents. dCertain noninsulin agents mayafter, diagnosis c Usually a basal insulin (NPH, begin with lifestyle changes; metformin monotherapy is added at, or soon be7.0% within a few years, requiring the (unless there are explicit contraindications). insulin. continued with If the HbA1c target is not achieved after ;3 months, consider one of the five treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historicaladdition of a second drug at that time. introduction 2. Algorithm for Individualized Management of Type 2 Diabetes According to the drug characteristics, with Figure and route of administration and is not meant to denote any specific preference.) Choice is based on patient and ADA.Unfortunately, Mrs Sullivan’s beta cell the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of The algorithm recommends initial monotherapy using metformin, followed by addition of a second therapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may befunction is likely to have deteriorated used in place of sulfonylureas. Other drugsA1c target levels are not achieved. antihyperglycemic agent if Hb not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line2 To e a r n C M E c redi t, compl ete the pos ttes t and whenaHbA1ctiisovery high (e.g., 2 0 1 2 c h a l ltherapeutic c a s e s ishould includessome m insulin before moving to more therapy, especially e v l u a n a t www. $9.0%). The e n g i n g regimen n d i a b e te . c o basal complex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two- drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c $10.0–12.0%). DPP-4-i, DPP-4 inhibitor; Fx’s, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at this stage in patients with very high HbA1c (e.g., $9%). bConsider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. cSee Table 1 for additional potential adverse effects and risks, under
  3. 3. over this time, and deteriorating betacell function could make treatmentmore challenging. UKPDS: β-Cell Loss Over TimeTo prevent long-term loss of beta cell 100function and reduce glycemic levels inthe short term, I recommend startingpatients on monotherapy (usually using β-Cell Function (%)* 75 Patients treatedmetformin) and then introducing a with insulin,second oral agent as soon as metformin is metformin,titrated to the maximum tolerated dosage, 50 sulfonylureas‡regardless of the patient’s Hb A1c level.The second drug should have a differentmechanism of action than the first drug, 25 IGT† Postprandial Type 2 Type 2 Diabetes Diabeteshave no risk or low risk of hypoglycemia, Hyperglycemia Phase I Type 2 Phase IIIand facilitate weight loss or weight Diabetes Phase IImaintenance, according to patient needs. 0This approach is more similar to the -12 -10 -6 -2 0 2 6 10 14glycemic control algorithm recommended Years From Diagnosisby the American Association of Clinical * Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based onEndocrinologists/American College of Homeostasis Model Assessment (HOMA) data from UKPDS. † IGT=impaired glucose testingEndocrinology (AACE/ACE) (Figure 5).6 ‡ The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and were determined by the HOMA model.This algorithm recommends that patients Lebovitz HE. Diabetes Rev. 1999;7:139-153.start with dual therapy if their Hb A1c isequal to or lower than 7.6%. Figure 3. Beta Cell Function Estimated Using the HOMA Model for Patients With Pre-diabetes and Type 2 Diabetes.Although Mrs Sullivan’s Hb A1c level isjust below the recommended threshold Long-term Efficacy of Monotherapy: ADOPTfor use of 2 drugs, for reasons discussed,I would advocate planning to use dual Long-term Efficacy of Monotherapy: ADOPTtherapy with her. However, therapiesoften need to be introduced gradually. 8.0Note also that the Hb A1c goal in the Treatment difference (95% Cl)AACE/ACE algorithm (6.5%) is lower Rosiglitazone vs metformin -0.13 (-0.22 to -0.05); P=.002than the ADA-recommended goal of 7.6 Rosiglitazone vs glyburide7.0%, and that all guidelines recommend -.042 (-0.50 to -0.33); P<.001adding a second antihyperglycemic 7.2agent if the goal is not reached within 2 A1C, %months to 3 months. 6.8Although there is no direct clinical Annualized slope (95% Cl) 6.4trial evidence to support the approach Rosiglitazone, 0.07 (0.06 to 0.09)outlined above, it is clear that the Metformin, 0.14 (0.13 to 0.16)traditional approach—monotherapy, 6.0 Glyburide, 0.24 (0.23 to 0.26)followed by waiting until the Hb A1c 0level returns to unacceptable levels, and 0 1 2 3 4 5then adding the second drug—appears Yearsto perpetuate beta cell failure and failsto provide long-term glycemic control Reproduced with permission from Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.in most patients. For this reason, thedual-therapy approach is advocated byexperts on the basis of indirect evidence Figure 4. Mean Hb A1c Levels in Patients in the ADOPT Trial.from the UKPDS data and otherstudies, such as the Insulin Resistance healthy, has a long life-expectancy with pursuing more stringent glycemic goalsAtherosclerosis Study.7,8 few comorbidities, and appears to be than the standard of less than 7.0%, such motivated and capable of self-care. as an Hb A1c level of 6.5%.Beyond considerations of beta cell Principles of individualizing Hb A1cfunction, we should consider how Hb targets and therapeutic approaches (see Tighter glycemic targets, as well asA1c targets should be individualized. next case and Figure 8)9,10 should lead us lower body weight, blood pressure, andThis patient is relatively young and to discuss with Mrs Sullivan the goal of blood lipid levels, have been advocated3 C M E c a se st u di es av ai l abl e at: w w w. 2012chall e n g i n g c a s e s i n d i a b e te s . c o m
  4. 4. in such patients as a way to prevent orforestall disease progression and thedevelopment of complications, and topreserve quality of life.9, 10Oral diabetes therapies need to beinitiated gradually and titrated tooptimize compliance, minimizeadverse effects, and reduce the riskof hypoglycemia. One importantbarrier to good self-managementis adverse effects. By immediatelybeginning dual-agent therapy at fulldosages, Mrs Sullivan could haveadverse effects that she may considerintolerable and be less motivated toadhere to recommended treatment.This problem is especially prevalentwith the use of metformin.As shown in Figure 6, metabolic defects * May not be appropriate for all patientsin diabetes include increases in the ** patients with diabetes and A1c 6.5%, Forappearance of glucose in the blood, as pharmacologix Rx may be considered *** f A1c goal not achieved safely Iwell as defects in the disposal or use of  Prefered initial agent 1 DPP4 if  PPG and  FPG or GLP-1 if  PPGglucose. Figure 7 shows that different 2 if metabolic syndrome and/or nonalcoholic TZD fatty liver disease (NAFLD)classes of oral antihyperglycemic 3 AGI if  PPG 4 Blinide if  PPG or SU if  FPGagents target different aspects of the 5 Low-dose secretagogue recommended 6 Discontinue insulin secretagogue with a)glucose control system. Metformin multidose insulin b) Can use pramlintide with prandial insulinprimarily reduces glucose output 7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4from the liver, thereby reducing 8 If A 8.5%, combination Rx with agents © AACE 1ccause hypoglycemia Update.used with be reproduced December 2009 should be May not thatglucose appearance, so a good choice caution 9 If A1c 8.5%, in patients on Dual Therapy,for a second drug would be one that Figure 5. From the AACE/ACE Algorithm for Glycemic Control.6 insulin should be consideredaffects glucose disposal, such as athiazolidinedione (TZD), a dipeptidylpeptidase-4 (DPP-4) inhibitor, or a Normal and Abnormal Glucose ControlGLP-1 agonist. 11 Nutrient Appearance vs DisappearanceWhat is a good strategy for initiatingtreatment with metformin? Plasma glucoseMetformin is often associated with changes only whenadverse side effects, especially diarrhea, appearance (Ra)causing difficulties in tolerability and does not match Meallack of compliance. These problems disappearance (Rd). Derivedoften can be overcome by introducing Hepatic Glucose Glucosethe drug at a low dosage and titrating In diabetes, appearance Productionthe dosage to the maximum that can be is increased and disposal Ratolerated (not exceeding a maximum is impaired.of 2000 mg to 2500 mg per day). The Plasma Glucoseproblem can also be mitigated by using Therapies may address Ra,an extended-release formulation of the Rd, or both. Rddrug, but titration is still important.At any dosage, if the diarrhea becomesintolerable, I advise the patient toback off to the last dosage they foundtolerable, wait 1 week, and then tryagain. If, despite this approach, they Figure 6. Normal and Abnormal Glucose Control.still are unable to tolerate the dosage In type 2 diabetes, hepatic glucose production is increased and disposal of blood glucose is impaired. Bothrequired to achieve target Hb A1c levels, effects contribute to high blood glucose levels.4 To e a r n C M E c redi t, compl ete the pos ttes t and e v a l u a ti o n a t www. 2 0 1 2 c h a l l e n g i n g c a s e s i n d i a b e te s . c o m
  5. 5. especially if they are already taking anextended-release formulation, I might No Single Class of Oral Antihyperglycemicconsider a metformin formulation Monotherapy Targets All Key Pathophysiologiesthat is released more slowly in theintestines, such as Glumetza. Incretin Alpha- Meglitinides3 SUs4,5 Mimetics/How would you discuss the treatment Glucosidase TZDs 6,7 Metformin 8 DPP-4 Inhibitors1,2 Inhibitorsplan with Mrs Sullivan? Major PathophysiologiesIt is important to combine active Insulin deficiency   pharmacologic treatment with patienteducation and counseling about the  goals of therapies, the therapeutic Insulin resistance *strategy, and future treatment plans,such as the plan to introduce a second Excess hepatic   agent after metformin therapy is glucose outputestablished. The goals of education Intestinaland counseling are to increase MrsSullivan’s understanding of the disease glucose absorption  process and the potential of her diabetes 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.to worsen, and enhance her confidence 3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.in her ability to follow an effective 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005. 8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.treatment plan. * Applies only to GLP1 agonistsMy discussion with Mrs Sullivan Figure 7. Pathophysiologic Processes Targeted by Different Antihyperglycemic Agents.will include several important topics, Although metformin improves insulin resistance, its main effect is to reduce hepatic glucose output.including:• Why treatment is necessary and amount of glucose that enters your body, Because metformin can cause diarrhea, I’m important and (2) improve the way your body uses the going to start you at a low dosage and then• Goals of treatment glucose to produce the energy you need to gradually increase it, because the diarrhea• Rationale for the treatment plan carry out your daily activities. goes away in most people once their body• How to manage side effects gets used to the medication. I want you to• Plans for monitoring What is the rationale for the treatment start taking 500 mg metformin as a single• Managing any barriers or challenges plan? pill with every evening meal. Taking it she anticipates To achieve these goals, we need to use 2 with the evening meal does 2 things: (1) it different drugs that work together. The makes the diarrhea less bothersome, and (2)More specifically, here is an example of safest drug – the one that has been around your liver tends to make the most glucosehow I would cover these issues with Mrs for the longest time – is metformin. Its main at nighttime, so taking metformin in theSullivan: effect is to reduce the amount of glucose evening will have the greatest effect. that your liver produces. Our first step is Why is treatment necessary and to get you started on metformin during Metformin will lower your blood sugar important? this first month. After 2 to 3 months, without making it go below normal limits Your blood sugar level (known as Hb A1c) your Hb A1c level may drop below 7.0% or because it only reduces the glucose your is 7.5%, indicating that your blood sugar even 6.5%. But from the results of many liver is making, and, therefore, doesn’t level is above the level known to increase studies, I know that it is likely that your carry the risk of making your blood sugar your risk for damage to your eyes, nerves, blood sugar level may not stay low for very bottom out. The goal is to eventually get and kidneys. So, we need to bring this long; therefore, we also need to use a drug you on the maximum dosage because it blood sugar level down. that improves how your body uses glucose. is most effective that way. So, I will ask you to gradually increase the amount you What are our goals of treatment? So, I plan to introduce a second drug at your take in weekly increments. You start now There are 2 main goals in bringing this blood next visit. This drug targets a different part by taking 500 mg for the first week with sugar down. One goal is to reduce the chances of the disease process in a different way than your evening meal. Next week, you’ll take that you’ll have complications related to high metformin. We will, however, need to make 500 mg in the morning with breakfast glucose values. Keeping your Hb A1c values sure that the 2 drugs together do not cause and 500 mg in the evening with dinner. below 7.0% will do that. your blood sugar to go too low. During the third week, you’ll take 500 mg in the morning and 1000 mg (2 pills) in The second goal is to help your body use What are the possible side effects of the the evening. And by the fourth week, you’ll glucose efficiently for energy. To do this, medicine and how can they be avoided take 1000 mg (2 pills) in the morning and we need to do 2 things: (1) decrease the or managed? 1000 mg (2 pills) in the evening.5 C M E c a se st u di es av ai l abl e at: w w w. 2012chall e n g i n g c a s e s i n d i a b e te s . c o m
  6. 6. If diarrhea is a problem and becomes should be avoided in patients with polypeptide. In turn, this stimulates intolerable when you start taking 4 pills heart failure. Both drugs are associated glucose-mediated insulin release and per day, for example, then you can go back with an increased risk of bone fracture,16 suppresses glucagon. These drugs to 3 pills per day, 1 in the morning and 2 in and some experts have argued that do not suppress appetite and do not the evening. Wait 1 week and then try the pioglitazone should be limited to a slow gastric emptying, thus their 4 pills again. If diarrhea is still intolerable, dosage of 30 mg per day to minimize use is not associated with nausea. then go back to the 3 pills that you could the risk of bladder cancer.17 Although they lower Hb A 1c levels in tolerate and that will be the dosage that you patients with diabetes, 21,22 they usually will continue to use because we want you The GLP-1 receptor agonists, which are less potent than GLP-1 receptor to take as much as you can tolerate up to a include exenatide, liraglutide, and agonists. The DPP-4 inhibitors also maximum of 2000 mg per day. exenatide extended-release (a once- have little effect on body weight and a-week formulation), increase insulin are considered weight neutral. 2 These How will you know that the treatment secretion in a glucose-dependent agents may also be a good option for is working? manner, decrease glucagon secretion, Mrs Sullivan, depending on whether At this time, I also want you to see a and thereby reduce hepatic glucose her goal is to maintain her weight or diabetes educator who will teach you how output, slow gastric emptying, and lose weight. Two key advantages of to monitor your own blood glucose levels. suppress appetite.2 They are also the DPP-4 inhibitors are that they are The purpose of this monitoring is so you associated with weight loss, making administered orally and are usually can see for yourself if you are reaching them valuable treatment options for well tolerated. Furthermore, there is your blood sugar target. Our treatment overweight or obese patients. But evidence that these agents improve plan is designed to get your blood sugar patients need to be counseled about beta cell function, lower Hb A 1c levels level between 70 mg/dL and 130 mg/dL how much weight loss to expect. A in patients already taking metformin, before you eat. realistic weight loss associated with and are associated with low rates GLP-1 receptor agonist therapy is 3 of hypoglycemia. 23-25 Cases of acuteWith the knowledge that Mrs Sullivan kg to 5 kg, though some patients can pancreatitis have been reported inis concerned about gaining weight, lose much more. These agents have patients receiving DPP-4 inhibitors.what antihyperglycemic agents also been reported to improve beta cellare the best choice to add after her function in some studies.18-20 CASE SUMMARYappropriate metformin dosage isestablished? GLP-1 receptor agonists do have Metformin is most often the first agent several disadvantages. Most notably, recommended for treatment initiation.The choices of add-on therapy for Mrs they are administered via injection and When considering dual therapy,Sullivan are a sulfonylurea, a TZD, a are associated with gastrointestinal numerous factors affect the choice ofDPP-4 inhibitor, or a GLP-1 receptor side effects (nausea, vomiting, which antihyperglycemic agent to useagonist. Since sulfonylureas are known diarrhea).2 However, the drugs are in combination with metformin. Mrsto be associated with weight gain in better tolerated when the dose is Sullivan has achieved a reasonablepatients with type 2 diabetes and may titrated gradually. New, long-acting Hb A1c level (6.5%), which is withinactually worsen beta cell function, they formulations of GLP-1 receptor the targets recommended by thewould not be our choice here.2,12 agonists (once-weekly exenatide) may ADA and on the border for targets be good options to minimize nausea recommended by AACE/ACE. In eitherThe TZDs, pioglitazone and (they are administered in a fixed dose case, a second drug is important torosiglitazone, have many characteristics and do not need titration) and for prevent the worsening of the Hb A1cthat would make them good agents for patients uncomfortable with frequent control that has been shown to occuruse in combination with metformin. injections. Cases of pancreatitis have with monotherapy alone.5,15 The secondThese drugs activate peroxisome been reported in patients receiving agent should be one that works by aproliferator-activated receptor-gamma GLP-1 receptor agonists, and patients different mechanism than metformin,leading to direct improvements in should be cautioned about this risk. does not cause weight gain, and hasperipheral insulin sensitivity.13 There There is also an increase in medullary a low potential for hypoglycemia. Ais also evidence that they may improve c-cell hyperplasia in animal studies DPP-4 inhibitor would be a good choicebeta cell function,14,15 and they are reported with some of these agents; for Mrs Sullivan, but because she hasassociated with very low incidence of thus, it is recommended that they expressed concerns about her weight,hypoglycemia. However, both agents not be used in patients with multiple a GLP-1 receptor agonist might be aare also associated with weight gain, endocrine neoplasia type 2. better choice for her because the GLP-1so Mrs Sullivan would not benefit from agonists have more of an effect on Hbeither of these drugs.2 Furthermore, The DPP-4 inhibitors include A1c levels and also facilitate weightrosiglitazone is now available only sitagliptin, saxagliptin, and linagliptin. loss. The recent availability of a once-through an enrollment-based access They are oral agents that inhibit the weekly formulation of exenatide mayprogram because of the potential risk breakdown of incretin hormones and reduce concerns about the frequency offor cardiovascular disease. Pioglitazone thus increase endogenous GLP-1 and required injections and also minimizeis also associated with edema and glucose-dependent insulinotropic nausea.6 To e a r n C M E c redi t, compl ete the pos ttes t and e v a l u a ti o n a t www. 2 0 1 2 c h a l l e n g i n g c a s e s i n d i a b e te s . c o m
  7. 7. The importance of lifestyle modifications His Hb A1c is now back up to 7.9%, and are important to you because everyonewithin a comprehensive treatment plan Mr Hamilton has curtailed some of is unique and has individual interestsshould be re-emphasized, preferably his favorite activities: He reveals that, and goals. What are one or two thingsas part of a formal diabetes education although he used to love to work in that you want to achieve from theprogram. This program should include his garden on evenings and weekends, treatment of your diabetes?guidance on starting and maintaining he recently hired someone to mow the Patient: Well, I know I need to get myan exercise regimen that includes at grass and just lets everything else go blood sugar down, but nothingleast 150 minutes of moderate-intensity because he gets tired too easily to do seems to work.aerobic exercise spread out throughout yard work. In discussing treatment Physician: Yes, I agree that we need tothe week, and resistance training at options for him, Mr Hamilton states get your blood sugar level down, andleast twice per week.2 that he never wanted to use a glucose that the treatments you’ve had up meter and just wants medication that to now have not worked as well as CLINICAL RECOMMENDATIONS will allow him to eat his favorite foods we’d hoped. Your lab results already without worrying about his blood show some signs of damage to your • When selecting noninsulin sugar, though he is becoming concerned kidneys, probably caused by a high therapies for patients with about his increasing weight. blood sugar level. type 2 diabetes, incorporate considerations for weight loss How would you develop a treatment In a very simple, nonjudgmental way, and long-term maintenance of plan for Mr Hamilton that has a strong we’ve raised the issue of his difficulties glycemic control, minimizing chance of success? in managing his care, expressed hypoglycemia. empathy, and given him the opportunity • Incorporate patient education into Mr Hamilton’s diabetes control is to express his goals in his own words. every clinic visit, including how suboptimal, and probably has been for By echoing those goals back to him and to minimize and respond to any some time. He clearly has difficulty reinforcing them, we have taken an side effects of medications, the adhering to lifestyle modifications, important first step toward increasing importance of continued lifestyle which are an important element his motivation to develop and adhere modifications, and the rationale of diabetes treatment. If treatment to a plan that can be more successful for each patient’s individualized goals are to be achieved, it is crucial in controlling his diabetes. We’ve also treatment plan. that he embraces the treatment plan, reframed his statement that “nothing believes it is realistic, and is willing seems to work” by introducing a and capable of following it. A recent timeframe (“up to now”) and a relativeCase #2: Frederick Hamilton: Position Statement from the ADA and value (“as well as we’d hoped”). By62-year-old man, given a the European Association for the Study reframing his treatment experiencediagnosis of type 2 diabetes 7 of Diabetes (EASD) has emphasized the from a failure to one that suggests theyears ago importance of using a patient-centered potential for change, we introduce hope. approach to the treatment diabetes, Using a patient-centered approach likeVital signs and clinical and laboratory findings stating that “recommendations should this helps many patients feel more Body weight, kg (lb) 101.4 (223.5) be considered within the context of engaged in their treatment plan and Blood pressure, mm Hg 134/84 the needs, preferences, and tolerances can improve their motivation to adhere Hb A1c 7.9% of each patient; individualization to the recommended treatment plan. Urinary albumin/creatinine ratio 30 mg/g on 2 of treatment is the cornerstone of determinations success.”9 Mr Hamilton’s belief that nothing worksMr Hamilton is a 62-year-old white man can be addressed through questioningwho works as a short-haul truck driver. Using a patient-centered approach that may help to elicit the reasons for this.On his time off, he is devoted to his hobby requires us to have a conversationof landscape gardening. He was given a with each patient to elicit their needs, Physician: Let’s talk about some problemsdiagnosis of type 2 diabetes 7 years ago, preferences, and tolerances. As we you’ve run into so we understand aat which time he was prescribed lifestyle review this case and develop a treatment little more about your situation. I’mmodification and glimepiride (initially 2 plan for Mr Hamilton, we will provide confident that we can find treatmentsmg/day, then 4 mg/day). Two years later, examples of how to engage patients in that work better for you.his Hb A1c was 8.1%, so pioglitazone was the kinds of conversations that establish • I know that you’re a truck driver. Doesadded at 30 mg per day, then increased a patient-centered approach and foster this make it hard for you to get healthyto 45 mg per day. Six months later, his better self-management. foods while you’re on the road?Hb A1c was down to 7.1%, but his • Do you have trouble taking yourweight had increased to 105 kilograms. Physician: I know that a number of medicine at the right time?His pioglitazone dose was reduced to factors, such as your job, have made • Are these medicines too expensive?30 mg per day because of concerns managing your diabetes a challenge. Are you taking the full doses?about the risk of bladder cancer at the I’m sure there are some things we • Have you had any problems with low45 mg dose. can talk about to make some of this blood sugar? Is that a concern for you easier. First, let’s discuss what goals while you’re driving?7 C M E c a se st u di es av ai l abl e at: w w w. 2012chall e n g i n g c a s e s i n d i a b e te s . c o m
  8. 8. • Are there other problems, such as family or social problems, that could Factors Influencing Individualization of A1c Targets be creating some challenges for you in controlling your diabetes? A1c target Patient: Well, driving does make it hard, and Most intensive Least intensive my medicine doesn’t always make me feel better. Like, sometimes when I take all my 6.0% 8.0%è medicine, I feel weak and light-headed. Patient attitude and expected treatment That worries me when I’m driving, so efforts I sometimes skip taking it if I know I’m Highly motivated, Less motivated, going to be driving. Other times when I adherent, nonadherent, feel light-headed after taking my medicine, I just eat something and it gets better, but excellent poor self-care I can’t always do that when I’m driving. self-care capabilities capabilitiesThis conversation has helped us Risks associated with Low Highunderstand some of the reasons hypoglycemiawhy he is having trouble getting his Disease duration 0-10 20+diabetes under control. We can usethis knowledge, along with his input, Life expectancy Long Shortto design an alternative treatment Important Absent Severeplan that is more compatible with his comorbiditieslifestyle, potentially improving hisadherence to therapy.9 Established vascular Absent Severe complicationsThese discussions can also help us to set Resources, support Readily available Limitedand adjust realistic Hb A1c goals that are systemachievable and that obtain the greatestbenefits without exposing him to excessive Figure 8. Factors that Influence the Selection of an Hb A1c Target for Individual Patients.9,10risks of hypoglycemia or to treatment sideeffects that may jeopardize compliance. occupation make it difficult for him to to bring him to an Hb A1c target of lessFactors based on recent opinions and comply with diet and exercise regimens. than 7%. Note that although the DPP-4position statements influencing the selection He needs more aggressive treatment inhibitors are generally well tolerated,of an Hb A1c target are shown in Figure that can help him achieve key clinical cases of pancreatitis have been reported8.9,10 We have learned that Mr Hamilton has goals while enabling him to adhere to in patients using these drugs.poor access to support resources, difficulty the treatment over time.with compliance, high risks associated We may choose to switch to a GLP-1with hypoglycemia, and some evidence of Our initial goal for Mr Hamilton is to receptor agonist in 6 months to 12 monthsmicrovascular complications. Therefore, negotiate a plan that works for him, if Mr Hamilton shows good compliancewe may choose to individualize his target which should involve reducing his risk with all changes necessary to improve hisHb A1c level to a goal of less than 7.0% to of hypoglycemia, thereby improving his diabetes control. One could argue that ifminimize worsening of his microvascular ability to comply with treatment. The Mr Hamilton has achieved his desiredcomplications; but at the same time, drug that is causing the hypoglycemia Hb A1c goals with a DPP-4 inhibitor andgiven his fear of hypoglycemia , we need is glimepiride, so it should be pioglitazone, there would be no needto choose a drug that mitigates that risk. discontinued. He can continue to take to change his medications. This would,We also need to consider a drug that he the pioglitazone that had been added to indeed, be a suitable decision. However,can take once a day with no relationship his treatment plan after 2 years since he if we want to work with him to achieveto meals, since his eating habits can be seems to be tolerating that well. his personal goal of weight loss, theninconsistent. switching the DPP-4 inhibitor to a GLP-1 To replace the glimepiride, we can receptor agonist would be a better choiceAfter factoring in Mr Hamilton’s consider a DPP-4 inhibitor. Even though for him. As shown in Figures 9 and 10,individual needs, goals, and desires, they are less potent than GLP-1 receptor both liraglutide and extended-releasewhat are the best treatment options for agonists in terms of reducing Hb A1c exenatide were associated with weighthim? levels, the DPP-4 inhibitors have been loss in clinical trials.22,27 In contrast, the reported to reduce blood sugar levels by DPP-4 inhibitors are considered weightMr Hamilton is already showing 0.5% to 0.8%.26 With improved adherence neutral. Another reason to consider thisearly signs of microvascular damage, to treatment from better tolerance of a change would be if his blood sugar goalsprobably related to poor glycemic DPP-4 inhibitor (versus a sulfonylurea), were not being met with the DPP-4/control. In addition, his lifestyle and it is realistic to expect that we will be able pioglitazone combination.8 To e a r n C M E c redi t, compl ete the pos ttes t and e v a l u a ti o n a t www. 2 0 1 2 c h a l l e n g i n g c a s e s i n d i a b e te s . c o m
  9. 9. Although short-acting exenatide islikely to reduce Mr Hamilton’s Hb A1c Liraglutide and Sitagliptin: Weight from Baselineto desirable levels, it has a number ofcharacteristics that would be drawbacksfor this particular patient. He mentionedthat he doesn’t always know when hewill be able to eat because of his driving Liraglutide or sitagliptin added to metformin in patients not achieving adequateschedule. Short-acting exenatide, glycemic control on metformin alonehowever, needs to be administeredwithin a 60-minute window before 0 4 8 12 16 20 24meals.28 Furthermore, when beginning 0 Change in bodyweight (kg)treatment with short-acting exenatide, -0.5many patients experience nausea. -1.0 -1.5This side effect could be especially Both -2.0 P0.0001problematic considering Mr Hamilton’s -2.5occupation and history of skipping -3.0treatment doses to avoid potential side -3.5effects. -4.0 -4.5CASE SUMMARY LAG 1.2 mg LAG 1.8 mg SITA 100 mgMy approach would be to discontinueglimepiride and start one of the Pratley R et al. Lancet. 2010;375:1447-1456.established DPP-4 inhibitors at fulldose. I would arrange for Mr Hamilton Figure 9. Change in Body Weight Associated with Adding Liraglutide (1.2 mg or 1.8 mg) or Sitagliptin toto participate in a formal educational Metformin in Patients with Type 2 Diabetes.program on diabetes self-management,even if he has participated in the past.The reason for him to repeat the class is Exenatide Once Weekly vsto reinforce his self-management skills Twice Daily in T2DMand help him recognize the criticalimportance of blood glucose monitoring,which he has been reluctant to do in the Exenatide once a weekpast. He should return to the clinic after (n=148), baseline 102 kg3 months so we can assess how this new Exenatide twice a daytreatment regimen is working for him. (n=147), baseline 102 kg 0It could be argued that stopping the Least Square Mean (SE)glimepiride completely might actually Change in Weight , kg -1result in worsening of glycemic control.This is indeed possible, but by getting -2the patient engaged in a diabetesself-management program, we might -3gain better glucose control than was -4being achieved with glimepiride.There are data showing that seeing a -5certified diabetes educator can result 0 3 6 10 14 18 22 26 30in substantial Hb A1c reduction.2 My Time, wkphilosophy is that the best care forpatients with diabetes is the care they Reproduced with permission from Drucker D, et al. Lancet. 2008;372:1240-1250.believe in.By discontinuing the drug that causes Figure 10. Change in Body Weight in Patients with Type 2 Diabetes During Treatment with Twice-Daily orhypoglycemia, we may even reduce Once-Weekly Formulations of Exenatide.“defensive eating,” and we might findthat his Hb A1c level actually improves In addition to his elevated Hb A1c level, converting enzyme (ACE) inhibitorafter the change. We can always add in Mr Hamilton currently has high blood is a preferred choice in this settinganother agent—after a 3-month period— pressure, which should be treated. And because of their dual antihypertensiveif his glycemic control continues to he has evidence of microalbuminuria, so and renal-protective properties. Thesedeteriorate. It is in his best interest to give controlling both his diabetes and blood drugs should to be titrated up to targethim a chance to try his best. pressure is crucial. An angiotensin- blood pressure of less than 130/80 mm9 C M E c a se st u di es av ai l abl e at: w w w. 2012chall e n g i n g c a s e s i n d i a b e te s . c o m
  10. 10. Hg and until his urine albumin declinesinto the normal range. Low HDL-C Elevated BP Inflammation CLINICAL RECOMMENDATIONS • Identify each patient’s goals for treatment, preferences, and Abdominal Insulin tolerances to optimize the chances Smoking adiposity resistance for long-term success in the treatment of type 2 diabetes. • Use a nonjudgmental conversational style to prompt Elevated LDL-C Elevated blood Elevated glucose patients to openly discuss their triglycerides individual concerns and barriers, and echo those challenges back to them, so they recognize that Figure 11. Hallmarks of Metabolic Syndrome. you are incorporating their concerns into the treatment plan and working to overcome their barriers. Goals to Prevent Complications • Use existing guidelines as a starting point for clinical Measure ADA Standard/Goal decision-making, then individualize glycemic targets A1c 7% and treatment strategies to Blood pressure 130/80, lower if kidney disease develop a plan that works best for each patient. Dilated eye exam At least once a year Foot exam Check feet every dayCase #3: Frank Molson:51-year-old man, metabolic Smoking Stop!!!syndrome 100 md/dL if no known CVC LDL (mg/dL)Vital signs and clinical and laboratory findings 70 mg/dL if known CVD Height, cm (in) 175 (5’9”) Triglycerides (mg/dL) 150 Body weight, kg (lb) 91.4 kg (201) 45 (men) Waist circumference, cm (in) 104 cm (41) HDL (mg/dL) 55 (women) Blood pressure, mm Hg 138/86 American Diabetes Association. Diabetes Care . 2011;34(supp 1):S11-S61 Hb A1c 7.6% Fasting plasma glucose, mg/dL 146 Figure 12. Clinical Goals for Each Risk Factor According to the ADA. LDL cholesterol, mg/dL 137 HDL cholesterol, mg/dL 39 Mr Molson was prescribed the following Mr Molson has most of the hallmarks medications: of metabolic syndrome (Figure 11), Total cholesterol, mg/dL 220 including a waist circumference Triglycerides, mg/dL 220 • Lisinopril: 10 mg per day greater than 40 inches ( 102 cm), type Urine albumin Negative • Metformin: 1000 mg twice daily 2 diabetes mellitus with ongoing poor Serum creatinine 1.1 mg/dL (reference • Sitagliptin: 100 mg once daily glycemic control, hypertension (blood range = 0.9-1.3 • Simvastatin: 20 mg once daily pressure 130/85 while taking an mg/dL) ACE inhibitor), elevated triglycerides Because of his budgetary restrictions, (≥ 150 mg/dL), and low high-densityFrank Molson is a 51-year-old white he had been taking sitagliptin every lipoprotein (HDL) cholesterol levelsman. He is a self-employed construction other day, but recently has not renewed ( 40 mg/dL for men). 1 Together andcontractor with an unpredictable work his sitagliptin prescription because he individually, these characteristics areschedule and a busy family life. He cannot afford the co-pay for (nongeneric) risk factors for cardiovascular disease,has indicated that he would like some sitagliptin. and all need to be addressed. Clinicaladvice on weight loss. He has a tight goals for each risk factor, according tobudget, and his insurance co-pay for Would you try to address all of Mr the ADA, are shown in Figure 12.nongeneric medications is very high. Molson’s problems at one clinic visit?10 To e a r n C M E c redi t, compl ete the pos ttes t and e v a l u a ti o n a t www. 2 0 1 2 c h a l l e n g i n g c a s e s i n d i a b e te s . c o m

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