Dc12 0413.full


Published on

  • Be the first to comment

  • Be the first to like this

No Downloads
Total Views
On Slideshare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Dc12 0413.full

  1. 1. Reviews/Consensus Reports/ADA Statements P O S I T I O N S T A T E M E N TManagement of Hyperglycemia in Type 2Diabetes: A Patient-Centered ApproachPosition Statement of the American Diabetes Association (ADA) andthe European Association for the Study of Diabetes (EASD)SILVIO E. INZUCCHI, MD1 MICHAEL NAUCK, MD6 These recommendations should beRICHARD M. BERGENSTAL, MD2 ANNE L. PETERS, MD7 considered within the context of the needs,JOHN B. BUSE, MD, PHD3 APOSTOLOS TSAPAS, MD, PHD8 preferences, and tolerances of each patient;MICHAELA DIAMANT, MD, PHD4 RICHARD WENDER, MD9 individualization of treatment is the cor-ELE FERRANNINI, MD5 DAVID R. MATTHEWS, MD, DPHIL10,11,12 nerstone of success. Our recommenda- tions are less prescriptive than and not as algorithmic as prior guidelines. This fol-G lycemic management in type 2 di- information on the benefits/risks of glycemic lows from the general lack of comparative- abetes mellitus has become increas- control, recent evidence concerning efficacy effectiveness research in this area. Our ingly complex and, to some extent, and safety of several new drug classes intent is therefore to encourage an appre-controversial, with a widening array of (16,17), the withdrawal/restriction of others, ciation of the variable and progressivepharmacological agents now available (1–5), and increasing calls for a move toward more nature of type 2 diabetes, the specific rolemounting concerns about their potential patient-centered care (18,19). of each drug, the patient and diseaseadverse effects and new uncertainties re- This statement has been written in- factors that drive clinical decision makinggarding the benefits of intensive glycemic corporating the best available evidence (20–23), and the constraints imposed bycontrol on macrovascular complications and, where solid support does not exist, age and comorbidity (4,6). The implemen-(6–9). Many clinicians are therefore per- using the experience and insight of the tation of these guidelines will requireplexed as to the optimal strategies for their writing group, incorporating an extensive thoughtful clinicians to integrate currentpatients. As a consequence, the American review by additional experts (acknowl- evidence with other constraints and im-Diabetes Association (ADA) and the European edged below). The document refers to peratives in the context of patient-specificAssociation for the Study of Diabetes (EASD) glycemic control; yet this clearly needs to factors.convened a joint task force to examine the be pursued within a multifactorial riskevidence and develop recommendations for reduction framework. This stems from the PATIENT-CENTEREDantihyperglycemic therapy in nonpregnant fact that patients with type 2 diabetes are at APPROACHdEvidence-based adviceadults with type 2 diabetes. Several guide- increased risk of cardiovascular morbidity depends on the existence of primaryline documents have been developed by and mortality; the aggressive management source evidence. This emerges onlymembers of these two organizations (10) of cardiovascular risk factors (blood pres- from clinical trial results in highly selectedand by other societies and federations sure and lipid therapy, antiplatelet treat- patients, using limited strategies. It does(2,11–15). However, an update was ment, and smoking cessation) is likely to not address the range of choices available,deemed necessary because of contemporary have even greater benefits. or the order of use of additional therapies. Even if such evidence were available, thec c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c data would show median responses andFrom the 1Section of Endocrinology, Yale University School of Medicine and Yale-New Haven Hospital, not address the vital question of who New Haven, Connecticut; the 2International Diabetes Center at Park Nicollet, Minneapolis, Minnesota; the responded to which therapy and why (24). 3 Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Patient-centered care is defined as an ap- the 4Diabetes Center/Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands; the 5Department of Medicine, University of Pisa School of Medicine, Pisa, Italy; 6Diabeteszentrum proach to “providing care that is respectful Bad Lauterberg, Bad Lauterberg im Harz, Germany; the 7Division of Endocrinology, Keck School of Medicine, of and responsive to individual patient University of Southern California, Los Angeles, California; the 8Second Medical Department, Aristotle Uni- preferences, needs, and values and ensur- versity Thessaloniki, Thessaloniki, Greece; the 9Department of Family and Community Medicine, Jefferson ing that patient values guide all clinical de- Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; the 10Oxford Centre for Diabetes, cisions” (25). This should be the organizing Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, U.K.; the 11National Institute for Health Research (NIHR), Oxford Biomedical Research Centre, Oxford, U.K.; and the 12Harris Manchester principle underlying health care for indi- College, University of Oxford, Oxford, U.K. viduals with any chronic disease, but givenCorresponding author: Silvio E. Inzucchi, silvio.inzucchi@yale.edu. our uncertainties in terms of choice or se-DOI: 10.2337/dc12-0413 quence of therapy, it is particularly appro-This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 priate in type 2 diabetes. Ultimately, it is .2337/dc12-0413/-/DC1.S.E. Inzucchi and D.R. Matthews were co-chairs for the Position Statement Writing Group. R.M. Bergenstal, patients who make the final decisions re- J.B. Buse, A.L. Peters, and R. Wender were the Writing Group for the ADA. M. Diamant, E. Ferrannini, garding their lifestyle choices and, to some M. Nauck, and A. Tsapas were the Writing Group for the EASD. degree, the pharmaceutical interventionsThis article is being simultaneously published in 2012 in Diabetes Care and Diabetologia by the American they use; their implementation occurs in Diabetes Association and the European Association for the Study of Diabetes.© 2012 by the American Diabetes Association and Springer-Verlag. Readers may use this article as long as the the context of the patients’ real lives and work is properly cited, the use is educational and not for profit, and the work is not altered. See http:// relies on the consumption of resources creativecommons.org/licenses/by-nc-nd/3.0/ for details. (both public and private).care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online April 19, 2012
  2. 2. Position Statement Patient involvement in the medical or insulin, with a subset of overweight were suggestions in these trials that patientsdecision making constitutes one of the patients randomized to metformin. The without overt CVD, with shorter durationcore principles of evidence-based medi- overall HbA1c achieved was 0.9% lower of disease, and lower baseline HbA 1c,cine, which mandates the synthesis of best in the intensive policy group compared benefited from the more intensive strat-available evidence from the literature with with the conventional policy arm (7.0% egies. Modest improvements in somethe clinician’s expertise and patient’s own vs. 7.9%). Associated with this difference in microvascular end points in the studiesinclinations (26). During the clinical encoun- glycemic control was a reduction in the risk were likewise demonstrated. Finally, ater, the patient’s preferred level of involve- of microvascular complications (retinopa- meta-analysis of cardiovascular out-ment should be gauged and therapeutic thy, nephropathy, neuropathy) with inten- comes in these trials suggested that everychoices explored, potentially with the uti- sive therapy. A trend toward reduced rates HbA1c reduction of ;1% may be associ-lization of decision aids (21). In a shared of myocardial infarction in this group did ated with a 15% relative risk reduction indecision-making approach, clinician and not reach statistical significance (30). By nonfatal myocardial infarction, butpatient act as partners, mutually exchanging contrast, substantially fewer metformin- without benefits on stroke or all-causeinformation and deliberating on options, in treated patients experienced myocardial mortality (36).order to reach a consensus on the therapeu- infarction, diabetes-related and all-causetic course of action (27). There is good ev- mortality (32), despite a mean HbA1c only Overview of the pathogenesis ofidence supporting the effectiveness of this 0.6% lower than the conventional policy type 2 diabetesapproach (28). Importantly, engaging pa- group. The UKPDS 10-year follow-up Any rise in glycemia is the net result oftients in health care decisions may enhance demonstrated that the relative benefit of glucose influx exceeding glucose outflowadherence to therapy. having been in the intensive management from the plasma compartment. In the fast- policy group was maintained over a de- ing state, hyperglycemia is directly relatedBACKGROUND cade, resulting in the emergence of statisti- to increased hepatic glucose production. cally significant benefits on cardiovascular In the postprandial state, further glucoseEpidemiology and health care disease (CVD) end points and total mortality excursions result from the combinationimpact in those initially assigned to sulfonylurea/ of insufficient suppression of this glucoseBoth the prevalence and incidence of type 2 insulin, and persistence of CVD benefits output and defective insulin stimulationdiabetes are increasing worldwide, particu- with metformin (33), in spite of the fact of glucose disposal in target tissues, mainlylarly in developing countries, in conjunction that the mean HbA1c levels between the skeletal muscle. Once the renal tubularwith increased obesity rates and westerni- groups converged soon after the ran- transport maximum for glucose is excee-zation of lifestyle. The attendant economic domized component of the trial had ded, glycosuria curbs, though does notburden for health care systems is skyrocket- concluded. prevent, further hyperglycemia.ing, owing to the costs associated with treat- In 2008, three shorter-term studies Abnormal islet cell function is a keyment and diabetes complications. Type 2 [Action to Control Cardiovascular Risk in and requisite feature of type 2 diabetes. Indiabetes remains a leading cause of car- Diabetes (ACCORD) (34), Action in Dia- early disease stages, insulin production isdiovascular disorders, blindness, end-stage betes and Vascular Disease: Preterax and normal or increased in absolute terms,renal failure, amputations, and hospitaliza- Diamicron Modified-Release Controlled but disproportionately low for the degreetions. It is also associated with increased risk Evaluation (ADVANCE) (35), Veterans Af- of insulin sensitivity, which is typicallyof cancer, serious psychiatric illness, cogni- fairs Diabetes Trial (VADT) (36)] reported reduced. However, insulin kinetics, suchtive decline, chronic liver disease, acceler- the effects of two levels of glycemic control as the ability of the pancreatic b-cell toated arthritis, and other disabling or deadly on cardiovascular end points in middle- release adequate hormone in phase withconditions. Effective management strategies aged and older individuals with well- rising glycemia, are profoundly compro-are of obvious importance. established type 2 diabetes at high risk for mised. This functional islet incompetence cardiovascular events. ACCORD and VADT is the main quantitative determinant ofRelationship of glycemic control aimed for an HbA1c ,6.0% using complex hyperglycemia (37) and progresses overto outcomes combinations of oral agents and insulin. time. In addition, in type 2 diabetes, pan-It is well established that the risk of micro- ADVANCE aimed for an HbA1c #6.5% creatic a-cells hypersecrete glucagon, fur-vascular and macrovascular complications using a less intensive approach based on ther promoting hepatic glucose productionis related to glycemia, as measured by the sulfonylurea gliclazide. None of the (38). Importantly, islet dysfunction is notHbA1c; this remains a major focus of ther- trials demonstrated a statistically signif- necessarily irreversible. Enhancing insulinapy (29). Prospective randomized trials icant reduction in the primary combined action relieves b-cell secretory burden, andhave documented reduced rates of micro- cardiovascular end points. Indeed, in any intervention that improves glycemiadvascular complications in type 2 diabetic ACCORD, a 22% increase in total mortality from energy restriction to, most strikingly,patients treated to lower glycemic targets. with intensive therapy was observed, bariatric surgerydcan ameliorate b-cellIn the UK Prospective Diabetes Study mainly driven by cardiovascular mortality. dysfunction to an extent (39). More re-(UKPDS) (30,31), patients with newly di- An explanation for this finding has re- cently recognized abnormalities in the in-agnosed type 2 diabetes were randomized mained elusive, although rates of hypogly- cretin system (represented by the gutto two treatment policies. In the standard cemia were threefold higher with intensive hormones, glucagon-like peptide 1 [GLP-1],group, lifestyle intervention was the main- treatment. It remains unclear, however, if and glucose-dependent insulinotropicstay with pharmacological therapy used hypoglycemia was responsible for the ad- peptide [GIP]) are also found in type 2only if hyperglycemia became severe. In the verse outcomes, or if other factors, such as diabetes, but it remains unclear whethermore intensive treatment arm, patients were more weight gain, or simply the greater these constitute primary or secondary de-randomly assigned to either a sulfonylurea complexity of therapy, contributed. There fects (40). In most patients with type 22 DIABETES CARE care.diabetesjournals.org
  3. 3. Inzucchi and Associatesdiabetes, especially the obese, insulin re-sistance in target tissues (liver, muscle,adipose tissue, myocardium) is a promi-nent feature. This results in both glucoseoverproduction and underutilization.Moreover, an increased delivery of fatty acidsto the liver favors their oxidation, whichcontributes to increased gluconeogenesis,whereas the absolute overabundance of lip-ids promotes hepatosteatosis (41). Antihyperglycemic agents are directedat one or more of the pathophysiologicaldefects of type 2 diabetes, or modifyphysiological processes relating to appetiteor to nutrient absorption or excretion.Ultimately, type 2 diabetes is a diseasethat is heterogeneous in both pathogenesisand in clinical manifestationda point to beconsidered when determining the optimaltherapeutic strategy for individual patients.ANTIHYPERGLYCEMICTHERAPYGlycemic targetsThe ADA’s “Standards of Medical Care inDiabetes” recommends lowering HbA1cto ,7.0% in most patients to reduce the Figure 1dDepiction of the elements of decision making used to determine appropriate efforts toincidence of microvascular disease (42). achieve glycemic targets. Greater concerns about a particular domain are represented by in-This can be achieved with a mean plasma creasing height of the ramp. Thus, characteristics/predicaments toward the left justify moreglucose of ;8.3–8.9 mmol/L (;150–160 stringent efforts to lower HbA1c, whereas those toward the right are compatible with lessmg/dL); ideally, fasting and premeal glu- stringent efforts. Where possible, such decisions should be made in conjunction with the patient,cose should be maintained at ,7.2 mmol/L reflecting his or her preferences, needs, and values. This “scale” is not designed to be applied(,130 mg/dL) and the postprandial glu- rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with per-cose at ,10 mmol/L (,180 mg/dL). mission from Ismail-Beigi et al. (20).More stringent HbA1c targets (e.g., 6.0–6.5%) might be considered in selectedpatients (with short disease duration, long patient should also be considered, since general diabetes education (individual orlife expectancy, no significant CVD) if this the achievement of any degree of glucose group, preferably using an approved cur-can be achieved without significant hypo- control requires active participation and riculum), with a specific focus on dietaryglycemia or other adverse effects of treat- commitment (19,23,45,46). Indeed, any interventions and the importance of in-ment (20,43). Conversely, less stringent target could reflect an agreement between creasing physical activity. While encourag-HbA 1c goalsde.g., 7.5–8.0% or even patient and clinician. An important related ing therapeutic lifestyle change is importantslightly higherdare appropriate for pa- concept is that the ease with which more at diagnosis, periodic counseling shouldtients with a history of severe hypoglycemia, intensive targets are reached influences also be integrated into the treatmentlimited life expectancy, advanced complica- treatment decisions; logically, lower tar- program.tions, extensive comorbid conditions and gets are attractive if they can be achieved Weight reduction, achieved throughthose in whom the target is difficult to attain with less complex regimens and no or dietary means alone or with adjunctivedespite intensive self-management educa- minimal adverse effects. Importantly, uti- medical or surgical intervention, improvestion, repeated counseling, and effective lizing the percentage of diabetic patients glycemic control and other cardiovasculardoses of multiple glucose-lowering agents, who are achieving an HbA1c ,7.0% as a risk factors. Modest weight loss (5–10%) con-including insulin (20,44). quality indicator, as promulgated by vari- tributes meaningfully to achieving improved The accumulated results from the ous health care organizations, is inconsis- glucose control. Accordingly, establishing aaforementioned type 2 diabetes cardio- tent with the emphasis on individualization goal of weight reduction, or at least weightvascular trials suggest that not everyone of treatment goals. maintenance, is recommended.benefits from aggressive glucose man- Dietary advice must be personalizedagement. It follows that it is important to Therapeutic options (49). Patients should be encouraged to eatindividualize treatment targets (5,34–36). Lifestyle. Interventions designed to im- healthy foods that are consistent with theThe elements that may guide the clinician pact an individual’s physical activity lev- prevailing population-wide dietary rec-in choosing an HbA1c target for a specific els and food intake are critical parts of ommendations and with an individual’spatient are shown in Fig. 1. As mentioned type 2 diabetes management (47,48). All preferences and culture. Foods high in fiberearlier, the desires and values of the patients should receive standardized (such as vegetables, fruits, whole grains, andcare.diabetesjournals.org DIABETES CARE 3
  4. 4. 4 Table 1dProperties of currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes mellitus Primary physiological Class Compound(s) Cellular mechanism action(s) Advantages Disadvantages Cost Biguanides c Metformin Activates AMP-kinase c ↓ Hepatic glucose c Extensive experience c Gastrointestinal side effects LowDIABETES CARE production c No weight gain (diarrhea, abdominal Position Statement cramping) c No hypoglycemia c Lactic acidosis risk (rare) c Likely ↓ CVD events c Vitamin B12 deficiency (UKPDS) c Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc. Sulfonylureas 2nd generation Closes KATP channels c ↑ Insulin secretion c Extensive experience c Hypoglycemia Low c Glyburide/ on b-cell plasma c ↓ Microvascular risk c Weight gain glibenclamide membranes (UKPDS) c ? Blunts myocardial ischemic c Glipizide preconditioning c Gliclazideb c Low durability c Glimepiride Meglitinides c Repaglinide Closes KATP channels c ↑ Insulin secretion c ↓ Postprandial glucose c Hypoglycemia High (glinides) c Nateglinide on b-cell plasma excursions c Weight gain membranes c Dosing flexibility c ? Blunts myocardial ischemic preconditioning c Frequent dosing schedule Thiazolidinediones c Pioglitazone Activates the nuclear c ↑ Insulin sensitivity c No hypoglycemia c Weight gain Highe c Rosiglitazonec transcription factor c Durability c Edema/heart failure PPAR-g c Bone fractures c ↑ HDL-C c ↓ Triglycerides c ↑ LDL-C (rosiglitazone) (pioglitazone) c ? ↑ MI (meta-analyses, c ? ↓ CVD events rosiglitazone) (ProACTIVE, c ? ↑ Bladder cancer pioglitazone) (pioglitazone) a-Glucosidase c Acarbose Inhibits intestinal c Slows intestinal c No hypoglycemia c Generally modest HbA1c Moderate inhibitorsa c Miglitol a-glucosidase carbohydrate c ↓ Postprandial glucose efficacy c Vogliboseb,d digestion/absorption excursions c Gastrointestinal side effects c ? ↓ CVD events (flatulence, diarrhea) (STOP-NIDDM) c Frequent dosing schedule c Nonsystemic DPP-4 inhibitors c Sitagliptin Inhibits DPP-4 activity, c ↑ Insulin secretion c No hypoglycemia c Generally modest HbA1c High c Vildagliptina increasing postprandial (glucose-dependent) c Well tolerated efficacy c Saxagliptin active incretin (GLP-1, c ↓ Glucagon secretion c Urticaria/angioedema c Linagliptin GIP) concentrations (glucose-dependent) c ? Pancreatitis c Alogliptinb,d Continued on p. 5care.diabetesjournals.org
  5. 5. Table 1dContinued Primary physiological Class Compound(s) Cellular mechanism action(s) Advantages Disadvantages Cost Bile acid c Colesevelam Binds bile acids in c Unknown c No hypoglycemia c Generally modest HbA1c High sequestrantsa intestinal tract, c ? ↓ Hepatic glucose c ↓ LDL-C efficacy increasing hepatic production c Constipationcare.diabetesjournals.org bile acid production; c ? ↑ Incretin levels c ↑ Triglycerides ? activation of farnesoid c May ↓ absorption of other X receptor (FXR) in liver medications Dopamine-2 c Bromocriptine Activates dopaminergic c Modulates hypothalamic c No hypoglycemia c Generally modest HbA1c High agonistsa (quick-release)d receptors regulation of metabolism c ? ↓ CVD events efficacy c ↑ Insulin sensitivity (Cycloset Safety c Dizziness/syncope Trial) c Nausea c Fatigue c Rhinitis GLP-1 receptor c Exenatide Activates GLP-1 c ↑ Insulin secretion c No hypoglycemia c Gastrointestinal side effects High agonists c Exenatide receptors (glucose-dependent) c Weight reduction (nausea/vomiting) extended c ↓ Glucagon secretion c ? Potential for c ? Acute pancreatitis release (glucose-dependent) improved b-cell c C-cell hyperplasia/medullary c Liraglutide c Slows gastric emptying mass/function thyroid tumors in animals c ↑ Satiety c ? Cardiovascular c Injectable protective actions c Training requirements Amylin mimeticsa c Pramlintided Activates amylin c ↓ Glucagon secretion c ↓ Postprandial glucose c Generally modest HbA1c High receptors c Slows gastric emptying excursions efficacy c ↑ Satiety c Weight reduction c Gastrointestinal side effects (nausea/vomiting) c Hypoglycemia unless insulin dose is simultaneously reduced c Injectable c Frequent dosing schedule Insulins c Human NPH Activates insulin c ↑ Glucose disposal c Universally effective c Hypoglycemia Variablef c Human Regular receptors c ↓ Hepatic glucose c Theoretically unlimited c Weight gain c Lispro production efficacy c ? Mitogenic effects c Aspart c ↓ Microvascular risk c Injectable c Glulisine (UKPDS) c Training requirements c Glargine c “Stigma” (for patients) c Detemir c Premixed (several types) a Limited use in the U.S./Europe. bNot licensed in the U.S. cPrescribing highly restricted in the U.S.; withdrawn in Europe. dNot licensed in Europe. eTo be available as a generic product in 2012, with expected significant reductions in cost. fDepends on type (analogs . human insulins) and dosage. CKD, chronic kidney disease; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic peptide;DIABETES CARE GLP-1, glucagon-like peptide 1; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; PPAR, peroxisome proliferator–activated receptor; ProACTIVE, Prospective Pioglitazone Clinical Trial in Macrovascular Events (60); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (134); UKPDS, UK Prospective Diabetes Study (29–33).5 Inzucchi and Associates
  6. 6. Position Statementlegumes), low-fat dairy products, and fresh production (54,55). It is generally consid- can be significant in some. A limiting sidefish should be emphasized. High-energy ered weight-neutral with chronic use and effect is nausea and vomiting, particularlyfoods, including those rich in saturated does not increase the risk of hypoglycemia. early in the course of treatment. Concernsfats, and sweet desserts and snacks should Metformin is associated with initial gastro- regarding an increased risk of pancreatitisbe eaten less frequently and in lower intestinal side effects, and caution is ad- remain unresolved. The oral dipeptidylamounts (50–52). Patients who eventually vised to avoid its use in patients at risk for peptidase 4 (DPP-4) inhibitors enhancelose and keep weight off usually do so after lactic acidosis (e.g., in advanced renal in- circulating concentrations of activenumerous cycles of weight loss and relapse. sufficiency, alcoholism), a rare complica- GLP-1 and GIP (64). Their major effectThe health care team should remain non- tion of therapy. As noted earlier, there appears to be in the regulation of insulinjudgmental but persistent, revisiting and may be some cardiovascular benefits and glucagon secretion; they are weightencouraging therapeutic lifestyle changes from this drug, but the clinical trial data neutral. Typically, neither of the incretin-frequently, if needed. are not robust. based classes cause hypoglycemia by As much physical activity as possible The oldest oral agent class is the sulfo- themselves.should be promoted, ideally aiming for at nylurea insulin secretagogues. Through Two agents that are used infrequentlyleast 150 min/week of moderate activity the closure of ATP-sensitive potassium in the U.S. and Europe are the a-glucosidaseincluding aerobic, resistance, and flexi- channels on b-cells, these drugs stimulate inhibitors (AGIs), which retard gut carbohy-bility training (53). In older individuals, insulin release (56). While effective in con- drate absorption (65), and colesevelam, aor those with mobility challenges, so trolling glucose levels, their use is associ- bile acid sequestrant whose mechanism oflong as tolerated from a cardiovascular ated with modest weight gain and risk of glucose-lowering action remains poorlystandpoint, any increase in activity level hypoglycemia. In addition, studies have understood and whose major additionalis advantageous. demonstrated a secondary failure rate benefit is LDL-cholesterol reduction (66). At diagnosis, highly motivated pa- that may exceed other drugs, ascribed to Both have gastrointestinal effects, mainlytients with HbA1c already near target (e.g., an exacerbation of islet dysfunction (57). flatulence with AGIs and constipation,7.5%) could be given the opportunity Shorter-acting secretagogues, the megliti- with colesevelam. The dopamine agonistto engage in lifestyle change for a period nides (or glinides), stimulate insulin re- bromocriptine is only available in the U.S.of 3–6 months before embarking on lease through similar mechanisms but as an antihyperglycemic agent (67). Itspharmacotherapy (usually metformin). may be associated with less hypoglycemia mechanism of action and precise roleThose with moderate hyperglycemia or (58). They require more frequent dosing, are unclear. The amylin agonist, pramlintide,in whom lifestyle changes are anticipated however. is typically reserved for patients treatedto be unsuccessful should be promptly Thiazolidinediones (TZDs) are per- with intensive insulin therapy, usually instarted on an antihyperglycemic agent oxisome proliferator–activated receptor g type 1 diabetes mellitus; it decreases post-(also usually metformin) at diagnosis, activators (59) that improve insulin sen- prandial glucose excursions by inhibitingwhich can later be modified or possibly sitivity in skeletal muscle and reduce he- glucagon secretion and slowing gastricdiscontinued if lifestyle changes are suc- patic glucose production (54,55). They emptying (68).cessful. do not increase the risk of hypoglycemia The glucose-lowering effectiveness ofOral agents and noninsulin injectables. and may be more durable in their effective- noninsulin pharmacological agents is saidImportant properties of antihyperglyce- ness than sulfonylureas and metformin to be high for metformin, sulfonylureas,mic agents that play a role in the choice of (57). Pioglitazone appeared to have a mod- TZDs, and GLP-1 agonists (expecteddrug(s) in individual patients are summa- est benefit on cardiovascular events as a HbA1c reduction ;1.0–1.5%) (1,69,70),rized in Table 1. Ultimately, the aims of secondary outcome in one large trial in- and generally lower for meglitinides,controlling glycemia are to avoid acute volving patients with overt macrovascular DPP-4 inhibitors, AGIs, colesevelam,osmotic symptoms of hyperglycemia, to disease (60). Another agent of this class, and bromocriptine (;0.5–1.0%). How-avoid instability in blood glucose over rosiglitazone, is no longer widely available ever, older drugs have typically beentime, and to prevent/delay the develop- owing to concerns of increased myocardial tested in clinical trial participants withment of diabetes complications without infarction risk (61). Pioglitazone has re- higher baseline HbA1c, which is itself as-adversely affecting quality of life. Infor- cently been associated with a possible in- sociated with greater treatment emergentmation on whether specific agents have creased risk of bladder cancer (62). glycemic reductions, irrespective of ther-this ability is incomplete; an answer to Recognized side effects of TZDs include apy type. In head-to-head studies, anythese questions requires long-term, large- weight gain, fluid retention leading to differential effects on glucose control arescale clinical trialsdnot available for most edema and/or heart failure in predisposed small. So agent- and patient-specific prop-drugs. Effects on surrogate measures for individuals, and increased risk of bone erties, such as dosing frequency, side-effectglycemic control (e.g., HbA1c) generally fractures (57,60). profiles, cost, and other benefits oftenreflect changes in the probability of de- Drugs focused on the incretin system guide their selection.veloping microvascular disease but not have been introduced more recently (63). Insulin. Due to the progressive b-cellnecessarily macrovascular complications. The injectable GLP-1 receptor agonists dysfunction that characterizes type 2 di-Particularly from a patient standpoint, mimic the effects of endogenous GLP-1, abetes, insulin replacement therapy is fre-stability of metabolic control over time thereby stimulating pancreatic insulin se- quently required (71). Importantly, mostmay be another specific goal. cretion in a glucose-dependent fashion, patients maintain some endogenous insu- Metformin, a biguanide, remains the suppressing pancreatic glucagon output, lin secretion even in late stages of disease.most widely used first-line type 2 diabetes slowing gastric emptying, and decreasing Accordingly, the more complex and in-drug; its mechanism of action predomi- appetite. Their main advantage is weight tensive strategies of type 1 diabetes arenately involves reducing hepatic glucose loss, which is modest in most patients but not typically necessary (72).6 DIABETES CARE care.diabetesjournals.org
  7. 7. Inzucchi and Associates Ideally, the principle of insulin use is glucotoxicity resolved, and the metabolicthe creation of as normal a glycemic profile KEY POINTS state stabilized, it may be possible to taperas possible without unacceptable weight insulin partially or entirely, transferring to c Glycemic targets and glucose-loweringgain or hypoglycemia (73). As initial ther- noninsulin antihyperglycemic agents, per- therapies must be individualized.apy, unless the patient is markedly hyper- haps in combination. c Diet, exercise, and education remainglycemic and/or symptomatic, a “basal” If metformin cannot be used, another the foundation of any type 2 diabetesinsulin alone is typically added (74). Basal oral agent could be chosen, such as a treatment program.insulin provides relatively uniform insulin sulfonylurea/glinide, pioglitazone, or a c Unless there are prevalent contra-coverage throughout the day and night, DPP-4 inhibitor; in occasional cases where indications, metformin is the op-mainly to control blood glucose by sup- weight loss is seen as an essential aspect of timal first-line drug.pressing hepatic glucose production in therapy, initial treatment with a GLP-1 c After metformin, there are limitedbetween meals and during sleep. Either receptor agonist might be useful. Where data to guide us. Combinationintermediate-acting (neutral protamine available, less commonly used drugs (AGIs, therapy with an additional 1–2 oralHagedorn [NPH]) or long-acting (insulin colesevelam, bromocriptine) might also be or injectable agents is reasonable,glargine [A21Gly,B31Arg,B32Arg hu- considered in selected patients, but their aiming to minimize side effectsman insulin] or insulin detemir [B29Lys modest glycemic effects and side-effect where possible.(´-tetradecanoyl),desB30 human insulin]) profiles make them less attractive candi- c Ultimately, many patients will requireformulations may be used. The latter two dates. Specific patient preferences, char- insulin therapy alone or in com-are associated with modestly less overnight acteristics, susceptibilities to side effects, bination with other agents tohypoglycemia (insulin glargine, insulin de- potential for weight gain and hypoglycemia maintain glucose control.temir) than NPH and possibly slightly less should play a major role in drug selection c All treatment decisions, where possi-weight gain (insulin detemir), but are (20,21). (See Supplementary Figs. for ad- ble, should be made in conjunctionmore expensive (75,76). Of note, the dos- aptations of Fig. 2 that address specific with the patient, focusing on his/hering of these basal insulin analogs may differ, patient scenarios.) preferences, needs, and values.with most comparative trials showing a Advancing to dual combination therapy. c Comprehensive cardiovascular riskhigher average unit requirement with insu- Figure 2 (and Supplementary Figs.) also reduction must be a major focus oflin detemir (77). depicts potential sequences of escalating therapy. Although the majority of patients glucose-lowering therapy beyond met-with type 2 diabetes requiring insulin formin. If monotherapy alone does nottherapy can be successfully treated with achieve/maintain an HbA1c target overbasal insulin alone, some, because of pro- ;3 months, the next step would be togressive diminution in their insulin secre- Implementation strategies add a second oral agent, a GLP-1 recep-tory capacity, will require prandial insulin Initial drug therapy. It is generally tor agonist, or basal insulin (5,10). No-therapy with shorter-acting insulins. This agreed that metformin, if not contraindi- tably, the higher the HbA1c, the moreis typically provided in the form of the cated and if tolerated, is the preferred and likely insulin will be required. On average,rapid insulin analogs, insulin lispro most cost-effective first agent (42) (Fig. 2 any second agent is typically associated(B28Lys,B29Pro human insulin), insulin and Supplementary Figs.). It is initiated at, with an approximate further reduction inaspart (B28Asp human insulin), or insulin or soon after, diagnosis, especially in pa- HbA1c of ;1% (70,79). If no clinicallyglulisine (B3Lys,B29Glu human insulin), tients in whom lifestyle intervention alone meaningful glycemic reduction (i.e., “non-which may be dosed just before the meal. has not achieved, or is unlikely to achieve, responder”) is demonstrated, then, adher-They result in better postprandial glucose HbA1c goals. Because of frequent gastroin- ence having been investigated, that agentcontrol than the less costly human regular testinal side effects, it should be started at a should be discontinued, and anotherinsulin, whose pharmacokinetic profile low dose with gradual titration. Patients with a different mechanism of actionmakes it less attractive in this setting. with a high baseline HbA1c (e.g., $9.0%) substituted. With a distinct paucity of Ideally, an insulin treatment program have a low probability of achieving a near- long-term comparative-effectiveness trialsshould be designed specifically for an in- normal target with monotherapy. It may available, uniform recommendations ondividual patient, to match the supply of therefore be justified to start directly the best agent to be combined with metfor-insulin to his or her dietary/exercise hab- with a combination of two noninsulin min cannot be made (80). Thus, advantagesits and prevailing glucose trends, as revealed agents or with insulin itself in this circum- and disadvantages of specific drugs for eachthrough self-monitoring. Anticipated glucose- stance (78). If a patient presents with sig- patient should be considered (Table 1).lowering effects should be balanced with nificant hyperglycemic symptoms and/or Some antihyperglycemic medicationsthe convenience of the regimen, in the has dramatically elevated plasma glucose lead to weight gain. This may be associ-context of an individual’s specific therapy concentrations (e.g., .16.7–19.4 mmol/L ated with worsening markers of insulingoals (Fig. 1). [.300–350 mg/dL]) or HbA 1c (e.g., resistance and cardiovascular risk. One Proper patient education regarding $10.0–12.0%), insulin therapy should be exception may be TZDs (57); weight gainglucose monitoring, insulin injection strongly considered from the outset. Such associated with this class occurs in asso-technique, insulin storage, recognition/ treatment is mandatory when catabolic ciation with decreased insulin resistance.treatment of hypoglycemia, and “sick features are exhibited or, of course, if Although there is no uniform evidence thatday” rules is imperative. Where available, ketonuria is demonstrated, the latter re- increases in weight in the range observedcertified diabetes educators can be in- flecting profound insulin deficiency. Im- with certain therapies translate into a sub-valuable in guiding the patient through portantly, unless there is evidence of type 1 stantially increased cardiovascular risk, itthis process. diabetes, once symptoms are relieved, remains important to avoid unnecessarycare.diabetesjournals.org DIABETES CARE 7
  8. 8. Position StatementFigure 2dAntihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potentialsequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis(unless there are explicit contraindications). If the HbA1c target is not achieved after ;3 months, consider one of the five treatment options combinedwith metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historicalintroduction and route of administration and is not meant to denote any specific preference.) Choice is based on patient and drug characteristics, withthe over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection oftherapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may beused in place of sulfonylureas. Other drugs not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used whereavailable 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 isreasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-linetherapy, especially when HbA1c is very high (e.g., $9.0%). The therapeutic regimen should include some basal insulin before moving to morecomplex 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-4inhibitor; Fx’s, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at thisstage in patients with very high HbA1c (e.g., $9%). bConsider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregularmeal schedules or who develop late postprandial hypoglycemia on sulfonylureas. cSee Table 1 for additional potential adverse effects and risks, under“Disadvantages.” dUsually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. eCertain noninsulin agents may becontinued with insulin (see text). Refer to Fig. 3 for details on regimens. Consider beginning at this stage if patient presents with severe hyperglycemia($16.7–19.4 mmol/L [$300–350 mg/dL]; HbA1c $10.0–12.0%) with or without catabolic features (weight loss, ketosis, etc.).weight gain by optimal medication selec- may be tolerated by some, but not others. glucose-lowering agents in many environ-tion and dose titration. Fluid retention may pose a clinical or ments. For resource-limited settings, less For all medications, consideration merely an aesthetic problem (82). The expensive agents should be chosen. How-should also be given to overall tolerability. risk of bone fractures may be a specific con- ever, due consideration should be alsoEven occasional hypoglycemia may be cern in postmenopausal women (57). given to side effects and any necessarydevastating, if severe, or merely irritating, It must be acknowledged that costs monitoring, with their own cost impli-if mild (81). Gastrointestinal side effects are a critical issue driving the selection of cations. Moreover, prevention of morbid8 DIABETES CARE care.diabetesjournals.org
  9. 9. Inzucchi and Associateslong-term complications will likely reducelong-term expenses attributed to the disease.Advancing to triple combination ther-apy. Some studies have shown advantagesof adding a third noninsulin agent to atwo-drug combination that is not yet orno longer achieving the glycemic target(83–86). Not surprisingly, however, atthis juncture, the most robust responsewill usually be with insulin. Indeed, sincediabetes is associated with progressiveb-cell loss, many patients, especially thosewith long-standing disease, will eventuallyneed to be transitioned to insulin, whichshould be favored in circumstances wherethe degree of hyperglycemia (e.g., $8.5%)makes it unlikely that another drug will beof sufficient benefit (87). If triple combina-tion therapy exclusive of insulin is tried, thepatient should be monitored closely, withthe approach promptly reconsidered if itproves to be unsuccessful. Many monthsof uncontrolled hyperglycemia shouldspecifically be avoided. In using triple combinations the es- Figure 3dSequential insulin strategies in type 2 diabetes. Basal insulin alone is usually thesential consideration is obviously to use optimal initial regimen, beginning at 0.1–0.2 units/kg body weight, depending on the degree ofagents with complementary mechanisms hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. Inof action (Fig. 2 and Supplementary Figs.). patients willing to take more than one injection and who have higher HbA1c levels ($9.0%), twice-Increasing the number of drugs heightens daily premixed insulin or a more advanced basal plus mealtime insulin regimen could also bethe potential for side effects and drug–drug considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptableinteractions, raises costs, and negatively im- fasting glucose but HbA1c remains above target, consider proceeding to basal plus mealtime in-pacts patient adherence. The rationale, ben- sulin, consisting of one to three injections of rapid-acting analogs (see text for details). A lessefits, and side effects of each new medication studied alternativedprogression from basal insulin to a twice-daily premixed insulindcould beshould be discussed with the patient. The also considered (straight dashed arrow line); if this is unsuccessful, move to basal plus mealtime insulin. The figure describes the number of injections required at each stage, together with the relativeclinical characteristics of patients more or complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, withless likely to respond to specific combina- dose adjustments made based on the prevailing glucose levels as reported by the patient. Noninsulintions are, unfortunately, not well defined. agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typicallyTransitions to and titrations of insulin. stopped once more complex regimens beyond basal insulin are utilized. Comprehensive educationMost patients express reluctance to be- regarding self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response to,ginning injectable therapy, but, if the hypoglycemia are critical in any patient on insulin therapy. Mod., moderate.practitioner feels that such a transition isimportant, encouragement and educationcan usually overcome such reticence. In- weekly if the fasting glucose levels are above glucose excursions (e.g., to .10.0 mmol/Lsulin is typically begun at a low dose (e.g., the preagreed target is a reasonable ap- [.180 mg/dL]) occur. This is suggested0.1–0.2 U kg21 day21), although larger proach (89). As the target is neared, dosage when the fasting glucose is at target butamounts (0.3–0.4 U kg21 day21) are rea- adjustments should be more modest and the HbA1c remains above goal after 3–6sonable in the more severely hyperglyce- occur less frequently. Downward adjust- months of basal insulin titration (91). Themic. The most convenient strategy is ment is advisable if any hypoglycemia oc- same would apply if large drops in glucosewith a single injection of a basal insulin, curs. During self-titration, frequent contact occur during overnight hours or in be-with the timing of administration depen- (telephone, e-mail) with the clinician may tween meals, as the basal insulin dose isdent on the patient’s schedule and overall be necessary. Practitioners themselves can, increased. In this scenario, the basal insulinglucose profile (Fig. 3). of course, also titrate basal insulin, but this dose would obviously need to be simulta- Although extensive dosing instruc- would involve more intensive contact with neously decreased as prandial insulin is ini-tions for insulin are beyond the scope of the patient than typically available in rou- tiated. Although basal insulin is titratedthis statement, most patients can be taught tine clinical practice. Daily self-monitoring primarily against the fasting glucose, gen-to uptitrate their own insulin dose based of blood glucose is of obvious importance erally irrespective of the total dose, practi-on several algorithms, each essentially in- during this phase. After the insulin dose is tioners should be aware that the need forvolving the addition of a small dose increase stabilized, the frequency of monitoring prandial insulin therapy will become likely theif hyperglycemia persists (74,76,88). For should be reviewed (90). more the daily dose exceeds 0.5 U kg21example, the addition of 1–2 units (or, in Consideration should be given to the day21, especially as it approaches 1 U kg21those already on higher doses, increments addition of prandial or mealtime insulin day21. The aim with mealtime insulin is toof 5–10%) to the daily dose once or twice coverage when significant postprandial blunt postprandial glycemic excursions,care.diabetesjournals.org DIABETES CARE 9
  10. 10. Position Statementwhich can be extreme in some individuals, 2. All insulins are associated with some events. It follows that glycemic targets forresulting in poor control during the day. weight gain and some risk of hypo- elderly with long-standing or more com-Such coverage may be provided by one of glycemia. plicated disease should be less ambitioustwo methods. 3. The larger the doses and the more than for the younger, healthier individuals The most precise and flexible prandial aggressive the titration, the lower the (20). If lower targets cannot be achievedcoverage is possible with “basal-bolus” HbA1c, but often with a greater likeli- with simple interventions, an HbA1c oftherapy, involving the addition of premeal hood of adverse effects. ,7.5–8.0% may be acceptable, transition-rapid-acting insulin analog to ongoing 4. Generally, long-acting insulin analogs ing upward as age increases and capacitybasal insulin. One graduated approach reduce the incidence of overnight hy- for self-care, cognitive, psychological andis to add prandial insulin before the poglycemia, and rapid-acting insulin economic status, and support systemsmeal responsible for the largest glucose analogs reduce postprandial glucose decline.excursiondtypically that with the greatest excursions as compared with corre- While lifestyle modification can becarbohydrate content, often, but not always, sponding human insulins (NPH, Reg- successfully implemented across all age-the evening meal (92). Subsequently, a sec- ular), but they generally do not result in groups, in the aged, the choice of anti-ond injection can be administered before the clinically significantly lower HbA1c. hyperglycemic agent should focus onmeal with the next largest excursion (often drug safety, especially protecting againstbreakfast). Ultimately, a third injection may Metformin is often continued when hypoglycemia, heart failure, renal dys-be added before the smallest meal (often basal insulin is added, with studies dem- function, bone fractures, and drug–druglunch) (93). The actual glycemic benefits onstrating less weight gain when the two interactions. Strategies specifically mini-of these more advanced regimens after are used together (95). Insulin secretago- mizing the risk of low blood glucose maybasal insulin are generally modest in typical gues do not seem to provide for additional be preferred.patients (92). So, again, individualization HbA1c reduction or prevention of hypo- In contrast, healthier patients withof therapy is key, incorporating the degree glycemia or weight gain after insulin is long life expectancy accrue risk for vas-of hyperglycemia needing to be ad- started, especially after the dose is titrated cular complications over time. Therefore,dressed and the overall capacities of the and stabilized. When basal insulin is lower glycemic targets (e.g., an HbA1cpatient. Importantly, data trends from used, continuing the secretagogue may ,6.5–7.0%) and tighter control of bodyself-monitoring may be particularly help- minimize initial deterioration of glycemic weight, blood pressure, and circulatingful in titrating insulins and their doses control. However, secretagogues should lipids should be achieved to prevent orwithin these more advanced regimens to be avoided once prandial insulin regi- delay such complications. This usually re-optimize control. mens are employed. TZDs should be re- quires combination therapy, the early in- A second, perhaps more convenient duced in dose (or stopped) to avoid stitution of which may have the bestbut less adaptable method involves “pre- edema and excessive weight gain, al- chance of modifying the disease processmixed” insulin, consisting of a fixed com- though in certain individuals with large and preserving quality of life.bination of an intermediate insulin with insulin requirements from severe insulinregular insulin or a rapid analog. Tradi- resistance, these insulin sensitizers may be Weighttionally, this is administered twice daily, very helpful in lowering HbA1c and mini- The majority of individuals with type 2before morning and evening meals. In mizing the required insulin dose (96). diabetes are overweight or obese (;80%)general, when compared with basal insu- Data concerning the glycemic benefits of (102). In these, intensive lifestyle inter-lin alone, premixed regimens tend to incretin-based therapy combined with vention can improve fitness, glycemiclower HbA1c to a larger degree, but often basal insulin are accumulating; combina- control, and cardiovascular risk factorsat the expense of slightly more hypogly- tion with GLP-1 receptor agonists may be for relatively small changes in bodycemia and weight gain (94). Disadvan- helpful in some patients (97,98). Once weight (103). Although insulin resistancetages include the inability to titrate the again, the costs of these more elaborate is thought of as the predominate driver ofshorter- from the longer-acting compo- combined regimens must be carefully diabetes in obese patients, they actuallynent of these formulations. Therefore, considered. have a similar degree of islet dysfunctionthis strategy is somewhat inflexible but to leaner patients (37). Perhaps as a result,may be appropriate for certain patients OTHER CONSIDERATIONS the obese may be more likely to requirewho eat regularly and may be in need combination drug therapy (20,104).of a simplified approach beyond basal in- Age While common practice has favored met-sulin (92,93). (An older and less commonly Older adults (.65–70 years) often have a formin in heavier patients, because ofused variation of this two-injection strategy higher atherosclerotic disease burden, re- weight loss/weight neutrality, this drugis known as “split-mixed,” involving a fixed duced renal function, and more comor- is as efficacious in lean individuals (75).amount of intermediate insulin mixed by bidities (99,100). Many are at risk for TZDs, on the other hand, appear to bethe patient with a variable amount of regu- adverse events from polypharmacy and more effective in those with higher BMIs,lar insulin or a rapid analog. This allows for may be both socially and economically although their associated weight gaingreater flexibility in dosing.) disadvantaged. Life expectancy is reduced, makes them, paradoxically, a less attractive The key messages from dozens of especially in the presence of long-term option here. GLP-1 receptor agonists arecomparative insulin trials in type 2 diabetes complications. They are also more likely associated with weight reduction (38),include the following: to be compromised by hypoglycemia; for which in some patients may be substantial. example, unsteadiness may result in falls Bariatric surgery is an increasingly1. Any insulin will lower glucose and and fractures (101), and a tenuous cardiac popular option in severe obesity. Type 2 HbA1c. status may deteriorate into catastrophic diabetes frequently resolves rapidly after10 DIABETES CARE care.diabetesjournals.org
  11. 11. Inzucchi and Associatesthese procedures. The majority of patients (112), but the actual clinical relevance of this ongoing debate, however, as to whetherare able to stop some, or even all, of their remains unproven. Metformin may have these thresholds are too restrictive andantihyperglycemic medications, although some cardiovascular benefits and would that those with mild–moderate renal im-the durability of this effect is not known appear to be a useful drug in the setting pairment would gain more benefit than(105). of CAD, barring prevalent contraindica- harm from using metformin (124,125). In In lean patients, consideration should tions (32). In a single study, pioglitazone the U.K., the National Institute for Healthbe given to the possibility of latent autoim- was shown to reduce modestly major ad- and Clinical Excellence (NICE) guidelinesmune diabetes in adults (LADA), a slowly verse cardiovascular events in patients are less proscriptive and more evidence-progressive form of type 1 diabetes. These with established macrovascular disease. based than those in the U.S., generally al-individuals, while presenting with mild It may therefore also be considered, unless lowing use down to a GFR of 30 mL/min,hyperglycemia, often responsive to oral heart failure is present (60). In very pre- with dose reduction advised at 45 mL/minagents, eventually develop more severe liminary reports, therapy with GLP-1 re- (14). Given the current widespread report-hyperglycemia and require intensive insu- ceptor agonists and DPP-4 inhibitors has ing of estimated GFR, these guidelineslin regimens (106). Measuring titres of islet- been associated with improvement in ei- appear very reasonable.associated autoantibodies (e.g., anti-GAD) ther cardiovascular risk or risk factors, but Most insulin secretagogues undergomay aid their identification, encouraging a there are no long-term data regarding clin- significant renal clearance (exceptions in-more rapid transition to insulin therapy. ical outcomes (113). There are very limited clude repaglinide and nateglinide) and data suggesting that AGIs (114) and bromo- the risk of hypoglycemia is thereforeSex/racial/ethnic/genetic differences criptine (115) may reduce cardiovascular higher in patients with chronic kidneyWhile certain racial/ethnic features that events. disease (CKD). For most of these agents,increase the risk of diabetes are well recog- Heart failure. With an aging population extreme caution is imperative at more severenized [greater insulin resistance in Latinos and recent decreases in mortality after degrees of renal dysfunction. Glyburide(107), more b-cell dysfunction in East myocardial infarction, the diabetic patient (known as glibenclamide in Europe),Asians (108)], using this information to with progressive heart failure is an in- which has a prolonged duration ofcraft optimal therapeutic strategies is in its creasingly common scenario (116). This action and active metabolites, shouldinfancy. This is not surprising given the population presents unique challenges be specifically avoided in this group.polygenic inheritance pattern of the dis- given their polypharmacy, frequent hos- Pioglitazone is not eliminated renally, andease. Indeed, while matching a drug’s pitalizations, and contraindications to therefore there are no restrictions for usemechanism of action to the underlying various agents. TZDs should be avoided in CKD. Fluid retention may be a concern,causes of hyperglycemia in a specific patient (117,118). Metformin, previously contra- however. Among the DPP-4 inhibitors,seems logical, there are few data that com- indicated in heart failure, can now be used sitagliptin, vildagliptin, and saxagliptinpare strategies based on this approach if the ventricular dysfunction is not se- share prominent renal elimination. In the(109). There are few exceptions, mainly vere, if patient’s cardiovascular status is face of advanced CKD, dose reduction isinvolving diabetes monogenic variants of- stable, and if renal function is normal necessary. One exception is linagliptin,ten confused with type 2 diabetes, such as (119). As mentioned, cardiovascular ef- which is predominantly eliminated enter-maturity-onset diabetes of the young fects of incretin-based therapies, includ- ohepatically. For the GLP-1 receptor ago-(MODY), several forms of which respond ing those on ventricular function, are nists exenatide is contraindicated in stagepreferentially to sulfonylureas (110). currently under investigation (120). 4–5 CKD (GFR ,30 mL/min) as it is re-While there are no prominent sex differ- Chronic kidney disease. Kidney disease nally eliminated; the safety of liraglutide isences in the response to various antihyper- is highly prevalent in type 2 diabetes, and not established in CKD though pharmaco-glycemic drugs, certain side effects (e.g., moderate to severe renal functional im- kinetic studies suggest that drug levels arebone loss with TZDs) may be of greater pairment (eGFR ,60 mL/min) occurs in unaffected as it does not require renal func-concern in women. approximately 20–30% of patients tion for clearance. (121,122). The individual with progres- More severe renal functional impair-Comorbidities sive renal dysfunction is at increased risk ment is associated with slower elimina-Coronary artery disease. Given the fre- for hypoglycemia, which is multifactorial. tion of all insulins. Thus doses need to bequency with which type 2 diabetic patients Insulin and, to some degree, the incretin titrated carefully, with some awarenessdevelop atherosclerosis, optimal manage- hormones are eliminated more slowly, as for the potential for more prolongedment strategies for those with or at high risk are antihyperglycemic drugs with renal activity profiles.for coronary artery disease (CAD) are excretion. Thus, dose reduction may be Liver dysfunction. Individuals with typeimportant. Since hypoglycemia may ex- necessary, contraindications need to be 2 diabetes frequently have hepatosteatosisacerbate myocardial ischemia and may observed, and consequences (hypoglyce- as well as other types of liver diseasecause dysrhythmias (111), it follows that mia, fluid retention, etc.) require careful (126). There is preliminary evidence thatmedications that predispose patients to evaluation. patients with fatty liver may benefit fromthis adverse effect should be avoided, if Current U.S. prescribing guidelines treatment with pioglitazone (45,127,128).possible. If they are required, however, to warn against the use of metformin in It should not be used in an individual withachieve glycemic targets, patients should patients with a serum creatinine $133 active liver disease or an alanine transami-be educated to minimize risk. Because of mmol/L ($1.5 mg/dL) in men or 124 nase level above 2.5 times the upper limit ofpossible effects on potassium channels in mmol/L ($1.4 mg/dL) in women. Metfor- normal. In those with steatosis but milderthe heart, certain sulfonylureas have been min is eliminated renally, and cases of lactic liver test abnormalities, this insulin sensi-proposed to aggravate myocardial ischemia acidosis have been described in patients tizer may be advantageous. Sulfonylureasthrough effects on ischemic preconditioning with renal failure (123). There is an can rarely cause abnormalities in liver testscare.diabetesjournals.org DIABETES CARE 11
  12. 12. Position Statementbut are not specifically contraindicated; and life-limiting complications, especially CA; Robert Ratner, MedStar Health Researchmeglitinides can also be used. If hepatic CVD (19,23,70). Another issue about which Institute/Georgetown University School ofdisease is severe, secretagogues should be more data are needed is the concept of du- Medicine, Washington, DC; Julio Rosenstock,avoided because of the increased risk of rability of effectiveness (often ascribed to Dallas Diabetes and Endocrine Center at Medi-hypoglycemia. In patients with mild he- b-cell preservation), which would serve cal City, Dallas, TX; Guntram Schernthaner, Rudolfstiftung Hospital, Vienna, Austria; Robertpatic disease, incretin-based drugs can be to stabilize metabolic control and decrease Sherwin, Yale University School of Medicine,prescribed, except if there is a coexisting the future treatment burden for patients. New Haven, CT; Jay Skyler, Miller School ofhistory of pancreatitis. Insulin has no re- Pharmacogenetics may very well inform Medicine, University of Miami, Miami, FL;strictions for use in patients with liver im- treatment decisions in the future, guiding Geralyn Spollett, Yale University School ofpairment and is indeed the preferred choice the clinician to recommend a therapy for an Nursing, New Haven, CT; Ellie Strock, In-in those with advanced disease. individual patient based on predictors of ternational Diabetes Center, Minneapolis, MN;Hypoglycemia. Hypoglycemia in type 2 response and susceptibility to adverse ef- Agathocles Tsatsoulis, University of Ioannina,diabetes was long thought to be a trivial fects. We need more clinical data on how Ioannina, Greece; Andrew Wolf, University ofissue, as it occurs less commonly than in phenotype and other patient/disease char- Virginia School of Medicine, Charlottesville,type 1 diabetes. However, there is emerg- acteristics should drive drug choices. As VA; Bernard Zinman, Mount Sinai Hospital/ University of Toronto, Toronto, ON, Canada.ing concern based mainly on the results new medications are introduced to the The American Association of Diabetes Edu-of recent clinical trials and some cross- type 2 diabetes pharmacopeia, their benefit cators, American College of Physicians, andsectional evidence of increased risk of and safety should be demonstrated in stud- The Endocrine Society, and several other or-brain dysfunction in those with repeated ies versus best current treatment, substan- ganizations who wished to remain anony-episodes. In the ACCORD trial, the fre- tial enough both in size and duration to mous nominated reviewers who providedquency of both minor and major hypo- provide meaningful data on meaningful input on the final draft. Such feedback doesglycemia was high in intensively managed outcomes. It is appreciated, however, that not constitute endorsement by these groupspatientsdthreefold that associated with head-to-head comparisons of all combina- or these individuals. The final draft was alsoconventional therapy (129). It remains tions and permutations would be impossi- peer reviewed and approved by the Professionalunknown whether hypoglycemia was bly large (133). Informed judgment and the Practice Committee of the ADA and the Panel for expertise of experienced clinicians will Overseeing Guidelines and Statements of thethe cause of the increased mortality in EASD. We are indebted to Dr. Sue Kirkman ofthe intensive group (130,131). Clearly, therefore always be necessary. the ADA for her guidance and support duringhowever, hypoglycemia is more danger- this process. We also thank Carol Hill and Maryous in the elderly and occurs consistently Merkin for providing administrative assistance.more often as glycemic targets are low- AcknowledgmentsdThis position statement Fundingered. Hypoglycemia may lead to dys- was written by joint request of the ADA and The three face-to-face meetings and therhythmias, but can also lead to accidents the EASD Executive Committees, which have travel of some of the writing group were sup-and falls (which are more likely to be dan- approved the final document. The process in- ported by the EASD and ADA. D.R. Matthewsgerous in the elderly) (132), dizziness volved wide literature review, three face-to-face acknowledges support from the National In-(leading to falls), confusion (so other ther- meetings of the Writing Group, several tele- stitute for Health Research.apies may not be taken or taken incor- conferences, and multiple revisions via e-mail Duality of interest communications. During the past 12 months, the followingrectly), or infection (such as aspiration We gratefully acknowledge the following relationships with companies whose productsduring sleep, leading to pneumonia). Hy- experts who provided critical review of a or services directly relate to the subject matterpoglycemia may be systematically under- draft of this statement: James Best, Melbourne in this document are declared:reported as a cause of death, so the true Medical School, The University of Melbourne, R.M. Bergenstal: membership of scientificincidence may not be fully appreciated. Melbourne, Australia; Henk Bilo, Isala Clinics, advisory boards and consultation for or clinicalPerhaps just as importantly, additional con- Zwolle, the Netherlands; John Boltri, Wayne research support with Abbott Diabetes Care,sequences of frequent hypoglycemia in- State University School of Medicine, Detroit, Amylin, Bayer, Becton Dickinson, Boehringerclude work disability and erosion of the MI; Thomas Buchanan, Keck School of Ingelheim, Calibra, DexCom, Eli Lilly, Halozyme,confidence of the patient (and that of family Medicine, University of Southern California, Helmsley Trust, Hygieia, Johnson & Johnson,or caregivers) to live independently. Accord- Los Angeles, CA; Paul Callaway, University of Medtronic, NIH, Novo Nordisk, Roche, Sanofi, Kansas School of Medicine-Wichita, Wichita, and Takeda (all under contracts with hisingly, in at-risk individuals, drug selection employer). Inherited stock in Merck (held KS; Bernard Charbonnel, University of Nantes,should favor agents that do not precipitate Nantes, France; Stephen Colagiuri, The Uni- by family)such events and, in general, blood glucose versity of Sydney, Sydney, Australia; Samuel J.B. Buse: research and consulting withtargets may need to be moderated. Dagogo-Jack, The University of Tennessee Health Amylin Pharmaceuticals, Inc.; AstraZeneca; Science Center, Memphis, TN; Margo Farber, Biodel Inc.; Boehringer Ingelheim; Bristol-FUTURE DIRECTIONS/ Detroit Medical Center, Detroit, MI; Cynthia Myers Squibb Company; Diartis Pharmaceuticals,RESEARCH NEEDSdFor antihyper- Fritschi, College of Nursing, University of Illi- Inc.; Eli Lilly and Company; F. Hoffmann-Laglycemic management of type 2 diabetes, nois at Chicago, Chicago, IL; Rowan Hillson, Roche Ltd; Halozyme Therapeutics; Johnsonthe comparative evidence basis to date is The Hillingdon Hospital, Uxbridge, U.K.; & Johnson; Medtronic MiniMed; Merck &relatively lean, especially beyond metfor- Faramarz Ismail-Beigi, Case Western Reserve Co., Inc.; Novo Nordisk; Pfizer Inc.; Sanofi; University School of Medicine/Cleveland and TransPharma Medical Ltd (all undermin monotherapy (70). There is a significant VA Medical Center, Cleveland, OH; Devan contracts with his employer)need for high-quality comparative- Kansagara, Oregon Health & Science University/ M. Diamant: member of advisory boards ofeffectiveness research, not only regarding Portland VA Medical Center, Portland, OR; Abbott Diabetes Care, Eli Lilly, Merck Sharp &glycemic control, but also costs and those Ilias Migdalis, NIMTS Hospital, Athens, Dohme (MSD), Novo Nordisk, Poxel Pharma.outcomes that matter most to patientsd Greece; Donna Miller, Keck School of Medicine, Consultancy for: Astra-BMS, Sanofi. Speakerquality of life and the avoidance of morbid University of Southern California, Los Angeles, engagements: Eli Lilly, MSD, Novo Nordisk.12 DIABETES CARE care.diabetesjournals.org