- Email: [email protected]
Evolving Treatment Strategies for the Management of Type 2 Diabetes
SYMPOSIUM ARTICLE
Evolving Treatment Strategies for the Management of Type 2 Diabetes William T. Cefalu, MD
Abstract: It is well known that improved metabolic control significantly reduces both micro- and macrovascular complications in diabetes. As it relates to specific treatment of type 2 diabetes mellitus, clinicians have traditionally initiated lifestyle intervention and progressed therapy using various drug treatments first as monotherapy and then as combination therapy throughout the course of the disease. This “stepwise” strategy has not always achieved the desired outcome of normal glycemic control; consequently, several clinical problems, such as hypoglycemia, weight gain and postprandial hyperglycemia, persist. However, new therapies that improve glycemic control and have favorable effects to address the unmet clinical problems have recently been developed or are still in development. These therapies include 2 classes of incretin-directed therapy, the dipeptidyl peptidase-4 inhibitors and the glucagon-like peptide-1 agonists, which help restore physiologic levels and activity of the incretin glucagon-like peptide-1. Also in development are additional therapies that have effects on the kidney to promote glucose excretion. These therapies are proposed to treat the key metabolic abnormalities associated with type 2 diabetes mellitus and minimize the side effects noted with conventional therapies. Key Indexing Terms: Diabetes; Incretins; Treatment. [Am J Med Sci 2012;343(1):21–26.]
O
ver the recent past, a great amount of research has been devoted to understand the contribution of hyperglycemia and its treatment on the complications of both type 1 and type 2 diabetes mellitus (T2DM). Specifically, the complications of diabetes have been classified as either microvascular (ie, retinopathy, nephropathy and neuropathy) or macrovascular [ie, cardiovascular disease (CVD), cerebrovascular accidents and peripheral vascular disease]. The development of complications is a cause of considerable morbidity and increases disability and mortality for the individual with diabetes. Fortunately, as a scientific community, we have recognized the pivotal role that chronic hyperglycemia contributes to the development of both microvascular and macrovacular disease.1,2 Chronic hyperglycemia is objectively measured by obtaining glycated hemoglobin levels, that is, A1c, which reflects glycemic control over the preceding 2 to 3 months. In this regard and based on landmark clinical trials such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, glucose control as defined by target levels for the A1c has been recommended.3 In addition, the concept of “metabolic memory” has been observed in which glucose control during the early stages of disease presentation seems to have long-term From the Joint Program on Diabetes, Endocrinology and Metabolism, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, and Louisiana State University Heath Sciences Center School of Medicine, New Orleans, Louisiana. This paper was presented as part of the Joint Plenary Session Symposium, which was held at the annual Southern Regional Meeting on February 18, 2011, New Orleans, Louisiana. Correspondence: William T. Cefalu, MD, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808 (E-mail: [email protected]).
effects on the development of micro- and macrovascular complications.1,2,4 However, despite these findings, data from largescale prospective trials report that in high-risk patients, intensive therapy to lower A1c levels below suggested targets may actually increase mortality or not favorably affect cardiovascular outcomes.5–7 Interestingly, it has been observed that certain subsets of patients may benefit from intensive glycemic control.5 More recent findings suggest that given that the excess mortality in the group randomized to intensive glycemic management was seen only at A1c levels ⬎7%, mortality may actually be greater for those who maintain a higher A1c level despite attempts at intensive glycemic management.8 Thus, the findings regarding A1c targets for selected patient populations as evaluated by the large-scale clinical trials continue to evolve to this day and remain important data for clinicians.
TRADITIONAL APPROACH TO TREATMENT To achieve the suggested glycemic targets for glucose control of T2DM, lifestyle intervention, that is, diet and exercise, has traditionally been the first step. However, diabetes is a progressive disease that is characterized not only by the presence of insulin resistance but also by the abnormalities in hepatic glucose production (HGP) and a progressive decline in -cell function over time.9 To treat patients with T2DM effectively, the provider must have a good understanding of both the underlying pathophysiology and the natural history of the disease. On the basis of the need to address the former, many antidiabetic agents from many classes are available for use by the clinician. These classes have included agents that increase insulin secretion, improve insulin action and delay absorption of carbohydrates. The newer treatments available, that is, incretin therapies, also modulate glucose supply.9 –11 Thus, given the natural history of the disease and the currently available options, treatment strategies have usually progressed from monotherapy with an oral antihyperglycemic agent, to uptitration of the agent chosen for monotherapy, to prescribing combination therapy with agents from different classes.10,11 When combination fails to provide acceptable control, insulin (generally a basal insulin) may be added to oral therapy. It is not uncommon—and, in fact, is generally the case—that more intensive insulin therapy (ie, addition of pre-meal fast-acting insulin) is needed. In many ways, this can be viewed as a treatment-to-failure approach as patients are generally advanced to the next stage only when their failure to respond has been well documented. Thus, current approaches to the management of T2DM have been described as suboptimal because patients may have inadequate glycemic control for most of their treatment (Figure 1).12,13 On the basis of the concerns with the traditional approach, recommendations have been suggested that the provider target the underlying pathophysiology of T2DM; treat hyperglycemia early and effectively with combination therapies; adopt a holistic, multidisciplinary approach and improve patient understanding of T2DM. If these recom-
The American Journal of the Medical Sciences • Volume 343, Number 1, January 2012
21
Cefalu
Traditional Stepwise Approach and Suggested Early Combination Approach to the Treatment of Type 2 Diabetes
Traditional stepwise approach Diet and OAD OAD OAD OAD plus exercise monotherapy up-titration combination basal insulin
OAD plus multiple daily insulin injections
HbA1c, %
10
Mean HbA1c of patients
9 8 7 6
Early combination approach
mendations were implemented, it was believed that the risk of diabetes-related complications would be decreased, patient’s quality of life increased and healthcare cost related to diabetes favorably impacted.12 It is now believed that the clinical issues not adequately addressed by current therapies are edema, weight gain, the need to improve glycemia with minimal hypoglycemia and the need to decrease gastrointestinal effects (Table 1). The risk for weight gain with conventional approaches has been noted for years and is one that is clearly being addressed by the newer therapies. Before the release of the incretin therapies, metformin was the agent that had the advantage over sulfonylureas and thiazolidinediones (TZDs) as it was considered relatively weight neutral. The limitations of the traditional approach were also highlighted in the landmark studies evaluating glycemic control and heart disease (ie, Accord and Advance) as intensive therapy revealed some unmet needs in conventional T2DM therapy. Thus, the results from the recent large-scale studies support the need for appropriate individualization of glycemic targets and of the means to achieve these targets, with the ultimate clinical goal of optimizing outcomes and minimizing the adverse events, such as hypoglycemia and marked weight gain.14 Patient groups requiring special consideration were recently identified and practical guidance specific to each group was also recently provided by the report of Del Prato et al.14 In addition to the failure of the current antidiabetic therapies to deal satisfactorily with hypoglycemia and weight gain, another consideration that has not been adequately addressed and that has been recently reviewed is the issue of glycemic variability or glucose fluctuations occurring postprandially.10,11 Obtaining adequate and reliable information on glycemic excursions after meals for patients in the outpatient clinics remains a challenge. As reviewed, it is recognized that most of the traditional therapies (ie, metformin, sulfonylureas, TZDs and insulin) do not adequately
TABLE 1. Clinical problems associated with conventional therapies Most therapies are associated with weight gain Hypoglycemia, generally associated with insulin and insulin secretagogues Other AEs with some therapies include GI side effects and edema Failure to adequately control postprandial glucose Failure to maintain long-term glycemic control AE, adverse event; GI, gastrointestinal.
22
FIGURE 1. Step-wise traditional treatment approach and an approach that is not only individualized but provides more aggressive treatment to achieve glycemic targets earlier in the course of disease for Type 2 diabetes. Adapted from Del Prato S, Felton AM, Munro N, et al. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract 2005;59:1345–5512 and Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000;7:625–31.13
address postmeal glucose. These “conventional therapies” have mechanisms either to address the pancreatic insufficiency (ie, increase insulin secretion and provide effective insulin levels) or to increase sensitivity in the tissues. In other words, the traditional approach to the treatment of T2DM focused primarily on “insulin demand” as these therapies addressed the deficits in insulin activity needed for the uptake, storage and utilization of glucose.9 –11 However, it was reported years ago that diabetes is also associated with defects in glucose production by the liver—specifically, a failure to suppress glucagon—which drives HGP and contributes greatly to postprandial glucose. The abnormalities in HGP currently remain well accepted in defining T2DM.9 –11,15 The clinical result from hepatic glucose oversupply is the resulting increase in both fasting and postprandial hyperglycemia. This concept was recently reviewed9 –11; in brief, glucose production by the liver or the appearance of glucose in the bloodstream from meal ingestion (ie, “glucose supply”) must be in balance with the amount of glucose that is taken up and used by peripheral tissues (ie, muscle and fat).9 If the glucose supply is greater than glucose disposal and utilization, glucose dysregulation is present, and the clinical result is hyperglycemia and a diagnosis of impaired glucose tolerance leading to T2DM. In general, HGP is measured with precise techniques such as the euglycemic-hyperinsulinemic clamp, but for the clinician, a valuable observation is that HGP is very much related to fasting glucose. DeFronzo et al16,17 clearly demonstrated this years ago, presenting data showing that patients with T2DM have higher HGP than their nondiabetic counterparts and that a significant, positive correlation (r ⫽ 0.847; P ⬍ 0.001) was also found between the rate of basal HGP and fasting glucose in the diabetic group.16,17 Other research has indicated that glucagon plays a pivotal role in HGP as studies revealed that if plasma glucagon is suppressed using somatostatin in patients with T2DM, the level of HGP can be reduced significantly.18 For the clinician, these studies provide valuable clinical information as, collectively, the research to date suggests the following: (1) that the level of fasting glucose in T2DM is clearly related to the level of basal HGP and gives a measure of endogenous glucose overproduction; (2) that glucose production by the liver is regulated by the glucagon–insulin axis; (3) the importance of not only insulin but also glucagon in the pathogenesis of T2DM and (4) that pharmacologic agents that modulate glucagon–insulin axis, that is, incretin therapy, may prove valuable in the treatment of diabetes.10,11 In addition to all the limitations of traditional therapies (Table 1), one that continues to be of great importance to patients in particular is the issue of weight gain with improved glycemic control. It has been recognized for years that agents such as insulin, thiazolidindiones, and sulfonylureas improve glycemic Volume 343, Number 1, January 2012
Treatment Options and Type 2 Diabetes
control while also associated with weight gain. Metformin has traditionally improved control while being weight neutral. An interesting study that provided some insight into the importance of weight gain with therapy was the Hyperinsulinemia: the Outcome of Its Metabolic Effects (HOME) trial.19 HOME was a randomized, placebo-controlled, multicenter trial that evaluated approximately 390 insulin-treated adults with T2DM. The study investigators postulated that metformin, when compared with placebo treatment, would have sustained, beneficial metabolic effects in insulin-treated patients with T2DM, even those with the same level of glycemic control, and that this may decrease CVD. It was observed in HOME that glycemic control was improved when insulin was combined with metformin; however, the most important observation was that not only did metformin cause sustained, beneficial effects on body weight but that this weight change accounted for a favorable influence on macrovascular disease, when compared with the other metabolic effects of metformin. These findings seem to be of clinical importance and suggest that treatment regimens that address weight issues in the management of T2DM might be more important from a CVD perspective than previously considered.20
EVOLVING TREATMENTS As outlined earlier and recently reviewed in detail, available treatments for patients with T2DM include oral medications—including secretagogues, such as sulfonylureas and “glinides” (repaglinide and nateglinide); metformin; TZDs and dipeptidyl peptidase-4 (DPP-4) inhibitors—and parenterally administered agents, for example, insulin and glucagon-like peptide-1 (GLP-1) receptor agonists.9 –11 Clearly, the traditional agents, such as sulfonylureas, insulin and metformin, have served clinicians well, but as outlined, there are still issues with obtaining and maintaining glycemic control. Thus, on the basis of the observation that the incretin therapies have different mechanisms as compared with traditional therapies, more detail will be provided in regard to their mechanism of action. For the remainder of medications, the reader is referred to the numerous reviews that outline the efficacy, benefits, indications and side effects for the other traditional medications.9 –11,21,22
PHYSIOLOGIC ROLE OF INCRETINS Two major incretin hormones in humans are GLP-1, which is secreted mainly by L cells in the distal intestine (ileum and colon), and glucose-dependent insulinotropic polypeptide from K cells of the small intestine (duodenum and proximal jejunum).23 Both peptides are released from the gastrointestinal tract in response to meal ingestion, and both are reported to play a major role in nutrient uptake. One of the key observations for incretins was the demonstration of the “incretin effect,” which essentially refers to the enhanced insulin secretion noted from the oral administration of glucose when compared with equimolar levels of glucose as achieved through intravenous administration. This important observation suggests that incretins have a major role in the modulation of insulin release, particularly at mealtime. Thus, it is now well established that both GLP-1 and glucose-dependent insulinotropic polypeptide stimulate insulin secretion and promote expansion of -cell mass (as observed in preclinical models).23 GLP-1 is also known to inhibit glucagon secretion.23 Given the observation that glucagon fails to be effectively suppressed in patients with T2DM, resulting in glucagon hypersecretion and excess HGP, the role of these agents in modulating HGP and postprandial glucose may be noted. Thus, on the basis of the known mechanisms of the endogenous incretins in modulating abnormalities present in diabetic states, the findings demonstrate © 2012 Lippincott Williams & Wilkins
GLP-1 Secretion and Metabolism Mixed meal Intestinal GLP-1 release
DPP-IV IV V
GLP-1 (7-36) G active
X
GLP-1 GL LP P (9-36) in inactive
DPP IV Inhibitor
Rapid inactivation (>80% of pool)
Plasma
GLP-1 actions GLP-1 Receptor Agonist
Renal clearance
FIGURE 2. Secretion and metabolism of glucagon-like peptide-1 (GLP-1). After ingestion of a meal, GLP-1 is released by intestinal L cells in its active form (7–36) in plasma, which is rapidly degraded to the inactive form (9⫺36) by the enzyme dipeptidyl peptidase-4 (DPP-4). Incretin therapy can increase available GLP-1 activity by inhibiting its enzymatic degradation by DPP-4 and increasing endogenous levels (oral DPP-4 inhibitors) or by injection of GLP-1 agonists, which resist degradation and can mimic its activity. From Cefalu.10 (As modified from Kieffer TJ, Habener JF. The glucagon- like peptides. Endocr Rev 1999;20:876⫺91324 and Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in Type II diabetic patients and in healthy subjects. Diabetes 1995;44:1126⫺31.25)
the potential benefit of incretin-based agents as therapy for the management of T2DM. In particular, on the basis of the observation that incretins may have an effect on ␣ cells (glucagon response) and on  cells (insulin response), there is great interest in these therapies that modulate physiologic processes in humans.
INCRETIN MODALITIES AS THERAPY FOR T2DM Despite the promise of GLP-1 as a modality in humans, GLP-1 is not considered to be a practical incretin therapy that can be used for the treatment of T2DM based on its secretion and metabolism, which is outlined schematically in Figure 2.24 –26 As aforementioned, GLP-1 is released predominantly by the L cells in the small intestine into the plasma in its active form and becomes rapidly inactivated by an enzyme that has been termed DPP-4 (Figure 2). On the basis of the observation of rapid inactivation in vivo, it is apparent that simply infusing GLP-1 into patients with T2DM is not an efficient means of administration. Essentially, because of the rapid inactivation of GLP-1, treatment would require continuous infusion. Therefore, for incretin-based therapies to be a viable option, distinct strategies to overcome the rapid in vivo inactivation were developed (Figure 2).
INCRETIN THERAPEUTICS DPP-4 Inhibitors As outlined earlier, one mechanism by which one could increase endogenous GLP-1 activity is to inhibit the activity of DPP-4, the enzyme that rapidly converts GLP-1 to its inactive state, thereby increasing the levels of GLP-1 (Figure 2). Such a strategy provides a rationale for the use of DPP-4 inhibitors, oral agents that are also called “incretin enhancers.” Sitagliptin, linagliptin vildagliptin and saxagliptin are already available in many countries and are representative compounds of the class. At the
23
Cefalu
writing of this manuscript, alogliptin is in development. DPP-4 inhibitors can be given either as monotherapy or, more commonly, in combination with other antidiabetic compounds. Studies to date have indicated that the DPP-4 inhibitors demonstrated considerable efficacy. Sitagliptin administration after oral glucose tolerance testing inhibits DPP-4 activity and significantly increases the levels of biologically active GLP-1 in plasma relative to placebo.26 The benefit of increasing bioavailable GLP-1 levels in patients with T2DM is associated with improved glycemic control. For example, on the background of metformin therapy, sitagliptin provided a comparable degree of glycemic control (the mean change from baseline in HBA1c in both groups was 0.67%) when compared with the glipizide/metformin combination.27 Moreover, safety and tolerability seemed to be better with sitagliptin than with glipizide, and the former was correlated with a slight decrease in body weight, whereas weight increased on glipizide. However, most studies with DPP-4 inhibitors report the agents to be weight neutral. Other trials have shown that sitagliptin/metformin given in combination may offer additive efficacy in reducing blood glucose when given either as initial antidiabetic therapy or as add-on therapy when pioglitazone alone fails to maintain glycemic control.28,29 In combination with the background medication (ie, metformin or pioglitazone) sitagliptin also seemed to be well tolerated. Thus, sitagliptin is currently approved as an adjunct to diet and exercise either as monotherapy or in combination when the initial agent, such as metformin or pioglitazone, does not provide adequate glycemic control.27–29 Saxagliptin, another oral “incretin enhancer,” has demonstrated efficacy when the agent is employed as an adjunctive treatment to diet alone, metformin, sulfonylurea or glitazone in patients with T2DM.29 –32 There seemed to be a good tolerability profile for saxagliptin, and the decrease in A1C averaged approximately 0.6% to 0.8% while not increasing the risk of hypoglycemia or promoting weight gain. Another DPP-4 inhibitor, alogliptin, has also shown efficacy in promoting glycemic control when used in combination with metformin or when added to a background regimen of a TZD in patients who have inadequate control.33,34 Linagliptin, a recently approved agent, was reported to have different pharmacokinetic properties when compared with previously commercialized DPP-4 inhibitors. Specifically, linagliptin appears to be the first DPP-4 inhibitor with a nonrenal elimination route. As such, it is suggested that it can be administered in patients with renal impairment without dose adjustment or monitoring of renal function.35 Collectively, the studies to date for the DPP-4 inhibitors suggest that improved glycemic control is observed when these agents are added in combination, regardless of the background therapy for the patient with T2DM. They also emphasize the potential of incretin modalities in correcting the metabolic abnormalities associated with T2DM and their further potential to overcome some of the shortcomings of the traditional therapy by doing so while minimizing hypoglycemia and weight gain. GLP-1 Agonists Another strategy employed to increase GLP-1 activity in patients with T2DM is to prevent its breakdown and inactivation by the DPP-4 enzyme. This has been accomplished by modifying the GLP-1 peptide molecule itself, and these agents are referred to as the GLP-1 receptor agonists (Figure 2). GLP-1 agonists differ from the oral DPP-4 inhibitors in that they need to be injected. In addition, there are differences in the levels of GLP-1 activity achieved as the GLP-1 agonists may attain pharmacologic levels when compared with the physiologic levels observed with the DPP-4 inhibitors. Representative
24
agents in this class are exenatide and liraglutide, but there are many in development. Exenatide, the first commercially available GLP-1 agonist, has been extensively studied in conjunction with many background medications, and its use and efficacy was recently reviewed.36 As reported, exenatide, when used in combination with selected oral antidiabetic drugs, reduces A1c by ⫺0.4% to ⫺1.5% in patients with T2DM that have been inadequately controlled on metformin with or without a sulfonylurea.36 Importantly, it seems that the GLP-1 agonist exenatide improves glycemic control while reducing body weight and maintaining low rates of hypoglycemia. However, the provider should recognize that when exenatide is used in combination with a sulfonylurea, consideration should be given to reduce the sulfonylurea dose to reduce the risk of hypoglycemia.36 In regard to weight loss, treatment with 10 g of exenatide, as an add-on to metformin, resulted in the greatest weight loss in patients previously treated with metformin alone.36 It has been proposed that exenatide can be used in conjunction with a long-acting basal insulin; the effects of this combination were recently examined in a 24-month retrospective chart review.37 In particular, the study examined the long-term effects of combination glargine/exenatide treatment on glycemic control in patients with inadequately controlled T2DM for whom glargine and exenatide were coprescribed in differing order (ie, glargine/ exenatide versus exenatide/glargine). Statistically significant A1c reductions persisted throughout 24 months in both treatment groups, and hypoglycemia rates were similar. Body weight remained unchanged after 24 months with exenatide/glargine, whereas with glargine/exenatide, body weight decreased. Thus, regardless of treatment order, long-term combined therapy with glargine and exenatide suggested a reduction in A1c without significant weight gain or increased hypoglycemia risk.37 Finally, because preclinical studies have suggested that the preservation of pancreatic function is a potential benefit of all incretin therapeutics, Bunck et al38 reported results of insulin secretion studies from patients treated with exenatide relative to glargine after a 3-year exposure. Both exenatide and glargine sustained glycemic control over the 3-year exposure period, but reduced body weight was noted with exenatide, whereas weight gain was noted with glargine. After the 3-year treatment, a measure of insulin secretion, the diposition index, was calculated; it was determined that the diposition index was increased with exenatide when compared with glargine, suggesting a beneficial effect on -cell health.38 Clinical results for liraglutide, another commercially available GLP-1 analog, were also recently reviewed.36 This analog is reported to share 97% sequence identity to native GLP-1, and its duration of action is reported to be over 24 hours, which was achieved by the addition of a C16 fatty acid side chain. As such, this analog is injected once daily.36,39 A considerable amount of clinical data has been reported for liraglutide in the phase 3 Liraglutide Effect and Action in Diabetes trials,40 – 45 which were recently reviewed by Garber.36 Garber36 reports that in individuals with T2DM, liraglutide consistently improves glycemic control (up to a 1.5% decrease in A1c) when used as monotherapy or in combination therapy. As noted with exenatide, this therapy improves glycemic control while decreasing weight. It was reported that the greatest amount of weight loss occurred when liraglutide was used in combination with metformin ⫾ sulfonylurea. Liraglutide seemed to be well tolerated across the trials though transient nausea was reported by patients, particularly at the initiation of therapy. However, although the rate of minor hypoglycemia was very low in these trials, just as it was in the exenatide trials, the provider should realize that hypoglycemia rates seemed to Volume 343, Number 1, January 2012
Treatment Options and Type 2 Diabetes
TABLE 2. Comparison of incretin therapies for patients with type 2 diabetes GLP-1 agonists
DPP-4 inhibitors
Injection Pharmacologic GLP-1 ⫹⫹⫹ ⫹⫹ Inhibited Yes Yes
Oral Physiologic GLP-1 ⫹ GIP ⫹ ⫹⫹ ⫹/⫺ No Yes
Yes Yes
No No .te
Variable Administration GLP-1 concentrations Mechanisms of action Insulin secretion (increase) Glucagon secretion (decrease) Gastric emptying Weight loss Expansion of -cell mass in preclinical studies Nausea and vomiting Potential immunogenicity
From Cefalu WT. The physiologic role of incretin hormones: clinical applications 关review兴. J Am Osteopath Assoc 2010;110(3 Suppl 2):S8 – S14. Source: Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929 – 40.23 GLP-1, glucagon-like peptide-1; DPP-4, dipeptidyl peptidase-4; GIP, glucose-dependent insulinotropic polypeptide.
glycosuria. In clinical trials to date, the resulting glucosuria has resulted in improved glycemic control but is also interestingly associated with weight loss.46 Two agents that have been reported recently are dapagliflozin and canaglifloxin,47,48 and their future availability will have the potential to provide additional agents to improve glycemic control on the background of other agents while minimizing side effects and having a favorable effect on weight.
CONCLUSIONS Over the recent past, considerably new information has been reported in regard to the need and approach to treat individuals with T2DM. New therapies that improve glycemic control and have favorable effects to address the unmet clinical problems are now commercially available, and many are still in development. The current approach to treatment is one that has a goal to meet the recommended glycemic targets by improving the key metabolic abnormalities associated with T2DM. The treatment regimen should provide for appropriate individualization of glycemic targets and with the ultimate clinical goal of optimizing outcomes and minimizing the adverse events that have been associated with conventional therapies. REFERENCES
increase slightly when liraglutide was used in combination with a sulfonylurea.36 Finally, there seemed to be favorable effects on blood pressure as reductions in systolic blood pressure were noted across the trials (mean decrease ⫺2.1 to ⫺6.7 mm Hg).36 On the basis of the considerable data that have been collected to date on both the DPP-4 inhibitors and the GLP-1 agonists, it is apparent that these modalities help to address some of the unmet needs in the treatment of T2DM. These agents both offer and provide different mechanisms of action and, when combined with other traditionally used agents, further improve glycemic control. In addition to improving glycemia and having favorable effects on body weight, incretins offer the promise of improving islet function. A general comparison of the benefits and differences between DPP-4 inhibitors and GLP-1 agonists is provided in Table 2.
NOVEL THERAPEUTIC APPROACHES: THE KIDNEY AS A NEW TARGET FOR DIABETIC THERAPIES It seems that the next class of agents that will be available for the clinical treatment of T2DM may involve those that address abnormalities in the kidney. It is well known that the kidney plays a major role in carbohydrate metabolism based on its role in gluconeogenesis and because of the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. As recently reported, the kidney filters approximately 180 g of glucose daily for a normal healthy adult, and the overwhelming majority of the glucose is reabsorbed, with ⬍1% being excreted in the urine.46 The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose cotransporters (SGLT1 and SGLT2), a family of membrane proteins. These proteins reportedly facilitate the transport of glucose across the brush-border membrane of proximal renal tubules and the intestinal epithelium. The SGLT2 transporter expressed chiefly in the kidney is observed to be a high-capacity, low-affinity transporter and may be responsible for approximately 90% of renal glucose reabsorption.46 Agents that inhibit the SGLT2 transporter result in a diminished reabsorption of filtered glucose, which leads to © 2012 Lippincott Williams & Wilkins
1. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53. 2. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359: 1577– 89. 3. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34:S11– 61. 4. Writing Team for the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002;287:2563–9. 5. The Action to Control Cardiovascular Risk in Diabetes Study Group Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59. 6. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560 –72. 7. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129 –39. 8. Riddle MC, Ambrosius WT, Brillon DJ, et al.; Action to Control Cardiovascular Risk in Diabetes Investigators. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33:983–90. 9. Cefalu WT. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: rationale and specific agents. Clin Pharmacol Ther 2007;81:636 – 49. 10. Cefalu WT. The physiologic role of incretin hormones: clinical applications [review]. J Am Osteopath Assoc 2010;110(3 Suppl 2):S8 –14. 11. Cefalu WT, Richards RJ, Melendez-Ramirez LY, et al. Redefining treatment success in type 2 diabetes mellitus: comprehensive targeting of core defects. Cleve Clin J Med 2009;76(Suppl 5):S39 – 47. 12. Del Prato S, Felton AM, Munro N, et al. Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Recommendations from the Global Partnership for Effective Diabetes Management. Int J Clin Pract 2005;59:1345–55.
25
Cefalu
13. Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000;7:625–31.
mal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res 2011;8:150 –9.
14. Del Prato S, LaSalle J, Matthaei S, et al. Global Partnership for Effective Diabetes Management. Tailoring treatment to the individual in type 2 diabetes practical guidance from the Global Partnership for Effective Diabetes Management. Int J Clin Pract 2010;64:295–304.
33. Nauck MA, Ellis GC, Fleck PR, et al.; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract 2009; 63:46.
15. Mu¨ller WA, Faloona GR, Aguilar-Parada E, et al. Abnormal alphacell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med 1970;283:109 –15. 16. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773–95. 17. DeFronzo RA, Ferrannini E, Simonson DC, et al. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989;38:387–95.
34. Pratley RE, Reusch JE, Fleck PR, et al.; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin 2009;25:2361–71. 35. Scheen AJ. Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation). Expert Opin Drug Metab Toxicol. 2011;7(12): 1561–76.
18. Baron AD, Schaeffer L, Shragg P, et al. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 1987;36:274 – 83.
36. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care 2011; 34(Suppl 2):S279 – 84.
19. Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009;169:616 –25.
37. Levin PA, Mersey JH, Zhou S, et al. Clinical outcomes using long-term combination therapy with insulin glargine and exenatide in patients with type 2 diabetes. Endocr Pract 2011;8:1–28.
20. Cefalu WT. Diabetes: HOME reveals new data on a cornerstone of treatment. Nat Rev Endocrinol 2009;5:478 –9. 21. Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral agents, insulins, and combinations. Endocrinol Metab Clin North Am 2005;34:77–98. 22. Riddle MC. Making the transition from oral to insulin therapy. Am J Med 2005;118(Suppl 5A):14S–20S.
38. Bunck MC, Corne´r A, Eliasson B, et al. Effects of exenatide on measures of -cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 2011;34:2041–7. 39. Russell-Jones D. Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue. Mol Cell Endocrinol 2009;297:137– 40.
24. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev 1999;20:876 –913.
40. Marre M, Shaw J, Bra¨ndle M, et al. Liraglutide,1a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26:268–78.
25. Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in Type II diabetic patients and in healthy subjects. Diabetes 1995;44:1126 –31.
41. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32:84 –90.
26. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006;91:4612–9.
42. Garber A, Henry R, Ratner R, et al Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373:473– 81.
27. Nauck MA, Meininger G, Sheng D, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007;9:194 –205.
43. Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met⫹TZD). Diabetes Care 2009;32:1224 –30.
23. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929 – 40.
28. Olansky L, Reasner C, Seck TL, et al. Treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. Diabetes Obes Metab 2011;13:841–9.
44. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met⫹SU): a randomised controlled trial. Diabetologia 2009;52:2046 –55.
29. Bailey CJ, Green BD, Flatt PR, et al. Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone [review]. Expert Opin Investig Drugs 2010;19:1017–25.
45. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374:39 – 47.
30. Rosenstock J, Aguilar-Salinas C, Klein E, et al.; CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin 2009;25:2401–11.
46. Neumiller JJ, White JR Jr, Campbell RK, et al. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs 2010;70:377– 85.
31. DeFronzo RA, Hissa MN, Garber AJ, et al.; Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009;32:1649 –55.
47. Chao ED. A paradigm shift in diabetes therapy— dapagliflozin and other SGLT2 inhibitors. Discov Med 2011;11:255– 63.
32. Chacra AR, Tan GH, Ravichandran S, et al.; CV181040 Investigators. Safety and efficacy of saxagliptin in combination with submaxi-
26
48. Sha S, Devineni D, Ghosh A, et al. A novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669 –72.
Volume 343, Number 1, January 2012
Evolving Treatment Strategies for the Management of Type 2 Diabetes William T. Cefalu, MD
Abstract: It is well known that improved metabolic control significantly reduces both micro- and macrovascular complications in diabetes. As it relates to specific treatment of type 2 diabetes mellitus, clinicians have traditionally initiated lifestyle intervention and progressed therapy using various drug treatments first as monotherapy and then as combination therapy throughout the course of the disease. This “stepwise” strategy has not always achieved the desired outcome of normal glycemic control; consequently, several clinical problems, such as hypoglycemia, weight gain and postprandial hyperglycemia, persist. However, new therapies that improve glycemic control and have favorable effects to address the unmet clinical problems have recently been developed or are still in development. These therapies include 2 classes of incretin-directed therapy, the dipeptidyl peptidase-4 inhibitors and the glucagon-like peptide-1 agonists, which help restore physiologic levels and activity of the incretin glucagon-like peptide-1. Also in development are additional therapies that have effects on the kidney to promote glucose excretion. These therapies are proposed to treat the key metabolic abnormalities associated with type 2 diabetes mellitus and minimize the side effects noted with conventional therapies. Key Indexing Terms: Diabetes; Incretins; Treatment. [Am J Med Sci 2012;343(1):21–26.]
O
ver the recent past, a great amount of research has been devoted to understand the contribution of hyperglycemia and its treatment on the complications of both type 1 and type 2 diabetes mellitus (T2DM). Specifically, the complications of diabetes have been classified as either microvascular (ie, retinopathy, nephropathy and neuropathy) or macrovascular [ie, cardiovascular disease (CVD), cerebrovascular accidents and peripheral vascular disease]. The development of complications is a cause of considerable morbidity and increases disability and mortality for the individual with diabetes. Fortunately, as a scientific community, we have recognized the pivotal role that chronic hyperglycemia contributes to the development of both microvascular and macrovacular disease.1,2 Chronic hyperglycemia is objectively measured by obtaining glycated hemoglobin levels, that is, A1c, which reflects glycemic control over the preceding 2 to 3 months. In this regard and based on landmark clinical trials such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, glucose control as defined by target levels for the A1c has been recommended.3 In addition, the concept of “metabolic memory” has been observed in which glucose control during the early stages of disease presentation seems to have long-term From the Joint Program on Diabetes, Endocrinology and Metabolism, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, and Louisiana State University Heath Sciences Center School of Medicine, New Orleans, Louisiana. This paper was presented as part of the Joint Plenary Session Symposium, which was held at the annual Southern Regional Meeting on February 18, 2011, New Orleans, Louisiana. Correspondence: William T. Cefalu, MD, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808 (E-mail: [email protected]).
effects on the development of micro- and macrovascular complications.1,2,4 However, despite these findings, data from largescale prospective trials report that in high-risk patients, intensive therapy to lower A1c levels below suggested targets may actually increase mortality or not favorably affect cardiovascular outcomes.5–7 Interestingly, it has been observed that certain subsets of patients may benefit from intensive glycemic control.5 More recent findings suggest that given that the excess mortality in the group randomized to intensive glycemic management was seen only at A1c levels ⬎7%, mortality may actually be greater for those who maintain a higher A1c level despite attempts at intensive glycemic management.8 Thus, the findings regarding A1c targets for selected patient populations as evaluated by the large-scale clinical trials continue to evolve to this day and remain important data for clinicians.
TRADITIONAL APPROACH TO TREATMENT To achieve the suggested glycemic targets for glucose control of T2DM, lifestyle intervention, that is, diet and exercise, has traditionally been the first step. However, diabetes is a progressive disease that is characterized not only by the presence of insulin resistance but also by the abnormalities in hepatic glucose production (HGP) and a progressive decline in -cell function over time.9 To treat patients with T2DM effectively, the provider must have a good understanding of both the underlying pathophysiology and the natural history of the disease. On the basis of the need to address the former, many antidiabetic agents from many classes are available for use by the clinician. These classes have included agents that increase insulin secretion, improve insulin action and delay absorption of carbohydrates. The newer treatments available, that is, incretin therapies, also modulate glucose supply.9 –11 Thus, given the natural history of the disease and the currently available options, treatment strategies have usually progressed from monotherapy with an oral antihyperglycemic agent, to uptitration of the agent chosen for monotherapy, to prescribing combination therapy with agents from different classes.10,11 When combination fails to provide acceptable control, insulin (generally a basal insulin) may be added to oral therapy. It is not uncommon—and, in fact, is generally the case—that more intensive insulin therapy (ie, addition of pre-meal fast-acting insulin) is needed. In many ways, this can be viewed as a treatment-to-failure approach as patients are generally advanced to the next stage only when their failure to respond has been well documented. Thus, current approaches to the management of T2DM have been described as suboptimal because patients may have inadequate glycemic control for most of their treatment (Figure 1).12,13 On the basis of the concerns with the traditional approach, recommendations have been suggested that the provider target the underlying pathophysiology of T2DM; treat hyperglycemia early and effectively with combination therapies; adopt a holistic, multidisciplinary approach and improve patient understanding of T2DM. If these recom-
The American Journal of the Medical Sciences • Volume 343, Number 1, January 2012
21
Cefalu
Traditional Stepwise Approach and Suggested Early Combination Approach to the Treatment of Type 2 Diabetes
Traditional stepwise approach Diet and OAD OAD OAD OAD plus exercise monotherapy up-titration combination basal insulin
OAD plus multiple daily insulin injections
HbA1c, %
10
Mean HbA1c of patients
9 8 7 6
Early combination approach
mendations were implemented, it was believed that the risk of diabetes-related complications would be decreased, patient’s quality of life increased and healthcare cost related to diabetes favorably impacted.12 It is now believed that the clinical issues not adequately addressed by current therapies are edema, weight gain, the need to improve glycemia with minimal hypoglycemia and the need to decrease gastrointestinal effects (Table 1). The risk for weight gain with conventional approaches has been noted for years and is one that is clearly being addressed by the newer therapies. Before the release of the incretin therapies, metformin was the agent that had the advantage over sulfonylureas and thiazolidinediones (TZDs) as it was considered relatively weight neutral. The limitations of the traditional approach were also highlighted in the landmark studies evaluating glycemic control and heart disease (ie, Accord and Advance) as intensive therapy revealed some unmet needs in conventional T2DM therapy. Thus, the results from the recent large-scale studies support the need for appropriate individualization of glycemic targets and of the means to achieve these targets, with the ultimate clinical goal of optimizing outcomes and minimizing the adverse events, such as hypoglycemia and marked weight gain.14 Patient groups requiring special consideration were recently identified and practical guidance specific to each group was also recently provided by the report of Del Prato et al.14 In addition to the failure of the current antidiabetic therapies to deal satisfactorily with hypoglycemia and weight gain, another consideration that has not been adequately addressed and that has been recently reviewed is the issue of glycemic variability or glucose fluctuations occurring postprandially.10,11 Obtaining adequate and reliable information on glycemic excursions after meals for patients in the outpatient clinics remains a challenge. As reviewed, it is recognized that most of the traditional therapies (ie, metformin, sulfonylureas, TZDs and insulin) do not adequately
TABLE 1. Clinical problems associated with conventional therapies Most therapies are associated with weight gain Hypoglycemia, generally associated with insulin and insulin secretagogues Other AEs with some therapies include GI side effects and edema Failure to adequately control postprandial glucose Failure to maintain long-term glycemic control AE, adverse event; GI, gastrointestinal.
22
FIGURE 1. Step-wise traditional treatment approach and an approach that is not only individualized but provides more aggressive treatment to achieve glycemic targets earlier in the course of disease for Type 2 diabetes. Adapted from Del Prato S, Felton AM, Munro N, et al. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract 2005;59:1345–5512 and Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000;7:625–31.13
address postmeal glucose. These “conventional therapies” have mechanisms either to address the pancreatic insufficiency (ie, increase insulin secretion and provide effective insulin levels) or to increase sensitivity in the tissues. In other words, the traditional approach to the treatment of T2DM focused primarily on “insulin demand” as these therapies addressed the deficits in insulin activity needed for the uptake, storage and utilization of glucose.9 –11 However, it was reported years ago that diabetes is also associated with defects in glucose production by the liver—specifically, a failure to suppress glucagon—which drives HGP and contributes greatly to postprandial glucose. The abnormalities in HGP currently remain well accepted in defining T2DM.9 –11,15 The clinical result from hepatic glucose oversupply is the resulting increase in both fasting and postprandial hyperglycemia. This concept was recently reviewed9 –11; in brief, glucose production by the liver or the appearance of glucose in the bloodstream from meal ingestion (ie, “glucose supply”) must be in balance with the amount of glucose that is taken up and used by peripheral tissues (ie, muscle and fat).9 If the glucose supply is greater than glucose disposal and utilization, glucose dysregulation is present, and the clinical result is hyperglycemia and a diagnosis of impaired glucose tolerance leading to T2DM. In general, HGP is measured with precise techniques such as the euglycemic-hyperinsulinemic clamp, but for the clinician, a valuable observation is that HGP is very much related to fasting glucose. DeFronzo et al16,17 clearly demonstrated this years ago, presenting data showing that patients with T2DM have higher HGP than their nondiabetic counterparts and that a significant, positive correlation (r ⫽ 0.847; P ⬍ 0.001) was also found between the rate of basal HGP and fasting glucose in the diabetic group.16,17 Other research has indicated that glucagon plays a pivotal role in HGP as studies revealed that if plasma glucagon is suppressed using somatostatin in patients with T2DM, the level of HGP can be reduced significantly.18 For the clinician, these studies provide valuable clinical information as, collectively, the research to date suggests the following: (1) that the level of fasting glucose in T2DM is clearly related to the level of basal HGP and gives a measure of endogenous glucose overproduction; (2) that glucose production by the liver is regulated by the glucagon–insulin axis; (3) the importance of not only insulin but also glucagon in the pathogenesis of T2DM and (4) that pharmacologic agents that modulate glucagon–insulin axis, that is, incretin therapy, may prove valuable in the treatment of diabetes.10,11 In addition to all the limitations of traditional therapies (Table 1), one that continues to be of great importance to patients in particular is the issue of weight gain with improved glycemic control. It has been recognized for years that agents such as insulin, thiazolidindiones, and sulfonylureas improve glycemic Volume 343, Number 1, January 2012
Treatment Options and Type 2 Diabetes
control while also associated with weight gain. Metformin has traditionally improved control while being weight neutral. An interesting study that provided some insight into the importance of weight gain with therapy was the Hyperinsulinemia: the Outcome of Its Metabolic Effects (HOME) trial.19 HOME was a randomized, placebo-controlled, multicenter trial that evaluated approximately 390 insulin-treated adults with T2DM. The study investigators postulated that metformin, when compared with placebo treatment, would have sustained, beneficial metabolic effects in insulin-treated patients with T2DM, even those with the same level of glycemic control, and that this may decrease CVD. It was observed in HOME that glycemic control was improved when insulin was combined with metformin; however, the most important observation was that not only did metformin cause sustained, beneficial effects on body weight but that this weight change accounted for a favorable influence on macrovascular disease, when compared with the other metabolic effects of metformin. These findings seem to be of clinical importance and suggest that treatment regimens that address weight issues in the management of T2DM might be more important from a CVD perspective than previously considered.20
EVOLVING TREATMENTS As outlined earlier and recently reviewed in detail, available treatments for patients with T2DM include oral medications—including secretagogues, such as sulfonylureas and “glinides” (repaglinide and nateglinide); metformin; TZDs and dipeptidyl peptidase-4 (DPP-4) inhibitors—and parenterally administered agents, for example, insulin and glucagon-like peptide-1 (GLP-1) receptor agonists.9 –11 Clearly, the traditional agents, such as sulfonylureas, insulin and metformin, have served clinicians well, but as outlined, there are still issues with obtaining and maintaining glycemic control. Thus, on the basis of the observation that the incretin therapies have different mechanisms as compared with traditional therapies, more detail will be provided in regard to their mechanism of action. For the remainder of medications, the reader is referred to the numerous reviews that outline the efficacy, benefits, indications and side effects for the other traditional medications.9 –11,21,22
PHYSIOLOGIC ROLE OF INCRETINS Two major incretin hormones in humans are GLP-1, which is secreted mainly by L cells in the distal intestine (ileum and colon), and glucose-dependent insulinotropic polypeptide from K cells of the small intestine (duodenum and proximal jejunum).23 Both peptides are released from the gastrointestinal tract in response to meal ingestion, and both are reported to play a major role in nutrient uptake. One of the key observations for incretins was the demonstration of the “incretin effect,” which essentially refers to the enhanced insulin secretion noted from the oral administration of glucose when compared with equimolar levels of glucose as achieved through intravenous administration. This important observation suggests that incretins have a major role in the modulation of insulin release, particularly at mealtime. Thus, it is now well established that both GLP-1 and glucose-dependent insulinotropic polypeptide stimulate insulin secretion and promote expansion of -cell mass (as observed in preclinical models).23 GLP-1 is also known to inhibit glucagon secretion.23 Given the observation that glucagon fails to be effectively suppressed in patients with T2DM, resulting in glucagon hypersecretion and excess HGP, the role of these agents in modulating HGP and postprandial glucose may be noted. Thus, on the basis of the known mechanisms of the endogenous incretins in modulating abnormalities present in diabetic states, the findings demonstrate © 2012 Lippincott Williams & Wilkins
GLP-1 Secretion and Metabolism Mixed meal Intestinal GLP-1 release
DPP-IV IV V
GLP-1 (7-36) G active
X
GLP-1 GL LP P (9-36) in inactive
DPP IV Inhibitor
Rapid inactivation (>80% of pool)
Plasma
GLP-1 actions GLP-1 Receptor Agonist
Renal clearance
FIGURE 2. Secretion and metabolism of glucagon-like peptide-1 (GLP-1). After ingestion of a meal, GLP-1 is released by intestinal L cells in its active form (7–36) in plasma, which is rapidly degraded to the inactive form (9⫺36) by the enzyme dipeptidyl peptidase-4 (DPP-4). Incretin therapy can increase available GLP-1 activity by inhibiting its enzymatic degradation by DPP-4 and increasing endogenous levels (oral DPP-4 inhibitors) or by injection of GLP-1 agonists, which resist degradation and can mimic its activity. From Cefalu.10 (As modified from Kieffer TJ, Habener JF. The glucagon- like peptides. Endocr Rev 1999;20:876⫺91324 and Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in Type II diabetic patients and in healthy subjects. Diabetes 1995;44:1126⫺31.25)
the potential benefit of incretin-based agents as therapy for the management of T2DM. In particular, on the basis of the observation that incretins may have an effect on ␣ cells (glucagon response) and on  cells (insulin response), there is great interest in these therapies that modulate physiologic processes in humans.
INCRETIN MODALITIES AS THERAPY FOR T2DM Despite the promise of GLP-1 as a modality in humans, GLP-1 is not considered to be a practical incretin therapy that can be used for the treatment of T2DM based on its secretion and metabolism, which is outlined schematically in Figure 2.24 –26 As aforementioned, GLP-1 is released predominantly by the L cells in the small intestine into the plasma in its active form and becomes rapidly inactivated by an enzyme that has been termed DPP-4 (Figure 2). On the basis of the observation of rapid inactivation in vivo, it is apparent that simply infusing GLP-1 into patients with T2DM is not an efficient means of administration. Essentially, because of the rapid inactivation of GLP-1, treatment would require continuous infusion. Therefore, for incretin-based therapies to be a viable option, distinct strategies to overcome the rapid in vivo inactivation were developed (Figure 2).
INCRETIN THERAPEUTICS DPP-4 Inhibitors As outlined earlier, one mechanism by which one could increase endogenous GLP-1 activity is to inhibit the activity of DPP-4, the enzyme that rapidly converts GLP-1 to its inactive state, thereby increasing the levels of GLP-1 (Figure 2). Such a strategy provides a rationale for the use of DPP-4 inhibitors, oral agents that are also called “incretin enhancers.” Sitagliptin, linagliptin vildagliptin and saxagliptin are already available in many countries and are representative compounds of the class. At the
23
Cefalu
writing of this manuscript, alogliptin is in development. DPP-4 inhibitors can be given either as monotherapy or, more commonly, in combination with other antidiabetic compounds. Studies to date have indicated that the DPP-4 inhibitors demonstrated considerable efficacy. Sitagliptin administration after oral glucose tolerance testing inhibits DPP-4 activity and significantly increases the levels of biologically active GLP-1 in plasma relative to placebo.26 The benefit of increasing bioavailable GLP-1 levels in patients with T2DM is associated with improved glycemic control. For example, on the background of metformin therapy, sitagliptin provided a comparable degree of glycemic control (the mean change from baseline in HBA1c in both groups was 0.67%) when compared with the glipizide/metformin combination.27 Moreover, safety and tolerability seemed to be better with sitagliptin than with glipizide, and the former was correlated with a slight decrease in body weight, whereas weight increased on glipizide. However, most studies with DPP-4 inhibitors report the agents to be weight neutral. Other trials have shown that sitagliptin/metformin given in combination may offer additive efficacy in reducing blood glucose when given either as initial antidiabetic therapy or as add-on therapy when pioglitazone alone fails to maintain glycemic control.28,29 In combination with the background medication (ie, metformin or pioglitazone) sitagliptin also seemed to be well tolerated. Thus, sitagliptin is currently approved as an adjunct to diet and exercise either as monotherapy or in combination when the initial agent, such as metformin or pioglitazone, does not provide adequate glycemic control.27–29 Saxagliptin, another oral “incretin enhancer,” has demonstrated efficacy when the agent is employed as an adjunctive treatment to diet alone, metformin, sulfonylurea or glitazone in patients with T2DM.29 –32 There seemed to be a good tolerability profile for saxagliptin, and the decrease in A1C averaged approximately 0.6% to 0.8% while not increasing the risk of hypoglycemia or promoting weight gain. Another DPP-4 inhibitor, alogliptin, has also shown efficacy in promoting glycemic control when used in combination with metformin or when added to a background regimen of a TZD in patients who have inadequate control.33,34 Linagliptin, a recently approved agent, was reported to have different pharmacokinetic properties when compared with previously commercialized DPP-4 inhibitors. Specifically, linagliptin appears to be the first DPP-4 inhibitor with a nonrenal elimination route. As such, it is suggested that it can be administered in patients with renal impairment without dose adjustment or monitoring of renal function.35 Collectively, the studies to date for the DPP-4 inhibitors suggest that improved glycemic control is observed when these agents are added in combination, regardless of the background therapy for the patient with T2DM. They also emphasize the potential of incretin modalities in correcting the metabolic abnormalities associated with T2DM and their further potential to overcome some of the shortcomings of the traditional therapy by doing so while minimizing hypoglycemia and weight gain. GLP-1 Agonists Another strategy employed to increase GLP-1 activity in patients with T2DM is to prevent its breakdown and inactivation by the DPP-4 enzyme. This has been accomplished by modifying the GLP-1 peptide molecule itself, and these agents are referred to as the GLP-1 receptor agonists (Figure 2). GLP-1 agonists differ from the oral DPP-4 inhibitors in that they need to be injected. In addition, there are differences in the levels of GLP-1 activity achieved as the GLP-1 agonists may attain pharmacologic levels when compared with the physiologic levels observed with the DPP-4 inhibitors. Representative
24
agents in this class are exenatide and liraglutide, but there are many in development. Exenatide, the first commercially available GLP-1 agonist, has been extensively studied in conjunction with many background medications, and its use and efficacy was recently reviewed.36 As reported, exenatide, when used in combination with selected oral antidiabetic drugs, reduces A1c by ⫺0.4% to ⫺1.5% in patients with T2DM that have been inadequately controlled on metformin with or without a sulfonylurea.36 Importantly, it seems that the GLP-1 agonist exenatide improves glycemic control while reducing body weight and maintaining low rates of hypoglycemia. However, the provider should recognize that when exenatide is used in combination with a sulfonylurea, consideration should be given to reduce the sulfonylurea dose to reduce the risk of hypoglycemia.36 In regard to weight loss, treatment with 10 g of exenatide, as an add-on to metformin, resulted in the greatest weight loss in patients previously treated with metformin alone.36 It has been proposed that exenatide can be used in conjunction with a long-acting basal insulin; the effects of this combination were recently examined in a 24-month retrospective chart review.37 In particular, the study examined the long-term effects of combination glargine/exenatide treatment on glycemic control in patients with inadequately controlled T2DM for whom glargine and exenatide were coprescribed in differing order (ie, glargine/ exenatide versus exenatide/glargine). Statistically significant A1c reductions persisted throughout 24 months in both treatment groups, and hypoglycemia rates were similar. Body weight remained unchanged after 24 months with exenatide/glargine, whereas with glargine/exenatide, body weight decreased. Thus, regardless of treatment order, long-term combined therapy with glargine and exenatide suggested a reduction in A1c without significant weight gain or increased hypoglycemia risk.37 Finally, because preclinical studies have suggested that the preservation of pancreatic function is a potential benefit of all incretin therapeutics, Bunck et al38 reported results of insulin secretion studies from patients treated with exenatide relative to glargine after a 3-year exposure. Both exenatide and glargine sustained glycemic control over the 3-year exposure period, but reduced body weight was noted with exenatide, whereas weight gain was noted with glargine. After the 3-year treatment, a measure of insulin secretion, the diposition index, was calculated; it was determined that the diposition index was increased with exenatide when compared with glargine, suggesting a beneficial effect on -cell health.38 Clinical results for liraglutide, another commercially available GLP-1 analog, were also recently reviewed.36 This analog is reported to share 97% sequence identity to native GLP-1, and its duration of action is reported to be over 24 hours, which was achieved by the addition of a C16 fatty acid side chain. As such, this analog is injected once daily.36,39 A considerable amount of clinical data has been reported for liraglutide in the phase 3 Liraglutide Effect and Action in Diabetes trials,40 – 45 which were recently reviewed by Garber.36 Garber36 reports that in individuals with T2DM, liraglutide consistently improves glycemic control (up to a 1.5% decrease in A1c) when used as monotherapy or in combination therapy. As noted with exenatide, this therapy improves glycemic control while decreasing weight. It was reported that the greatest amount of weight loss occurred when liraglutide was used in combination with metformin ⫾ sulfonylurea. Liraglutide seemed to be well tolerated across the trials though transient nausea was reported by patients, particularly at the initiation of therapy. However, although the rate of minor hypoglycemia was very low in these trials, just as it was in the exenatide trials, the provider should realize that hypoglycemia rates seemed to Volume 343, Number 1, January 2012
Treatment Options and Type 2 Diabetes
TABLE 2. Comparison of incretin therapies for patients with type 2 diabetes GLP-1 agonists
DPP-4 inhibitors
Injection Pharmacologic GLP-1 ⫹⫹⫹ ⫹⫹ Inhibited Yes Yes
Oral Physiologic GLP-1 ⫹ GIP ⫹ ⫹⫹ ⫹/⫺ No Yes
Yes Yes
No No .te
Variable Administration GLP-1 concentrations Mechanisms of action Insulin secretion (increase) Glucagon secretion (decrease) Gastric emptying Weight loss Expansion of -cell mass in preclinical studies Nausea and vomiting Potential immunogenicity
From Cefalu WT. The physiologic role of incretin hormones: clinical applications 关review兴. J Am Osteopath Assoc 2010;110(3 Suppl 2):S8 – S14. Source: Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929 – 40.23 GLP-1, glucagon-like peptide-1; DPP-4, dipeptidyl peptidase-4; GIP, glucose-dependent insulinotropic polypeptide.
glycosuria. In clinical trials to date, the resulting glucosuria has resulted in improved glycemic control but is also interestingly associated with weight loss.46 Two agents that have been reported recently are dapagliflozin and canaglifloxin,47,48 and their future availability will have the potential to provide additional agents to improve glycemic control on the background of other agents while minimizing side effects and having a favorable effect on weight.
CONCLUSIONS Over the recent past, considerably new information has been reported in regard to the need and approach to treat individuals with T2DM. New therapies that improve glycemic control and have favorable effects to address the unmet clinical problems are now commercially available, and many are still in development. The current approach to treatment is one that has a goal to meet the recommended glycemic targets by improving the key metabolic abnormalities associated with T2DM. The treatment regimen should provide for appropriate individualization of glycemic targets and with the ultimate clinical goal of optimizing outcomes and minimizing the adverse events that have been associated with conventional therapies. REFERENCES
increase slightly when liraglutide was used in combination with a sulfonylurea.36 Finally, there seemed to be favorable effects on blood pressure as reductions in systolic blood pressure were noted across the trials (mean decrease ⫺2.1 to ⫺6.7 mm Hg).36 On the basis of the considerable data that have been collected to date on both the DPP-4 inhibitors and the GLP-1 agonists, it is apparent that these modalities help to address some of the unmet needs in the treatment of T2DM. These agents both offer and provide different mechanisms of action and, when combined with other traditionally used agents, further improve glycemic control. In addition to improving glycemia and having favorable effects on body weight, incretins offer the promise of improving islet function. A general comparison of the benefits and differences between DPP-4 inhibitors and GLP-1 agonists is provided in Table 2.
NOVEL THERAPEUTIC APPROACHES: THE KIDNEY AS A NEW TARGET FOR DIABETIC THERAPIES It seems that the next class of agents that will be available for the clinical treatment of T2DM may involve those that address abnormalities in the kidney. It is well known that the kidney plays a major role in carbohydrate metabolism based on its role in gluconeogenesis and because of the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. As recently reported, the kidney filters approximately 180 g of glucose daily for a normal healthy adult, and the overwhelming majority of the glucose is reabsorbed, with ⬍1% being excreted in the urine.46 The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose cotransporters (SGLT1 and SGLT2), a family of membrane proteins. These proteins reportedly facilitate the transport of glucose across the brush-border membrane of proximal renal tubules and the intestinal epithelium. The SGLT2 transporter expressed chiefly in the kidney is observed to be a high-capacity, low-affinity transporter and may be responsible for approximately 90% of renal glucose reabsorption.46 Agents that inhibit the SGLT2 transporter result in a diminished reabsorption of filtered glucose, which leads to © 2012 Lippincott Williams & Wilkins
1. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53. 2. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359: 1577– 89. 3. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34:S11– 61. 4. Writing Team for the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002;287:2563–9. 5. The Action to Control Cardiovascular Risk in Diabetes Study Group Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59. 6. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560 –72. 7. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129 –39. 8. Riddle MC, Ambrosius WT, Brillon DJ, et al.; Action to Control Cardiovascular Risk in Diabetes Investigators. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33:983–90. 9. Cefalu WT. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: rationale and specific agents. Clin Pharmacol Ther 2007;81:636 – 49. 10. Cefalu WT. The physiologic role of incretin hormones: clinical applications [review]. J Am Osteopath Assoc 2010;110(3 Suppl 2):S8 –14. 11. Cefalu WT, Richards RJ, Melendez-Ramirez LY, et al. Redefining treatment success in type 2 diabetes mellitus: comprehensive targeting of core defects. Cleve Clin J Med 2009;76(Suppl 5):S39 – 47. 12. Del Prato S, Felton AM, Munro N, et al. Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Recommendations from the Global Partnership for Effective Diabetes Management. Int J Clin Pract 2005;59:1345–55.
25
Cefalu
13. Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000;7:625–31.
mal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res 2011;8:150 –9.
14. Del Prato S, LaSalle J, Matthaei S, et al. Global Partnership for Effective Diabetes Management. Tailoring treatment to the individual in type 2 diabetes practical guidance from the Global Partnership for Effective Diabetes Management. Int J Clin Pract 2010;64:295–304.
33. Nauck MA, Ellis GC, Fleck PR, et al.; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract 2009; 63:46.
15. Mu¨ller WA, Faloona GR, Aguilar-Parada E, et al. Abnormal alphacell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med 1970;283:109 –15. 16. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773–95. 17. DeFronzo RA, Ferrannini E, Simonson DC, et al. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989;38:387–95.
34. Pratley RE, Reusch JE, Fleck PR, et al.; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin 2009;25:2361–71. 35. Scheen AJ. Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation). Expert Opin Drug Metab Toxicol. 2011;7(12): 1561–76.
18. Baron AD, Schaeffer L, Shragg P, et al. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 1987;36:274 – 83.
36. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care 2011; 34(Suppl 2):S279 – 84.
19. Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009;169:616 –25.
37. Levin PA, Mersey JH, Zhou S, et al. Clinical outcomes using long-term combination therapy with insulin glargine and exenatide in patients with type 2 diabetes. Endocr Pract 2011;8:1–28.
20. Cefalu WT. Diabetes: HOME reveals new data on a cornerstone of treatment. Nat Rev Endocrinol 2009;5:478 –9. 21. Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral agents, insulins, and combinations. Endocrinol Metab Clin North Am 2005;34:77–98. 22. Riddle MC. Making the transition from oral to insulin therapy. Am J Med 2005;118(Suppl 5A):14S–20S.
38. Bunck MC, Corne´r A, Eliasson B, et al. Effects of exenatide on measures of -cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 2011;34:2041–7. 39. Russell-Jones D. Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue. Mol Cell Endocrinol 2009;297:137– 40.
24. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev 1999;20:876 –913.
40. Marre M, Shaw J, Bra¨ndle M, et al. Liraglutide,1a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26:268–78.
25. Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in Type II diabetic patients and in healthy subjects. Diabetes 1995;44:1126 –31.
41. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32:84 –90.
26. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006;91:4612–9.
42. Garber A, Henry R, Ratner R, et al Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373:473– 81.
27. Nauck MA, Meininger G, Sheng D, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007;9:194 –205.
43. Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met⫹TZD). Diabetes Care 2009;32:1224 –30.
23. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929 – 40.
28. Olansky L, Reasner C, Seck TL, et al. Treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. Diabetes Obes Metab 2011;13:841–9.
44. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met⫹SU): a randomised controlled trial. Diabetologia 2009;52:2046 –55.
29. Bailey CJ, Green BD, Flatt PR, et al. Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone [review]. Expert Opin Investig Drugs 2010;19:1017–25.
45. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374:39 – 47.
30. Rosenstock J, Aguilar-Salinas C, Klein E, et al.; CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin 2009;25:2401–11.
46. Neumiller JJ, White JR Jr, Campbell RK, et al. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs 2010;70:377– 85.
31. DeFronzo RA, Hissa MN, Garber AJ, et al.; Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009;32:1649 –55.
47. Chao ED. A paradigm shift in diabetes therapy— dapagliflozin and other SGLT2 inhibitors. Discov Med 2011;11:255– 63.
32. Chacra AR, Tan GH, Ravichandran S, et al.; CV181040 Investigators. Safety and efficacy of saxagliptin in combination with submaxi-
26
48. Sha S, Devineni D, Ghosh A, et al. A novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669 –72.
Volume 343, Number 1, January 2012