understanding the mechanisms to maintain glucose ... · mechanisms to maintain glucose homeostasis:...

understanding the Mechanisms to Maintain glucose Homeostasis: a Review for Managed Care

Volume 18, number 1, Supplement – January 2012

Highlights

n examining the mechanisms of glucose regulation

n understanding the Kidneys’ role in Blood glucose regulation

n review of current and emerging Therapies in Type 2 diabetes mellitus n cPe Posttest and evaluation

Supplement to The American Journal of Managed Care © 2012 managed care & healthcare communications, llc

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n The AmericAn JournAl of mAnAged cAre n

• • •The contents of this supplement may include information regarding the use of products that may be inconsistent with or outside the approved labeling for these products in the United States. Physicians should note that the use of these products outside current approved labeling is considered experimental and are advised to consult prescribing information for these products.

Continuing Education

Understanding the Mechanisms to Maintain Glucose Homeostasis: A Review for Managed Care

Release date: January 12, 2012 Expiration date: January 12, 2014 Estimated time to complete activity: 2.5 hoursType of activity: Knowledge

This activity is supported by an educational grant from Bristol-myers Squibb and AstraZeneca lP.

Intended audience: Pharmacists

Statement of Educational Need The core pathophysiologic defects in type 2 diabetes mellitus (T2dm) include insulin resistance in the muscle and liver and βb-cell failure. however, there are other contributing defects in T2dm that affect the regulation of glucose balance in the body, and these include accelerated lipolysis in adipocytes, incretin deficiency/resistance in the gastrointestinal tract, hyperglucagonemia in α-cells, increased glucose reabsorption in the kidneys, and insulin resistance in the brain. The involvement of all these organ systems is part of a system that helps to maintain glucose balance, an important part of homeostasis. The body regulates glucose levels within a tight window, maintaining levels at around 85 to 90 mg/dl. This is a very finely tuned system, and in any given individual the fasting glucose levels change by less than 1 to 2 mg/dl. however, when this system falters, the resulting hypo- or hyperglycemia leads to adverse consequences.

hyperglycemia is not only the biochemical marker by which the diagnosis of diabetes is made, but it is also responsible for the development of microvascular complications, as seen in the dccT and uKPdS trials. in addition, hyperglycemia has been shown to contribute to macrovas-cular disease, albeit to a lesser extent, as seen in the edic trial. But, most importantly, it is a self-perpetuating cause of diabetes that leads to glucose toxicity, which then contributes to insulin resistance in the muscle, liver, and adipocytes, as well as impairment in insulin secretion. in such states of hyperglycemia, it is known that elevated glucose levels worsen insulin resistance in the liver, upregulate key enzymes involved in gluconeogenesis, down-regulate glucose transport in muscle, inhibit the insulin signal transduction system, and impair insulin secretion.

These defects in glucose regulation were thought to be the result of defects of only a few organs. however, new evidence has shown that the progression of hyperglycemia to the development of T2dm can be attributed to an octet of defects. one of these defects involves the kidneys. The kidneys play a vital role in normal human physiology by helping to maintain fluid and electrolyte balance, acid-base balance, excretion of metabolic waste products and foreign chemicals, regulation of arterial pressure, secretion of hormones, and glucose balance (via glucose reabsorption and/or gluconeogenesis). new research into the role of the kidneys in glucose regulation has enhanced the understanding of the process involved in glucose reabsorption and release, including the role of sodium-glucose cotransporters (SglTs) and facilitated glucose trans-porters (gluTs) in glucose reabsorption.

in light of these new understandings of the kidneys’ role in maintaining glucose balance and the pathophysiologic derangements that contrib-ute to the development of T2dm, healthcare professionals involved in diabetes care need to be educated on these findings. A better under-standing of the myriad ways whereby glucose balance is maintained should provide a platform for the rational management of hyperglycemia in the patient with diabetes. A review of the physiology and mechanisms by which the kidneys help to maintain glucose homeostasis, kidney physiology in states of hyperglycemia, and the resulting injury that can occur if balance is not restored can be of benefit to all clinicians in their daily encounters with patients with glucose imbalance, such as those with diabetes.

Overall Educational Objectives

Upon completion of the educational activity, the participant should be able to:• Explain the pathophysiology of diabetes and the different mechanisms involved in maintaining glucose balance

• Describe the role of therapies and where they fit into the treatment paradigm based on defects of glucose homeostasis

• Examine newer and emerging agents, their potential role in diabetes management, and implications for managed care

Activity Fee

The activity is free for participants submitting evaluation forms and posttests online for Pharmacy credit (AcPe). for participants submitting evaluation forms and posttest for Pharmacy credit via fax or mail, there is a nominal fee of $10.00.

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Pharmacy Times office of continuing Professional education is accredited by the Accreditation council for Pharmacy education (AcPe) as a provider of continuing pharmacy education. This activity is approved for 2.5 contact hours (0.25 ceus) under the AcPe universal activity number 0290-0000-12-065-h01-P. The activity is available for ce credit through January 12, 2014.

Obtaining Credit: Participants must read each article in this supplement, complete the evaluation form, and achieve a passing score of 70% or higher on the posttest. detailed instructions on obtaining ce credit are included on the posttest and evaluation page contained in this supplement.

Vol. 18, no. 1 n The AmericAn JournAl of mAnAged cAre n S1

January 2012 – Vol. 18, no. 1, Sup.


Table of contents

Participating Faculty S2

Reports

n Examining the Mechanisms of glucose Regulation S4 Curtis L. Triplitt, PharmD, CDE

n understanding the Kidneys’ Role in Blood glucose Regulation S11

Curtis L. Triplitt, PharmD, CDE

n Review of Current and Emerging Therapies in Type 2 Diabetes Mellitus S17

Nissa Mazzola, PharmD, CGP

CPE Posttest and Evaluation S27

A Supplement to The American Journal of Managed Care www.ajmc.com PROJ ACE005

Publishing Staff Vice PresidentClinical and Scientific AffairsJeff D. Prescott, PharmD, RPh

Clinical Projects ManagersKara guarini, MSIda Delmendo

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Chairman/Chief Executive Officer/PresidentMike Hennessy

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Executive Assistant Teresa M. Fallon-yandoli

copyright © 2012 by managed care& healthcare communications, llc

S2 n www.ajmc.com n JAnuAry 2012

n PaRTICIPaTIng FaCulTy n


This supplement to The American Journal of Managed Care explores mechanisms involved in physiologic blood glucose regulation and imbalances in glucose homeostasis, including the mechanisms by which the kidneys contribute to glucose regulation and the potential impact of glucose imbalance on the kidneys. Specific pharmacologic agents are also discussed, in the context of guidelines from the American diabetes Association and the european Association for the Study of diabetes as well as relevant clinical studies. An extensive update on the newest drugs for the management of type 2 diabetes mellitus and managed care aspects of diabetes care is also included.

n Faculty

Nissa Mazzola, PharmD, CGPAssistant Clinical Professor, Clinical Pharmacy Practice College of Pharmacy and Allied Health Professions St. John’s University Queens, New York Ambulatory Care Specialist North Shore University Hospital Manhasset, New York

Curtis L. Triplitt, PharmD, CDEAssistant ProfessorDepartment of MedicineDivision of DiabetesUniversity of Texas Health Science Center at San Antonio Texas Diabetes InstituteSan Antonio, Texas

n Disclosures

Disclosure Policy According to the disclosure policies of the Pharmacy Times Office of Continuing Professional Education, faculty, editors, managers, and other individuals who are in a position to control content are required to disclose any relevant financial relationships with commercial com-panies related to this activity. If a conflict is identified, it is the responsibility of the Pharmacy Times Office of Continuing Professional Education to initiate a mechanism to resolve the conflict(s). The existence of these interests or relationships is not viewed as imply-ing bias or decreasing the value of the presentation. All educational materials are reviewed for fair balance, scientific objectivity of studies reported, and levels of evidence.

The faculty and planning staff have disclosed the following relevant commercial financial relationships or affiliations in the past 12 months.

FacultyNissa Mazzola, PharmD, CGP, has disclosed no relevant commercial financial relationships related to this activity.

Curtis L. Triplitt, PharmD, CDE Consultant/Advisory Board: Roche, Takeda PharmaceuticalsSpeaker’s Bureau: Amylin, Eli Lilly, Pfizer

Vol. 18, no. 1 n The AmericAn JournAl of mAnAged cAre n S3

n PaRTICIPaTIng FaCulTy n

Signed disclosures are on file at the office of The American Journal of Managed Care, Plainsboro, New Jersey.

The American Journal of Managed Care Publishing Staff—Jeff D. Prescott, PharmD, RPh; Kara Guarini, MS; Ida Delmendo; and Christina Doong have disclosed no relevant com-mercial financial relationships related to this activity.

Pharmacy Times Office of Continuing Professional Education Planning Staff—Judy V. Lum, MPA; Ann C. Lichti, CCMEP; and Donna W. Fausak have disclosed no relevant commercial financial relationships related to this activity.

The contents of this supplement may include information regarding the use of products that may be inconsistent with or outside the approved labeling for these products in the United States. Physicians should note that the use of these products outside current approved labeling is considered experimental and are advised to consult pre-scribing information for these products.

S4 n www.ajmc.com n january 2012

© Managed Care &Healthcare Communications, LLC

D espite vigorous research aimed at combating type 2 diabetes mellitus (T2DM) and the availability of numerous medications, this disease continues to affect people of all ages, and the prevalence of dia-

betes mellitus (DM) has reached epidemic proportions. Currently, an estimated 25.8 million individuals are affected by DM (both type 1 and type 2).1 From 1990 to 2000, the prevalence of DM increased by 49%, a rise that appears linked to the increasing rate of obesity.1 In 2010, type 1 or 2 DM was estimated to affect nearly 30% (10.9 million) of people 65 years and older, and 215,000 of those younger than 20 years. approximately 1.9 million people older than 20 years were newly diagnosed with DM, and up to 45% of newly diagnosed children had T2DM, with the majority being overweight or obese.2 In 2005 to 2008, based on fasting glucose or glycated hemoglobin (a1C) levels, 35% of adults older than 20 years, and 50% of those older than 65 years, had predia-betes. applying this percentage to the entire uS population in 2010 yields an estimated 79 million american adults older than 20 years with prediabetes.1

DM is a major cause of heart disease and stroke, and is the sev-enth leading cause of death in the united States. DM is also the leading cause of kidney failure, nontraumatic lower-limb amputa-tions, and new cases of blindness among adults.1 With respect to complications, the rising incidence of T2DM in children is particularly alarming, because as people develop the disease at a younger age, they may experience significant morbidity and potential mortality in their fourth decade of life.2 The aging of the population is also expected to drive a substantial increase in the incidence of DM and associated complications, particularly since research has found that elderly people with newly diagnosed DM experience much higher rates of complications in the years after diagnosis than do their peers without DM.2

Based on 2007 data, the economic impact of DM is consider-able, with total costs, direct medical costs, and indirect costs (eg, disability, work loss, premature mortality) estimated at $174 bil-lion, $116 billion, and $58 billion, respectively.1 Medical costs attributed to DM include $27 billion for direct care of the disease, $58 billion for treatment of DM-related chronic complications (Figure 1), and $31 billion in excess general medical costs.2 The

Abstract

The prevalence of diabetes mellitus (DM) increased by 49% between 1990 and 2000, reaching nearly epidemic proportions. In 2010, DM (type 1 or 2) was estimated to affect nearly 30% (10.9 million) of people 65 years and older and 215,000 of those younger than 20 years. Macrovascular and microvascular complications can occur; DM is a major cause of heart disease and stroke, and is the seventh leading cause of death in the United States. Based on 2007 data, the economic impact of DM is considerable, with total costs, direct medi-cal costs, and indirect costs estimated at $174 billion, $116 billion, and $58 billion, respectively. Normal glucose regulation is maintained by an intricate interaction between pancreatic β-cells (insulin/amylin), pancreatic a-cells (glucagon), and associ-ated organs (eg, intestines, liver, skeletal muscle, adipose tissue). Newly elucidated mechanisms include the involvement of the kidneys in glucose regulation, as well as central glucose regulation by the brain. The central defects in type 2 diabetes mellitus (T2DM) are decreased insulin secretion, glucoregulatory hormone deficiency/resis-tance, and insulin resistance, resulting in abnormal glucose homeostasis. This article provides an extensive review of mecha-nisms involved in physiologic blood glu-cose regulation and imbalances in glucose homeostasis.

(Am J Manag Care. 2012;18:S4-S10)

For author information and disclosures, see end of text.

n reportS n

Examining the Mechanisms of Glucose regulation



VOL. 18, nO. 1 n ThE aMErICan jOurnaL OF ManaGED CarE n S5

largest components of medical expenditures attributed to DM are hospital inpatient care (50% of total cost), medication and supplies for DM (12%), retail prescriptions for DM com-plications (11%), and physician office visits (9%). People with diagnosed DM incur average expenditures of $11,744 per year, of which $6649 is attributed directly to the disease.2 after adjusting for population age and sex differences, aver-age medical expenditures among people diagnosed with DM are estimated to be 2.3 times higher than what expenditures would be in the absence of the disease. Factoring in addi-tional costs of undiagnosed DM, prediabetes, and gestational DM brings the total costs of DM to $218 billion, with $18 billion for people with undiagnosed DM, $25 billion for adults with prediabetes, and $623 million for women with gestational DM.1 The burden of DM is imposed on all sectors of society, through, for example, higher insurance premiums paid by employees and employers, reduced earnings as a result of productivity loss, and reduced overall quality of life for patients and their families.2

In broad terms, the most recognized pathophysiologic defects in T2DM are decreased insulin secretion and insulin resistance, but in order to fully examine these and other

pathophysiologic origins of DM, it is critical to review the mechanisms involved in normal and abnormal glucose homeostasis.

Normal Glucose Homeostasis

Glucose, a fundamental source of cellular energy, is released by the breakdown of endogenous glycogen stores that are primarily located in the liver. Glucose is also released indirectly in the muscle through intermediary metabolites. These whole-body energy stores are replenished from dietary glucose, which, after being digested and absorbed across the gut wall, is distributed among the various tissues of the body.3 although glucose is required by all cells, its main consumer is the brain in the fasting or “postabsorptive” phase, which accounts for approximately 50% of the body’s glucose use. another 25% of glucose disposal occurs in the splanchnic area (liver and gastrointestinal tissue), and the remaining 25% takes place in insulin-dependent tissues, including muscle and adipose tissue.4 approximately 85% of endogenous glucose production is derived from the liver, with glycogenolysis (conversion of glycogen to glucose) and gluconeogenesis (glucose formation) contributing equally to

n Figure 1. Percent of Category Expenditures Associated With Diabetes Mellitus Complications2

35

30

25

20

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Cat

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ure

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Chronic Complications of Diabetes Mellitus

15

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Reprinted with permission from American Diabetes Association. Diab Care. 2008;31(3):596-615.

reports


the basal rate of hepatic glucose production. The remaining ~15% of glucose is produced by the kidneys.4

normally, following glucose ingestion, the increase in plasma glucose concentration triggers insulin release, which stimulates splanchnic and peripheral glucose uptake and sup-presses endogenous (primarily hepatic) glucose production. In healthy adults, blood glucose levels are tightly regulated within a range of 70 to 99 mg/dL, and maintained by specific hormones (eg, insulin, glucagon, incretins) as well as the central and peripheral nervous system, to meet metabolic requirements.5-7 Various cells and tissues (within the brain, muscle, gastrointestinal tract, liver, kidney, and adipose tis-sue) are also involved in blood glucose regulation by means of uptake, metabolism, storage, and excretion (Figure 2).4,6-8 This highly controlled process of glucose regulation may be particularly evident during the postprandial period, during which, under normal physiologic circumstances, glucose lev-els rarely rise beyond 140 mg/dL, even after consumption of a high-carbohydrate meal.6

among the various hormones involved in glucose regula-tion, insulin and glucagon (both produced in the pancreas by islets of Langerhans) are the most relevant.7 Within the islets of Langerhans, β-cells produce insulin and a-cells pro-duce glucagon. Insulin, a potent antilipolytic (inhibiting fat breakdown) hormone, is known to reduce blood glucose lev-els by accelerating transport of glucose into insulin-sensitive

cells and facilitating its conversion to storage compounds via glycogenesis (conversion of glucose to glycogen) and lipogenesis (fat formation).7 Glucagon, which also plays a central role in glucose homeostasis, is produced in response to low normal glucose levels or hypoglycemia and acts to increase glucose levels by accelerating glycogenolysis and promoting gluconeogenesis.7 after a glucose-containing meal, however, glucagon secretion is inhibited by hyperinsu-linemia, which contributes to suppression of hepatic glucose production and maintenance of normal postprandial glucose tolerance.7 The hormone amylin contributes to reduction in postprandial glucagon, as well as modest slowing of gastric emptying.9

Incretins, which include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are also involved in regulation of blood glucose, in part by their effects on insulin and glucagon.9,10 however, both GLP-1 and GIP are considered glucose-dependent hormones, meaning that they are secreted only when glucose levels rise above normal fasting plasma glucose levels; they do not directly stimulate insulin secretion. normally, these hormones are released in response to meals and, by activating certain recep-tors (G protein–coupled) on pancreatic β-cells, they aid in stimulation of insulin secretion. When glucose levels are low, however, GLP-1 and GIP levels (and their stimulating effects on insulin secretion) are diminished.11

n Figure 2. Glucose Disposal by Various Tissues After a Hypothetical Meal Containing 100 g of Glucose8

Gut: 100 g of glucose ingested

Liver: 30% of ingested glucose is taken up by the liver

Systemic circulation: 70% of ingested glucose is released into the systemic circulation. Of this 70%:

• 20% is extracted by the liver

• 20% is taken up by the brain

• 40% is taken up by skeletal muscle

• 20% is taken up by the kidney, adipose tissue, skin, and blood cells

When 100 g of glucose is ingested, 30% is taken up by the liver and 70% is released into the systemic circulation. Of this 70 g, 15 g (20%) is extracted by the liver, 15 g (20%) is taken up by the brain, 27 g (40%) is taken up by skeletal muscle, and the remaining 20% is taken up by kidney, adipose tissue, skin, and blood cells. Adapted from Gerich JE. Diabetes Obes Metab. 2000;2:345-350.



Transport of Glucose Into Cells

Since glucose cannot readily diffuse through (imper-meable) cell membranes, it requires assistance from both insulin and a family of transport proteins (facilitated glucose transporter [GLuT] molecules) in order to gain entry into most cells.3 Essentially, GLuTs act as shuttles, forming an aqueous pore across otherwise hydrophobic cellular mem-branes, through which glucose can move more easily.3 Of the 12 known GLuT molecules, GLuT4 is considered the major transporter for adipose, muscle, and cardiac tissue, whereas GLuTs 1, 2, 3, and 8 facilitate glucose entry into other organs (eg, brain, liver), though we continue to learn more about the role of GLuTs in DM.6,7,12 activation of GLuT4 and, in turn, facilitated glucose diffusion into muscle and adipose tissue, is dependent on the presence of insulin, whereas the function of other GLuTs is more independent of insulin.7,13 Once glucose enters cells, it is phosphorylated (via glucokinase in the liver and hexokinase in most other cells), after which it cannot diffuse out of cells and can then be either used for energy production or converted to a storage compound (ie, glycogen, fat).4,6

Major Systems Involved in Glucose Utilization and Regulation

The majority of glucose uptake (>80%) in peripheral tissue occurs in muscle, where glucose may either be used immediately for energy or stored as glycogen.6 as stated previously, skeletal muscle is insulin-dependent, and thus requires insulin for activation of the major enzyme (glycogen synthase) that regulates production of glycogen.10 While adipose tissue is responsible for a much smaller amount of peripheral glucose uptake (2%-5%), it plays an important role in the maintenance of total body glucose homeostasis by regulating the release of free fatty acids (which increase glu-coneogenesis) from stored triglycerides, influencing insulin sensitivity in the muscle and liver.4

While the liver does not require insulin to facilitate glu-cose uptake, it does need insulin to regulate glucose output.4 So, for example, when insulin concentrations are low, hepat-ic glucose output rises.10 additionally, insulin helps the liver store most of the absorbed glucose in the form of glycogen.6

The kidneys are increasingly recognized to play an impor-tant role in glucose homeostasis via release of glucose into the circulation (gluconeogenesis), uptake of glucose from the circulation to meet renal energy needs, and reabsorption of glucose at the proximal tubule.12 The kidneys also aid in elimination of excess glucose (when levels exceed approxi-mately 180 mg/dL, though this threshold may rise during chronic hyperglycemia) by facilitating its excretion in the

urine.2 In DM, where glucose levels are high and may exceed the threshold of glucose reabsorption, more glucose may be excreted in the urine if concentrations in filtered urine become high.6

Pathophysiology of T2DM

DM is a group of metabolic diseases characterized by hyperglycemia. The hallmark state of chronic hyperglycemia is associated with long-term damage, dysfunction, and poten-tial failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.14 numerous factors contrib-ute to the development of T2DM, with the central defects being inadequate insulin secretion (insulin deficiency) and/or diminished tissue responses to insulin (insulin resistance) at 1 or more points in the complex pathways of hormone action.14 Insulin deficiency and insulin resistance frequently coexist, though the contribution to hyperglycemia can vary widely along the spectrum of T2DM.

The pancreas has a remarkable capacity to adapt to condi-tions of increased insulin demand (eg, in obesity, pregnancy, cortisol excess) to maintain normoglycemia. Compensatory hyperinsulinemia maintains glucose homeostasis. however, when β-cell secretion of insulin becomes inadequate for the glucose load, hyperglycemia occurs. Progressive deteriora-tion in β-cell function and mass is well known to occur over time in T2DM and the resultant state of impaired insulin secretion is found uniformly in T2DM patients of all ethnic backgrounds.4,15 research has shown that at time of diagnosis, islet cell function/responsiveness to glucose is approximately 30% to 50% of normal, and β-cell mass is reduced by about 60%; both of these are important determinants of the amount of insulin that is secreted.4 Based on analyses from the united Kingdom Prospective Diabetes Study, a direct correlation exists between progressive loss in β-cell function and poor glycemic control (as measured by a1C levels).16 The major factors implicated in progressive loss of β-cell function and mass include glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. research indicates that progressive impaired β-cell function and possibly β-cell mass may be arrested, though clinical evidence in humans remains scarce.15

Impaired insulin secretion is often exacerbated by insulin resistance, which is characterized by the inability of insulin to decrease plasma glucose levels through suppression of hepatic glucose production and stimulation of glucose utiliza-tion in skeletal muscle and adipose tissue.10 In the presence of physiologically possible levels of insulin in humans, there is decreased glucose uptake in subjects with T2DM versus normal subjects, confirming that glucose uptake is severely

reports


impaired due to insulin resistance (Figure 3).4,17 as a conse-quence of insulin resistance, inefficient glucose utilization is eventually replaced by cellular utilization of fats and proteins for energy. Insulin resistance is contributed to by genetic and environmental factors. Family history can contribute directly to insulin resistance, but multiple environmental factors such as obesity, comorbidities, and central adiposity (visceral) can all contribute. The exact cause of insulin resistance in any given patient is complex, but may include defects in insulin-mediated cell signaling pathways, reduced insulin-stimulated muscle glycogen synthesis,18 or even potentially fewer insulin receptors (particularly in skeletal muscle, liver, and adipose tissue in obese subjects).6

The relative contribution of insulin secretion and insulin resistance to the development of hyperglycemia may differ due to the heterogeneity of T2DM. under most circumstances, insulin resistance is the earliest detectable defect in individuals with prediabetes.19 Initially, enhanced insulin secretion may compensate for the insulin resistance; however, early phase insulin secretion is impaired. In the transition from normal glucose tolerance to impaired glucose tolerance and DM, insulin sensitivity deteriorates about 40%, whereas insulin secretion deteriorates 3- to 5-fold.19 In DM, chronic hyperglycemia may result in fur-ther deterioration of insulin sensitivity and secretion (glu-cotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity).19

Other increasingly more well-understood mechanisms contrib-uting to the pathophysiology of T2DM include increased hepatic glucose output and adipocyte dys-function. Following glucose inges-tion, insulin is normally secreted into the portal vein, where it is taken up by the liver and sup-presses hepatic glucose output. however, if the liver does not perceive this insulin signal and continues to produce glucose, the 2 sources of glucose input (from the liver and the gastrointestinal tract) will result in marked hyper-glycemia.4 The increased hepatic glucose output seen in T2DM is thought to be related partly to insulin resistance and is closely correlated with the severity of fast-ing hyperglycemia. To the latter

point, it has been shown that while the postabsorptive level of chronic hyperinsulinemia seen in mild hyperglycemia (<140 mg/dL) is enough to offset hepatic insulin resistance and maintain a normal basal rate of hepatic glucose output, moderate fasting hyperglycemia is associated with significant increases in hepatic glucose output.4 In individuals with T2DM with overt fasting hyperglycemia (>140 mg/dL), an excessive rate of hepatic glucose output is considered the major abnormality responsible for the elevated fasting plasma glucose.4 although hyperinsulinemia and hyperglycemia (both certainly present in T2DM) are potent inhibitors of hepatic glucose output, they do not appear to fully correct excessive glucose output by the liver, which is suggestive of existing hepatic resistance to insulin and potential hyperglu-cagonemia contributing to an elevated plasma glucose.4

With regard to adipocyte dysfunction, considerable evi-dence implicates deranged metabolism and altered disposi-tion of fat in the pathogenesis of glucose intolerance in T2DM.20 Because fat cells are resistant to insulin’s antilipo-lytic effect, the resultant chronically elevated plasma free fatty acid levels stimulate gluconeogenesis, induce hepatic/muscle insulin resistance, and impair insulin secretion in predisposed individuals.20 These free fatty acid–induced disturbances are referred to as lipotoxicity. Beyond this phenomenon, dysfunctional fat cells also produce exces-sive amounts of insulin resistance–inducing, inflammatory, and atherosclerotic-provoking cytokines and fail to secrete

n Figure 3. Plasma Insulin Concentration and Whole Body Glucose Uptake17

500

400

300

200

100Tota

l Glu

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Up

take

(mg

/m2

� m

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Insulin Concentration(�U/mL)

0

0 50 100 150 200 250

*P <.01 versus control

Control

Type 2 Diabetes Mellitus

*

*

*

Reprinted with permission from Groop LC, Bonadonna RC, DelPrato S, et al. J Clin Invest. 1989;84:205-213.



normal amounts of insulin-sensitizing adipocytokines (adi-ponectin).20 also, the pattern of fat disposition in T2DM is abnormal, essentially because enlarged adipocytes (in visceral fat) are insulin-resistant and have diminished capacity to store fat, which leads to lipid overflow into muscle, liver, and potentially β-cells, further exacerbating muscle/hepatic insulin resistance and impaired insulin secretion. They are also major sources of proinflammatory adipocytokines. Within liver cells, the elevated free fatty acids are converted to triglycerides, which accumulate and cause steatosis (or fatty liver) and consequently may increase the chances of nonalcoholic steatohepatitis (naSh) and even cirrhosis.10 These disturbances in adipocyte function are particularly rel-evant in light of the fact that many individuals with T2DM are obese.

The development of glucose intolerance in T2DM involves multiple systems including the muscle, liver, β-cell, fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), a-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resis-tance).21 Collectively, these 8 players comprise the omi-nous octet and dictate the need for combination therapy. Treatment should be based upon reversal of known patho-genic abnormalities and should not be directed simply at the reduction of a1C. Early initiation of therapy may help to prevent or slow progressive β-cell failure.21

Clinical Manifestations of T2DM

The majority of patients with T2DM are either obese (with obesity itself contributing to insulin resistance) or have an increased proportion of body fat in the abdominal region. Many factors increase the risk of developing T2DM, including family history, age, obesity, and lack of physical activity. also, DM occurs more frequently in women with prior gestational DM and in individuals with hypertension or dyslipidemia.14 T2DM is frequently undiagnosed for many years, since the hyperglycemia develops gradually and, at least in the early stages, is not severe enough to cause clinical symptoms. Symptoms of marked hyperglycemia include poly-uria, polydypsia, weight loss, polyphagia, and blurred vision.14

although the degree of hyperglycemia seen with T2DM may not cause symptoms initially, it is sufficient to cause pathologic and functional changes in target tissues, and as such, will increase the risk of microvascular and macrovas-cular complications.14 hyperglycemia, or long-term glycemic burden, appears to be cumulative, increasing the chances of complications with longer exposure. These long-term com-plications include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy

with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitouri-nary, and cardiovascular symptoms and sexual dysfunction. Diabetic patients also have an increased incidence of ath-erosclerotic cardiovascular, peripheral arterial, and cerebro-vascular disease.14

Summary

Glucose, a vital energy source for many cells and tissues, is tightly regulated via a complex interaction between pancre-atic β-cells and a-cells, associated organs (eg, intestines, liver, skeletal muscle, adipose tissue), and respective hormones (ie, insulin, glucagon, GLP-1, GIP, amylin, and others). a summary of the major factors responsible for maintenance of normal glucose tolerance in healthy subjects is provided in the table.4 Beyond these primary controllers of glucose regu-lation, incretin hormones (GIP and GLP-1) further assist in maintenance of normal plasma glucose and a host of transport proteins (GLuT molecules) facilitate movement of glucose through otherwise impermeable cellular membranes. The pri-mary tissues involved in glucose utilization include the brain, muscle, fat, and the splanchnic area, with muscle tissue com-prising the most important site of peripheral glucose uptake.

Knowledge of the fundamentals of normal glucose homeo-stasis is essential to understanding the pathophysiologic derangements that may result from glucose imbalance dis-orders. Conditions such as T2DM are characterized by an imbalance in glucose regulation, causing chronic hypergly-cemia and ultimately leading to multiorgan damage. Several factors are implicated in the development of T2DM, includ-ing insulin resistance, insulin deficiency, increased hepatic glucose production, and adipocyte dysfunction. an increas-ingly clear understanding of these derangements has helped both researchers and clinicians to better manage T2DM and improve clinical outcomes.

n Table. Major Factors Responsible for Maintenance of Normal Glucose Tolerance in Healthy Subjects4

Insulin secretion

Tissue glucose uptake

• Peripheral (primarily muscle)

• Splanchnic (liver plus gut)

Suppression of hepatic glucose production

• Decreased free fatty acids

• Decreased glucagon

Route of glucose administration

Reprinted with permission from DeFronzo RA. Med Clin N Am. 2004; 88:787-835.

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Author affiliations: Department of Medicine, Division of Diabetes, university of Texas health Science Center at San antonio; and Texas Diabetes Institute, San antonio, TX.

Funding source: This activity is supported by an educational grant from Bristol-Myers Squibb and astraZeneca LP.

Author disclosure: Dr Triplitt reports being a consultant or a member of the advisory board for roche and Takeda Pharmaceuticals. he also reports being a member of the speakers’ bureau for amylin, Eli Lilly, and Pfizer.

Authorship information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: E-mail: [email protected].

REFEREnCES 1. National Diabetes Fact Sheet, 2011. Center for Disease Control and Prevention. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011 .pdf. Accessed August 21, 2011.

2. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diab Care. 2008;31(3):596-615.

3. Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol. 2002;3(4): 267-277.

4. DeFronzo RA. Diabetes: pathogenesis of type 2 diabetes mel-litus. Med Clin N Am. 2004;88:787-835.

5. Wardlaw GM, Hampl JS. Perspectives in Nutrition. 7th ed. New York, NY: McGraw-Hill; 2007.

6. Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Inc; 2006.

7. Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York, NY: Wiley; 2003.

8. Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2:345-350.

9. Drucker DJ, Nauck M. The incretin system: glucagon-like pep-tide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-1705.

10. Porte D, Sherwin RS, Baron A. Ellenberg & Rifkin’s Diabetes Mellitus. 6th ed. New York, NY: McGraw-Hill; 2003.

11. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-165.

12. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Int Med. 2007;261:31-43.

13. Uldry M, Thorens B. The SLC2 family of facilitated hexose and polyol transporters. Eur J Physiol. 2004;447:480-489.

14. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(suppl 1):S62-S69.

15. Wajchenberg BL. β-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007;28:187-218.

16. Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism. 2006;55(suppl 1):S2-S5.

17. Groop LC, Bonadonna RC, DelPrato S, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. J Clin Invest. 1989;84:205-213.

18. Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med. 2006;119(5A):10S-16S.

19. Groop L. Pathogenesis of type 2 diabetes: the relative contri-bution of insulin resistance and impaired insulin secretion. Int J Clin Pract Suppl. 2000;(113):3-13.

20. Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab. 2004;89(2):463-478.

21. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.

VOL. 18, NO. 1 n The AmericAN JOurNAL Of mANAged cAre n S11


P ublished studies over the last 60 years have provided considerable evidence regarding the ability of the kid-neys to make and release glucose under various physi-ologic conditions. Yet traditionally, the kidneys have

not been considered an important source of glucose (except during acidosis or after prolonged fasting), with most clinical discussions on glucose dysregulation centering on the intestine, pancreas, liver, adipose tissue, and muscle.1-3 more recently, however, the full significance of the kidneys’ contribution to glucose homeosta-sis, under both physiologic and pathologic conditions, has become well recognized, and is thought to involve functions well beyond glucose uptake and release. Besides the liver, the kidney is the only organ capable of generating sufficient glucose (gluconeogen-esis) to release into the circulation, and it is also responsible for filtration and subsequent reabsorption or excretion of glucose.2-4 These findings have provided considerable insight into the myriad of pathophysiologic mechanisms involved in the development of hyperglycemia and type 2 diabetes mellitus (T2dm).5,6 This article provides a review of the kidneys’ role in normal human physiology, the mechanisms by which they contribute to glucose regulation, and the potential impact of glucose imbalance on the kidneys.

Overview of Renal Physiology

The kidneys are essentially designed to filter large quantities of plasma, reabsorb substances that the body must conserve, and secrete substances that must be eliminated. These basic functions are critical to regulation of fluid and electrolyte balance, body fluid osmolality, acid-based balance, excretion of metabolic waste and foreign chemicals, arterial pressure, hormone secretion, and, most relevant to this discussion, glucose balance.7,8 The 2 kidneys produce a total of approximately 120 mL/min of ultrafiltrate, yet only 1 mL/min of urine is produced. The basic urine-forming unit of the kidney is the nephron, which serves to filter water and small solutes from plasma and reabsorb electrolytes, amino acids, glucose, and protein. The nephron, of which there are approxi-mately 1 million in each kidney, consists of a filtering apparatus (the glomerulus) that is connected to a long tubular portion that reabsorbs and conditions the glomerular ultrafiltrate. fluid filtered from the glomerular capillaries flows into the tubular portion, which is made up of a proximal tubule, the Loop of henle, and

Abstract

While not traditionally discussed, the kid-neys’ contributions to maintaining glucose homeostasis are significant and include such functions as release of glucose into the circulation via gluconeogenesis, uptake of glucose from the circulation to satisfy their energy needs, and reabsorption of glucose at the level of the proximal tubule. Renal release of glucose into the circula-tion is the result of glycogenolysis and gluconeogenesis, respectively involving the breaking down and formation of glucose-6-phosphate from precursors (eg, lactate, glycerol, amino acids). With regard to renal reabsorption of glucose, the kidneys normally retrieve as much glucose as pos-sible, rendering the urine virtually glucose free. The glomeruli filter from plasma approximately 180 grams of d-glucose per day, all of which is reabsorbed through glucose transporter proteins that are pres-ent in cell membranes within the proximal tubules. If the capacity of these transporters is exceeded, glucose appears in the urine. The process of renal glucose reabsorption is mediated by active (sodium-coupled glu-cose cotransporters) and passive (glucose transporters) transporters. In hyperglyce-mia, the kidneys may play an exacerbating role by reabsorbing excess glucose, ulti-mately contributing to chronic hyperglyce-mia, which in turn contributes to chronic glycemic burden and the risk of microvas-cular consequences. This article provides an extensive review of the kidneys’ role in normal human physiology, the mechanisms by which they contribute to glucose regula-tion, and the potential impact of glucose imbalance on the kidneys.



n reportS n

understanding the Kidneys’ role in Blood glucose regulation


reports

S12 n www.ajmc.com n JANuArY 2012

the distal tubule, all of which assist in reabsorbing essential substances and converting filtered fluid into urine.7

evaluation of renal function is an important part of care, and with that, creatinine clearance (crcl) or glomerular filtration rate (gfr), most frequently estimated (egfr), are considered most useful in determining the degree of renal insufficiency and the stage of chronic kidney disease in accordance with the National Kidney foundation clas-sification system. Since alterations in all renal functions (ie, filtration, secretion, reabsorption, endocrine and meta-bolic function) have been associated primarily with gfr, this quantitative index may be used to measure any functional changes that result from kidney-related disease progression, therapeutic intervention, or toxic insult.9

Mechanisms of Glucose Homeostasis in the Kidneys

As described in greater detail in the first article in this supplement, maintenance of glucose homeostasis is crucial in preventing pathological consequences that may result from hyperglycemia or hypoglycemia. chronically uncontrolled hyperglycemia leads to a higher risk of macrovascular and microvascular complications, such as cardiovascular disease, nephropathy, neuropathy, and retinopathy.10 hypoglycemia, on the other hand, may lead to a myriad of central nervous system complications (eg, confusion, behavioral changes, seizures, loss of consciousness, and even death), since the brain is the body’s largest consumer of glucose in the fasting or “postabsorptive” state.10,11 maintenance of glucose homeo-stasis involves several complementary physiologic processes, including glucose absorption (in the gastrointestinal tract), glycogenolysis (in the liver), glucose reabsorption (in the kid-neys), gluconeogenesis (in the liver and kidneys), and glucose excretion (in the kidneys).10,12

As alluded to previously, the kidneys are capable of syn-thesizing and secreting many important hormones (eg, renin, prostaglandins, kinins, erythropoietin) and are involved in a wide variety of metabolic processes such as activation of vitamin d3, gluconeogenesis, and metabolism of numerous endogenous compounds (eg, insulin, steroids).9 With respect to renal involvement in glucose homeostasis, the primary mechanisms include release of glucose into the circulation via gluconeogenesis, uptake of glucose from the circulation to satisfy the kidneys’ energy needs, and reabsorption of glucose at the level of the proximal tubule.13

Glycogenolysis and Gluconeogenesisrenal release of glucose into the circulation is the

result of glycogenolysis and gluconeogenesis. glycogenolysis involves the breakdown of glycogen to glucose-6-phosphate

from precursors (eg, lactate, glycerol, amino acids) and its subsequent hydrolysis (via glucose-6-phosphatase) to free glucose. conversely, gluconeogenesis involves formation of glucose-6-phosphate from those same precursors and subse-quent conversion to free glucose. interestingly, the liver and skeletal muscles contain most of the body’s glycogen stores, but only the liver contains glucose-6-phosphatase. As such, the breakdown of hepatic glycogen leads to release of glucose, whereas the breakdown of muscle glycogen leads to release of lactate. Lactate (generated via glycolysis of glucose by blood cells, the renal medulla, and other tissues) may be absorbed by organs and reformed into glucose.2

With regard to glucose utilization, the kidney may be perceived as 2 separate organs, with glucose utilization occur-ring predominantly in the renal medulla and glucose release limited to the renal cortex. These activities are separated as a result of differences in the distribution of various enzymes along the nephron. To this point, cells in the renal medulla (which, like the brain, are obligate users of glucose) have significant glucose-phosphorylating and glycolytic enzyme activity, and can therefore phosphorylate and accumulate glycogen. however, since these cells lack glucose-6-phospha-tase and other gluconeogenic enzymes, they cannot release free glucose into the circulation. On the other hand, renal cortex cells do possess gluconeogenic enzymes (including glu-cose-6-phosphatase), and therefore can make and release glu-cose into the circulation. But because these cells have little phosphorylating capacity, they cannot synthesize glycogen.2

The magnitude of renal glucose release in humans is somewhat unclear, with inconclusive evidence regarding the contribution of the kidneys to total body gluconeogenesis.4 One analysis of 10 published studies concluded that the renal contribution to total body glucose release in the postabsorp-tive state is approximately 20%. Based on the assumption that gluconeogenesis accounts for approximately half of all circulatory glucose release during the fasting state, renal glu-coneogenesis is projected, although not conclusively proven, to potentially be responsible for approximately 40% of all gluconeogenesis.2 Taking into consideration the potential contribution of renal gluconeogenesis, the kidneys appear to play a substantial role in overall glucose release in normal as well as pathophysiologic states (eg, hepatic insufficiency, counterregulation of hypoglycemia). To this point, evidence suggests that in patients with T2dm, renal glucose release is increased in both the postprandial and postabsorptive states, implicating the kidneys’ contribution to the hyperglycemia that characterizes this condition.4 in one study, a 3-fold increase in renal glucose release was observed in patients with diabetes versus those without.14 in contrast, hepatic glucose



release increased by only 30% in the diabetic state. Potential mechanisms involved in excessive renal glucose release in T2dm include fasting gluconeogenesis, decreased postpran-dial insulin release, insulin resistance (known to suppress renal/hepatic insulin release), increased free fatty acid (ffA) concentrations (ffAs stimulate gluconeogenesis), greater availability of gluconeogenic precursors, and increased glycog-enolysis.3 Again, it is clear that there is a renal contribution to glucose output in the body, but the actual contribution in individual patients with T2dm is still controversial.

Glucose Reabsorptionin addition to their important role in gluconeogenesis,

the kidneys contribute to glucose homeostasis by filtering and reabsorbing glucose. under normal conditions, the kidneys retrieve as much glucose as possible, rendering the urine virtually glucose free. The glomeruli filter from plasma approximately 180 grams of d-glucose per day, all of which is reabsorbed through glucose transporter proteins that are present in cell membranes within the proximal tubules.4 if the capacity of these transporters is exceeded, glucose appears in the urine. This maximum capacity, known as the tubular maximum for glucose (Tmg), ranges from 260 to 350 mg/min/1.73 m2 in healthy adults and children, and corresponds to a plasma glucose level of approximately 200 mg/dL.4 Once the Tmg (the threshold) is reached and transporters are unable to reabsorb all the glucose (as in T2dm), glucosuria ocurrs.7,15 The correlation between the degree of hypergly-cemia and degree of glucosuria becomes linear when blood glucose concentrations have increased beyond a threshold.4 it should be noted that slight differences between individual nephrons and the imprecise nature of biological systems may alter this linear concentration/reabsorption curve, as indicat-ed by a splay from the theoretical as the Tmg is approached.4 As such, glucosuria may potentially develop before the expected Tmg is reached. glucosuria may also occur at lower plasma glucose concentrations in certain conditions of hyperfiltration (eg, pregnancy), but as a consequence of hyperfiltration rather than significant hyperglycemia.12

Renal Glucose TransportersThe transport of glucose (a polar compound with positive

and negative charged areas, making it soluble in water) into and across cells is dependent on specialized carrier proteins in 2 gene families: the facilitated glucose transporters (gLuTs) and the sodium-coupled glucose cotransporters (SgLTs). These transporters control glucose transport and reabsorption in several tissue types, including the proximal renal tubule, small intestine, blood-brain barrier, and peripheral tissues (table).13,16 gLuTs are involved in the passive transport of glucose across cell membranes, facilitating its downhill move-ment as it equilibrates across a membrane. SgLTs, on the other hand, mediate active transport of glucose against a con-centration gradient by means of cotransport with sodium. Of the various SgLT proteins expressed in the kidneys, SgLT2 is considered most important; based on animal studies, it is responsible for reabsorbing 90% of the glucose filtered at the glomerulus.4 SgLT1 contributes to the other 10% of glucose reabsorbed in the proximal tubule. This predominant role of SgLT2 in renal reabsorption of glucose raises the prospect of therapeutically blocking this protein in patients with diabe-tes. Of the various gLuT proteins expressed in the kidneys, gLuT2 is the major transporter, releasing into circulation the glucose reabsorbed by SgLTs in the proximal tubular cells (Figure).4,17

in examining disorders involving renal glucose transport, gene mutations within SgLTs lead to inherited disorders of renal glucosuria, including familial (primary) renal gluco-suria (frg) and glucose-galactose malabsorption (ggm). frg, an autosomal recessive or autosomal dominant dis-order resulting from several different SgLT2 mutations, is characterized by persistent glucosuria in the absence of hyperglycemia or general renal tubular dysfunction. Because the majority of patients with frg have no clinical manifes-tations, frg is commonly described as a “nondisease” and is synonymous with the condition known as benign glucosuria.

even the most severe form of frg (type O), where non-functioning mutations within the SgLT2 gene result in a complete absence of renal tubular glucose reabsorption, is

n Table. Distribution of Several Major GLUT and SGLT Transporters13

Transporter (Gene) Distribution

SGLT1 (SLC5A1) Intestine, renal proximal tubule (S3), brain, heart, trachea

SGLT2 (SLC5A2) Renal proximal tubule (S1 and S2–S1 segment is where a majority of glucose reabsorption is mediated)

GLUT1 (SLC2A1) Widespread; highest levels in erythrocytes and vascular endothelium

GLUT2 (SLC2A2) Liver, pancreas, intestine, renal proximal tubule

GLUT indicates facilitated glucose transporter; SGLT, sodium-coupled glucose cotransporter. Adapted from Wright EM, Hirayama BA, Loo DF. J Int Med. 2007;261(1):32-43.

reports


associated with a favorable prognosis. Because frg is gener-ally asymptomatic, affected individuals are identified through routine urinalysis.4

ggm, a more serious autosomal recessive disease caused by mutation of the SgLT1 transporter, is characterized by intestinal symptoms that manifest within the first few days of life and result from failure to absorb glucose and galactose from the intestinal tract. The resultant severe diarrhea and dehydration may be fatal if a glucose- and galactose-free diet is not initiated. in some patients with ggm, glucosuria is pres-ent but typically mild, while in others, no evidence of abnor-mal urinary glucose excretion exists, affirming the minor role of SgLT1 in renal glucose reabsorption of glucose.4

gene mutations involving gLuTs are associated with more severe consequences, as these transporters are more

widespread throughout the major organ systems. compared with SgLT2 and SgLT1, which are present mostly in the renal system, gLuT2 is a widely distributed facilitative glu-cose transporter that has a key role in glucose homeostasis through its involvement in intestinal glucose uptake, renal reabsorption of glucose, glucosensing in the pancreas, and hepatic uptake and release of glucose.4 mutations of the gene encoding this protein result in fanconi-Bickel syn-drome, a rare autosomal recessive glycogen storage disease that encompasses a multitude of complications (glucose and galactose intolerance, postprandial hyperglycemia, fasting hypoglycemia, tubular nephropathy, hepatomegaly, reno-megaly, rickets, and stunted growth). Because gLuT2 is involved in the tubular reabsorption of glucose, glucosuria is a feature of the nephropathy.4

n Figure. Renal Glucose Filtration and Reabsorption in the Proximal Tubule17

ATPase indicates adenosine triphosphatase; GLUT, facilitated glucose transporter; SGLT, sodium-coupled glucose cotransporter. The major active glucose transporters present in the human kidneys are SGLT1 and SGLT2. Accounting for 90% of glucose reabsorption in the kidneys is SGLT2, which is a low-affinity, high-capacity transporter found primarily in the convoluted segment (S1) of the proximal tubule (closest to Bowman’s cap-sule). SGLT1 is a high-affinity, low-capacity transporter that is located more distally in the straight S3 segment of the proximal tubule (further down along the nephron but before the loop of Henle), and accounts for the other 10% of renal glucose reabsorption. Reprinted with permission from Komoroski B, Vachharajani N, Boulton D, et al. Clin Pharmacol Ther. 2009;85(5):520-526.

Proximal tubuleThe Nephron

Bowman’s capsule

Loop of Henle

To bladder

S1 proximal tubule

Lumen

K+

K+

Na+

Na+

ATPase

ATPase

GlucoseSGLT2

SGLT1

GLUT2

GLUT1Glucose

Lumen

Blood vessel

Blood vessel

Glucose

Glucose

1Na+

2Na+

S3 proximal tubule



Impact of Hyperglycemia on the Kidneys

While renal glucose reabsorption is a glucose-conserving mechanism in normal physiologic states, it is known to con-tribute to hyperglycemia in conditions such as T2dm.15 renal glucose reabsorption tends to increase with plasma glucose levels, up to plasma concentrations of 180 mg/dL to 200 mg/dL.7 Among patients with diabetes, an excess of approximately 13 grams of glucose is taken up from the systemic circulation, of which 85% is attributed to increased renal glucose uptake.3 evidence suggesting a higher Tmg in patients with diabetes compared with healthy controls attests to the increased state of renal glucose reabsorption seen in chronic hyperglycemia, which in turn can increase the risk of microvascular complica-tions.13,18 Over time, the glomeruli become damaged and are unable to filter blood efficiently and glomerular membranes leak protein (more than 50% of the protein is albumin) into the urine.19 in patients with diabetes, the kidneys may be particularly susceptible to the effects of hyperglycemia, as many kidney cells are unable to sufficiently decrease glucose transport rates to prevent intracellular hyperglycemia in states of increased glucose concentration.19

Diabetic Nephropathydiabetes has become the most common single cause of end-

stage renal disease (eSrd) in the united States and europe; this is most likely due to several evolving factors, including an increased prevalence of T2dm, longer life spans among patients with diabetes, and better formal recognition of renal insufficiency.20 Based on the most current (2008) uS statistics from the American diabetes Association, diabetes accounted for more than 40% of new cases of kidney failure, with 48,374 patients with diabetes beginning treatment for eSrd, and 202,290 people with diabetes-related eSrd on chronic dialysis or undergoing a kidney transplant.20 compared with patients with type 1 diabetes mellitus, a considerably smaller fraction of those with T2dm progress to eSrd, but due to the much higher prevalence of T2dm, these individuals consti-tute over half of those with diabetes on dialysis. considerable racial/ethnic variability exists in this regard, with Native Americans, hispanics (especially mexican Americans), and African Americans at much greater risk of developing eSrd than non-hispanic whites with T2dm.20

dialysis is a very expensive therapy, costing more than $50,000 per patient per year. Total medical spending for the approximately 400,000 patients with eSrd (representing those with and without diabetes) was $22.8 billion in 2001, an almost 3-fold increase over the 1991 to 2001 decade. eSrd spending represents 6.4% of the total medicare

budget, a 33% increase from 4.8% in 1991. The epidemic growth in eSrd cases has led to skyrocketing utilization of healthcare resources.21

The earliest clinical evidence of nephropathy is the appearance of low, but abnormal, levels (≥30 mg/day or 20 μg/min) of albumin in the urine (referred to as microalbu-minuria).20 Although the course for each patient with T2dm is different, once albumin is detected in the urine, the chance of progression to more persistent albuminuria, progressive decline in gfr, raised arterial blood pressure, and increased cardiovascular morbidity and mortality is increased. Since undetected T2dm may be present for many years, a higher proportion of individuals with T2dm (vs type 1 diabetes mellitus) have microalbuminuria and overt nephropathy shortly after diagnosis. Without specific interventions, 20% to 40% of patients with T2dm and microalbuminuria prog-ress to overt nephropathy; however, within 20 years of onset of overt nephropathy, only 20% will have progressed to eSrd.20 This may be attributable to the greater risk of dying from associated coronary artery disease than progressing to eSrd among the older diabetic population. As interven-tions for coronary artery disease continue to improve, how-ever, more patients with T2dm may survive long enough to develop renal failure.20

increasing evidence demonstrates that the onset and course of diabetic nephropathy may be significantly altered by several interventions (eg, tight glucose control, use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), all of which have their greatest impact if instituted early. As such, annual screening for micro-albuminuria is critical since it leads to early identifica-tion of nephropathy. Well-known data from the diabetes control and complications Trial and the united Kingdom Prospective diabetes Study established that intensive glyce-mic control may significantly reduce the risk of developing microalbuminuria and overt nephropathy.20 recent research (eg, the Action in diabetes and Vascular disease: Preterax and diamicron mr controlled evaluation [AdVANce] trial) offers more perspective on the effects of tight glucose control and reduction of nephropathy.22 AdVANce evalu-ated progression to major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy) in 11,140 patients with T2dm randomly assigned to undergo standard or inten-sive glucose control (glycated hemoglobin level ≤6.5%). After a median of 5 years, intensive glucose control produced a 10% relative reduction in the combined outcome of major

Glucose

Glucose

Blood vessel

Blood vessel

reports


macrovascular and microvascular events, primarily as a result of a 21% relative reduction in the risk of developing new or worsening nephropathy. The intensive glucose control group was also associated with a 9% reduction in new onset micro-albuminuria, but a higher incidence of severe hypoglycemia (2.7% vs 1.5% in the standard control group). The observed reduction in nephropathy is important, since indices of renal impairment are strongly associated with future risk of major vascular events, eSrd, and death in patients with diabetes.

Conclusion

The regulation of glucose production, uptake, reabsorption, and elimination is handled by several organs, most notably (historically) the pancreas and liver. While not tradition-ally discussed, the kidneys’ contributions to maintaining glucose homeostasis are multifaceted and include such func-tions as gluconeogenesis and glucose reabsorption, the lat-ter being mediated by active (SgLT) and passive (gLuT) transporters. under normal circumstances, glucose filtered by glomeruli is completely reabsorbed, but in conditions of hyperglycemia or reduced resorptive capacity, glucosuria may occur. in hyperglycemia, the kidneys may play an exacerbat-ing role by reabsorbing excess glucose, ultimately contributing to chronic hyperglycemia, and subsequently to pancreatic b-cell failure, insulin resistance, and decreased glucose uptake. hyperglycemia in turn detrimentally affects the kidneys by damaging glomeruli, ultimately causing microalbuminuria and nephropathy. Knowledge of the kidneys’ role in glucose homeostasis and the effect of glucose dysregulation on the kidneys is critical to optimal management of T2dm and pre-vention of associated renal complications.

Author affiliations: department of medicine, division of diabetes, university of Texas health Science center at San Antonio; and Texas diabetes institute, San Antonio, TX.

Funding source: This activity is supported by an educational grant from Bristol-myers Squibb and AstraZeneca LP.

Author disclosure: dr Triplitt reports being a consultant or a member of the advisory board for roche and Takeda Pharmaceuticals. he also reports being a member of the speakers’ bureau for Amylin, eli Lilly, and Pfizer.

Authorship information: concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: e-mail: [email protected].

REFERENCES 1. Meyer C, Dostou JM, Welle SL, Gerich JE. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab. 2002;282(2):E419-E427.2. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeo-genesis: its importance in human glucose homeostasis. Diabetes Care. 2001;24(2):382-391.

3. Meyer C, Woerle HJ, Dostou JM, Welle SL, Gerich JE. Abnormal renal, hepatic, and muscle glucose metabolism follow-ing glucose ingestion in type 2 diabetes. Am J Physiol Endocrinol Metab. 2004;287(6):E1049-E1056.

4. Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Disease. 2009;53(5):875-883.

5. Shaefer CF. The ever-expanding universe. Physician’s Corner. 2008;3(4):204-207.

6. Defronzo R. Banting Lecture. From the triumvirate to the omi-nous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.

7. Guyton AC, Hall JE. Urine formation in the kidneys: I: glomer-ular filtration, renal blood flow, and their control. In: Textbook of Medical Physiology. 9th ed. Philadelphia, PA: W. B. Saunders Company; 1996:315-330.

8. Reilly RF, Jackson EK. Regulation of renal function and vascu-lar volume. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:671-720.

9. DiPiro J, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill; 2002.

10. Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2(6):345-350.

11. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26(6):1902-1912.

12. Moe OW, Wright SH, Palacín M. Renal handling of organic solutes. In: Brenner BM, Rector FC, eds. Brenner & Rector’s The Kidney. Vol. 1. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:214-247.

13. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Int Med. 2007;261(1):32-43.

14. Meyer C, Stumvoll M, Nadkarni J, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest. 1998;102(3):619-624.

15. Ganong WF. Renal function and micturition. In: Review of Medical Physiology. 21st ed. New York, NY: Lange Medical Publishing; 2003:702-732.

16. Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin on the maximum capacity of the renal tubules to reabsorb glu-cose. J Clin Invest. 1951;30(2):125-129.

17. Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85(5):520-526.

18. Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glu-cose infusion in normal and diabetic subjects. Scand J Clin Lab Invest. 1971;28(1):101-109.

19. Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes. 2008;57(6): 1446-1454.

20. Molitch ME, DeFronzo RA, Franz MJ, et al; American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004;27(1):S79-S83.

21. Rodby RA. Pharmacoeconomic challenges in the manage-ment of diabetic nephropathy. J Manag Care Pharm. 2004;10(5)(suppl A):S6-S11.

22. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascu-lar outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.



T he prevalence of type 2 diabetes mellitus (T2dm) is approaching epidemic proportions, and diabetes mellitus (dm) affects people of all ages. There has been a dramatic increase in the prevalence of dm

over the past 30 years, while previously, far fewer adults (and rarely children) were affected by this condition, mostly because obesity and physical inactivity were not as pervasive. On the other hand, treatments that prevented diabetes-related compli-cations and tests for assessing patient control of blood glucose levels did not exist, and the only marketed drugs included pork or bovine insulin and sulfonylureas.

fortunately, today’s available pharmacologic options include agents that not only target b-cell dysfunction or supplement insulin, but also act at various other recognized landmarks along the pathologic cascade of glucose deregulation. While the core pathophysiologic defects in T2dm still include insulin resistance and b-cell failure, researchers are increasingly recognizing other contributing factors such as accelerated lipolysis in adipocytes, incretin deficiency/resistance in the gastrointestinal tract, hyper-glucagonemia in a-cells, and increased glucose reabsorption in the kidneys.1,2 As such, new and emerging drugs aim to address some of these important defects that contribute to the clinical profile of T2dm. Also, while the management of hyperglycemia, the hallmark metabolic abnormality associated with T2dm, has traditionally taken center stage, therapies directed at associated comorbidities (eg, dyslipidemia, hypertension, obesity, hyperco-agulability) have become an additional focus of current manage-ment. This article focuses on current and emerging therapies for T2dm.

Glycemic Goals of Therapy

maintaining glycemic levels as close to the nondiabetic range as possible has been demonstrated in landmark trials such as the diabetes control and complications Trial (dccT) and the u.K. Prospective diabetes Study (uKPdS) to have a substantial impact on diabetes-related complications, including retinopathy, nephrop-athy, and neuropathy.3-5 Achieving lower glycated hemoglobin (A1c) levels with intensive therapy has also been shown to have a beneficial effect on cardiovascular disease (cVd) complications in type 1 dm (T1dm); however, its effect on cVd in T2dm has historically been unclear. A recently published study (the Action

Abstract

Significant advances in the treatment of type 2 diabetes mellitus (T2DM) include the implementation of prevention efforts aimed at delaying progression of glucose intoler-ance to overt diabetes mellitus (DM) and the development of new classes of blood glucose–lowering medications to supple-ment existing therapies. While the current management approach for T2DM continues to encompass traditional drugs that focus on b-cell failure and/or insulin resistance, newer agents that target other defects (eg, incretin deficiency/resistance) are increasingly incor-porated. Furthermore, the effect of therapies on associated comorbidities (eg, dyslipid-emia, hypertension, obesity, hypercoagula-bility) has become an additional therapeutic focus. This article provides a discussion of specific pharmacologic agents, based on guidelines from the American Diabetes Association/European Association for the Study of Diabetes and relevant clinical stud-ies. An extensive update on the newest drugs (eg, incretin-based therapies, amylin agonists) and managed care aspects of diabetes care is also included.



n reportS n

review of current and emerging Therapies in Type 2 diabetes mellitus

Nissa Mazzola, PharmD, CGP

reports

S18 n www.ajmc.com n JANuAry 2012

in diabetes and Vascular disease: Preterax and diamicron modified release controlled evaluation [AdVANce] trial) offers more perspective on the effects of tight glucose control in T2dm. As with previous research, the AdVANce trial also failed to show a significant effect of intensive glucose con-trol on the risk of major macrovascular events.6 AdVANce evaluated progression to major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy) in 11,140 patients with T2dm randomly assigned to undergo standard or inten-sive glucose control (glycated hemoglobin [A1c] <6.5%). After a median of 5 years of follow-up, intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs 20.0% with standard con-trol), as well as that of major microvascular events (9.4% vs 10.9%). however, the combined risk reduction was observed primarily because of a reduction in the incidence of nephropa-thy (4.1% vs 5.2%), with no significant effect on retinopathy. The type of glucose control had no effect on major macro-vascular events or death from cardiovascular or any cause. As expected, the incidence of severe hypoglycemia was higher in the intensive control group (2.7% vs 1.5%). Beyond intense glucose control, much attention has also been given to correc-tion of comorbidities (eg, hypertension, dyslipidemia), which has been shown to improve microvascular and cardiovascular complications of dm.6

The most recent glycemic goal recommended by the American diabetes Association (AdA) is, in general, an A1c level of less than 7%.7,8 more stringent A1c levels of 6.5% or less have been proposed by earlier guidelines9; how-ever, recent studies have found these lower glycemic targets to be associated with either excess cVd mortality (at A1c <6%) or to have no benefit on primary cVd outcomes.6,10 clinical judgment should be used in evaluating vulnerable or unstable patients (eg, those with a history of severe hypo-glycemia, limited life expectancy, advanced complications, extensive comorbid conditions), for whom less stringent A1c goals may be appropriate.8 An A1c of 7% or greater serves as a call to action to initiate or change therapy, with the goal of achieving an A1c level as close to the nondia-betic range as possible or, at a minimum, decreasing the A1c to less than 7%. The target fasting and preprandial levels of plasma or capillary glucose are between 70 mg/dL and 130 mg/dL. if these levels are not consistently achieved, or A1c remains above the desired target, then postprandial levels, usually measured 120 minutes after a meal, may be checked. These levels should be less than 180 mg/dL in order to achieve A1c levels in the target range.9

Principles in Selecting Antihyperglycemic Interventions

The development of new classes of glucose-lowering medi-cations to supplement older drugs (insulin, sulfonylureas, metformin) has certainly broadened the palette of available treatments and possible combinations; however, it has also highlighted the uncertainty that accompanies the selection of appropriate therapeutic regimens for the heterogeneous popu-lation of patients with diabetes. According to a consensus algo-rithm (released by the AdA and the european Association for the Study of diabetes) on initiation and adjustment of therapy for T2dm, the choice of specific antihyperglycemic agents is based on several considerations: their effectiveness in lowering glucose levels, extraglycemic effects that may reduce long-term complications, safety profiles, ease of use, and expense.9 in regard to reducing long-term complications, the consensus statement refrains from recommending one class of glucose-lowering agents (or one combination of medications) over others, since the beneficial effects of therapy on long-term complications appear to be derived from the level of glycemic control achieved, rather than from any other attributes of a particular drug.9 The effects of individual therapies on cVd risk factors (eg, hypertension, dyslipidemia), as well as on other factors influencing long-term glycemic control (eg, body mass, insulin resistance, insulin secretory capacity), are also impor-tant. Another critical aspect of optimal long-term control of T2dm is early diagnosis, when dm-associated metabolic abnormalities are usually less severe. Lower levels of glycemia at time of initial therapy are correlated with lower A1c over time and decreased long-term complications.11

With regard to lifestyle modifications, overnutrition and a sedentary lifestyle (both contributing to obesity) are the major environmental factors that increase the risk of T2dm. Not surprisingly, exercise and weight loss almost always improve glycemic levels, as well as other cVd risk factors (eg, blood pressure, atherogenic lipid profiles). The benefits of these lifestyle modifications are usually seen rapidly (with-in weeks to months), and often before substantial weight loss ocurrs.12,13 Long-term adherence remains a major limitation of diet and exercise, as seen by the high rate of weight regain among overweight patients. While bariatric surgery has generated impressive data on the elimination of T2dm with sustained weight loss of 20 kg or more, medication manage-ment remains the primary long-term intervention for the majority of patients.9

Pharmacologic Therapy

The characteristics of currently available glucose-lowering interventions, when used as monotherapy, are summarized



in the table.7 A major factor in selecting initial therapy or in changing therapy is the level of glycemic control. When levels of glycemia are high (eg, A1c >8.5%), classes with greater and more rapid glucose-lowering effectiveness, or potentially earlier initiation of combination therapy, are recommended. Likewise, when glycemic levels are closer to target goals (eg, A1c <7.5%), medications with lower hypo-glycemic potential and/or a slower onset of action may be considered.9 Since T2dm is a progressive disease, the addi-tion of medications to control worsening glycemia over time tends to be the rule rather than the exception. The following sections provide an overview of traditional and newer/emerg-ing agents used in T2dm.

MetforminThe only biguanide available in most of the world, met-

formin lowers glycemia by reducing hepatic glucose output and increasing insulin sensitivity. metformin monotherapy will lower A1c by approximately 1.5 percentage points and it is generally well tolerated, with the most common adverse effects being gastrointestinal in nature.9 While metformin monotherapy is usually not accompanied by hypoglycemia and has been used safely in patients with prediabetic hyper-glycemia, concomitant use with other agents (eg, insulin, sul-fonylureas) may result in hypoglycemic episodes. Although lactic acidosis is rarely reported, this complication has a potentially fatal outcome.9 renal dysfunction (defined as a serum creatinine >1.5 mg/dL in males or >1.4 mg/dL in females) is considered a contraindication to the use of met-formin, since renal dysfunction predisposes patients to lactic acidosis. The major nonglycemic effect of metformin remains either weight stability or modest weight loss. The uKPdS demonstrated a beneficial effect of metformin therapy on cVd outcomes; however, these results need to be confirmed in other studies.14

Sulfonylureas Sulfonylureas lower glucose levels by enhancing insulin

secretion and appear similar to metformin in efficacy at low-ering A1c levels (1.5% reduction).9 metformin, however, is associated with better long-term maintenance of glycemic targets.15 The major adverse effect associated with sulfonyl-ureas is hypoglycemia, with severe episodes (accompanied by coma or seizures) being infrequent and more common in elderly patients. Longer-acting agents (eg, chlorpropamide, glyburide, glibenclamide, sustained-release glipizide) are con-sidered more likely to cause hypoglycemia than second-generation agents (eg, glipizide, glimepiride). The initiation of sulfonylurea therapy may be accompanied by weight

gain of approximately 2 kg; however, several newer agents (eg, glimepiride) have been reported to be weight neutral. Sulfonylureas have historically been implicated as a poten-tial cause of increased cVd mortality (eg, in the university group diabetes Program study); however, this has not been substantiated by the uKPdS or the more recent AdVANce study.6,16

GlinidesSimilar to sulfonylureas, glinides (ie, repaglinide, nateg-

linide) stimulate insulin secretion; however, glinides bind to a different site within the sulfonylurea receptor and have a shorter circulating half-life, necessitating more fre-quent administration. Of the 2 currently available glinides, repaglinide is considered to be most similar in efficacy to metformin or sulfonylureas in decreasing A1c (1.5% reduc-tion).9 The glinides have a risk of weight gain similar to the sulfonylureas. hypoglycemia may be less frequent (at least with nateglinide) than with some sulfonylureas.17

a-Glucosidase Inhibitors a-glucosidase inhibitors (eg, acarbose) reduce the rate of

digestion of polysaccharides in the proximal small intestine, thus primarily lowering postprandial glucose levels without causing hypoglycemia. compared with metformin and sulfo-nylureas, these agents are less effective in lowering glucose, and reduce A1c by 0.5% to 0.8%.9 Because a-glucosidase inhibitors ultimately result in increased delivery of carbo-hydrates to the colon, they are commonly associated with increased gas production and other gastrointestinal symp-toms, causing discontinuation in 25% to 45% of patients.9 however, interest in this class has remained due to a study examining acarbose as a means of preventing the develop-ment of dm in high-risk patients with impaired glucose tolerance. The study results showed an unexpected reduction in severe cVd outcomes and a 25% reduction in the progres-sion from impaired glucose tolerance to dm.18

Thiazolidinediones (TZDs or Glitazones)TZds (ie, pioglitazone, rosiglitazone) act by increasing

the sensitivity of muscle, fat, and liver to endogenous and exogenous insulin. Because TZds are mostly used as part of combination therapy, data on glycemic effects of mono-therapy are limited, with A1c reductions reported in the range of 0.5% to 1.4%.9 The most common adverse effects associated with TZds include weight gain and fluid reten-tion. The latter complication usually manifests as peripheral edema, although new or worsened heart failure may occur. TZds may also increase subcutaneous adiposity, with some

reports


studies showing redistribution of fat from visceral deposits.9 This class has been surrounded by controversy since trogli-tazone, the first TZd, was removed from the market due to its potential to cause liver failure. While the currently avail-able TZds have not had the same deleterious hepatic effects as troglitazone, rosiglitazone (but not pioglitazone) has been associated with a 30% to 40% relative increase in the risk of myocardial infarction, according to several meta-analy-ses.19,20 TZds have also been shown to be associated with a 3- to 6-fold increased risk for diabetic macular edema (dme) in a retrospective analysis of more than 100,000 patients in england and Wales. The increased risk of dme, which may damage the retina and cause blindness, was observed after 1

year of exposure and continued to accrue over the 10-year follow-up of the study.21

Insulin Of all the diabetes medications, insulin is the most

effective in lowering glycemia, and will reduce any level of elevated A1c to, or close to, the therapeutic goal. however, compared with insulin doses used in T1dm, relatively large doses (>1 unit/kg) may be necessary to overcome the insulin resistance that is seen in T2dm.9 While initially, patients with T2dm may only require a daily dose of an intermedi-ate- or long-acting insulin (eg, “bedtime insulin”), as the disease progresses, they may eventually also need prandial

n Table. Summary of Glucose-Lowering Interventions7

Intervention

Expected Decrease in A1C With

Monotherapy (%)

Advantages

Disadvantages

Tier 1: Well-Validated Core

Step 1: Initial Therapy

Lifestyle to decrease weight and increase activity

1.0-2.0 Broad benefits Insufficient for most within first year

Metformin 1.0-2.0 Weight neutral GI side effects, contraindicated with renal insufficiency

Step 2: Additional Therapy

Insulin 1.5-3.5 No dose limit, rapidly effective, improved lipid profile

One to 4 injections daily, monitoring, weight gain, hypoglycemia, analogues are expensive

Sulfonylurea 1.0-2.0 Rapidly effective Weight gain, hypoglycemia (especially with glibenclamide or chlorpropamide)

Tier 2: Less Well Validated

TZDs 0.5-1.4 Improved lipid profile (pioglitazone), potential decrease in MI (pioglitazone)

Fluid retention, CHF, weight gain, bone fractures, expensive, potential increase in MI (rosiglitazone)

GLP-1 agonist 0.5-1.0 Weight loss Two injections daily, frequent GI side effects, long-term safety not established, expensive

Other Therapy

a-Glucosidase inhibitor 0.5-0.8 Weight neutral Frequent GI side effects, 3 times/day dosing, expensive

Glinide 0.5-1.5a Rapidly effective Weight gain, 3 times/day dosing, hypoglycemia, expensive

Pramlintide 0.5-1.0 Weight loss Three injections daily, frequent GI side effects, long-term safety not established, expensive

DPP-4 inhibitor 0.5-0.8 Weight neutral Long-term safety not established, expensive

aRepaglinide more effective in lowering A1C than nateglinide. A1C indicates glycated hemoglobin; CHF, congestive heart failure; DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; MI, myocardial infarction; TZD, thiazolidinedione. Reprinted with permission from Nathan DM, Buse JB, Davidson MB, et al. Diabetes Care. 2009;32:193-203.



therapy with short- or rapid-acting insulins to mimic physi-ologic control of glycemia. Although insulin therapy has beneficial effects on triglyceride and hdL-cholesterol levels, it is known to cause weight gain of approximately 2 to 4 kg, probably in proportion to the correction of glycemia. insulin therapy is also associated with hypoglycemia, which occurs less frequently in T2dm versus T1dm. compared with NPh and regular insulin, insulin analogues with longer, non-peaking pharmacokinetic profiles (eg, insulin glargine), as well as analogues with very short durations of action (eg, insulin lispro), may decrease the risk of hypoglycemia.9

New and Emerging Therapies

Incretin-Based Therapies: Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors

incretin hormones, the major ones being glucose-depen-dent insulinotropic polypeptide (giP) and glucagon-like peptide-1 (gLP-1), are involved in the regulation of blood glucose, and to a lesser extent, insulin and glucagon secre-tion.22,23 Both gLP-1 and giP are considered glucose-dependent hormones, meaning that they are secreted when glucose levels rise above fasting levels and that they indi-rectly stimulate insulin secretion. Normally, these incretin hormones are released from endocrine cells in the small intestine in response to oral nutrient ingestion and, by acti-vating g protein–coupled receptors on pancreatic b-cells, they aid in stimulation of insulin secretion. gLP-1 also reduces the secretion of glucagon, a hormone produced by the pancreas that stimulates the liver to convert glycogen to glucose. Additionally, gLP-1 is known to have central effects, including a reduction in gastric emptying and appe-tite, and an increased sensation of satiety. in contrast, giP has a direct stimulatory effect on glucagon secretion and no effect on gastric emptying or satiety.24

in T2dm, incretin function (essentially the ability of orally ingested nutrients to further augment glucose-induced insulin secretion) is impaired, potentially as a result of gLP-1 secretory defects and giP resistance. Among individuals with T2dm, therapeutic gLP-1 receptor agonists have been shown to enhance insulin release and inhibit glucagon secretion. Because these effects are glucose-dependent, the risk of hypoglycemia appears to be low with gLP-1–based therapies.25,26 unfortunately, the actions of native gLP-1 and giP in vivo are short-lived, due to rapid inactivation by the proteolytic enzyme dipeptidyl peptidase-4 (dPP-4). This shortcoming has prompted the development of therapeutic strategies to circumvent effects of dPP-4 and maintain incre-tin action. These strategies include development of dPP-4–resistant gLP-1 analogues (eg, exenatide, liraglutide), as

well as agents that inhibit the enzymatic activity of dPP-4 (sitagliptin, vildagliptin, saxagliptin), and perhaps other dPP enzymes such as dPP-8 and dPP-9.25,26

exenatide, a twice-daily subcutaneous injection approved in 2005, is a synthetic form of the naturally occurring exen-din-4, a peptide similar to human gLP-1 (but with a longer half-life and slower elimination) that binds avidly to the gLP-1 receptor on pancreatic b-cells and augments glucose-mediated insulin secretion.27 The agent, which is used as an adjunct to other treatments (eg, sulfonylureas, metformin, TZds), appears to lower A1c levels by 0.5% to 1%, primar-ily by lowering postprandial blood glucose levels. exenatide also suppresses glucagon secretion and slows gastric motility, leading to weight loss of 2 to 3 kg over 6 months. The agent is rarely associated with hypoglycemia, and only in patients treated with sufonylureas, postprandial regulators, or insulin. exenatide is known to cause a relatively high frequency (30%-45%) of gastrointestinal disturbances (eg, nausea, vomiting, diarrhea), which may subside over time.9,27

Liraglutide, approved more recently, is a longer-acting, once-daily human gLP-1 analogue that, like exenatide, is resistant to dPP-4 degradation. Liraglutide’s efficacy and safety profile is similar to that of exenatide, but head-to-head studies have indicated that longer-acting gLP-1 analogues generally appear to have better efficacy and fewer gastrointestinal side effects. data comparing weekly (not yet approved) versus daily exenatide favor weekly exenatide, and data comparing once-daily liraglutide versus twice-daily exenatide favor liraglutide, specifically in regard to gastro-intestinal tolerance, incidence of minor hypoglycemia, and glycemic control.24,28 The preference for long-acting gLP-1 agonists has led researchers to develop several investigational compounds (eg, modified dosage form exenatide, albiglutide, taspoglutide), all of which have longer half-lives, allowing weekly dosing.

While the safety profile of gLP-1 agonists was not con-cerning after their initial introduction, the food and drug Administration (fdA) did issue a warning in 2007 following reports of pancreatitis in some patients taking exenatide. Since then, additional cases have been reported, includ-ing instances of hemorrhagic or necrotizing pancreatitis, and 6 deaths associated with pancreatitis.24 Postmarketing surveillance has also identified isolated cases of pancreatitis in patients taking sitagliptin. in an analysis of a uS health-care database, the rates of pancreatitis with exenatide or sitagliptin were no different from those associated with met-formin or glyburide, so while a definitive causal relationship between gLP-1 agonists and pancreatitis has not been estab-lished, a possible association remains.24 As such, the fdA

reports


urges physicians to observe patients initiating or undergoing dose increases of gLP-1 agonists for signs and symptoms of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting).

more recently, the fdA also issued a warning regard-ing the ability of liraglutide to cause dose-dependent and treatment-duration–dependent thyroid c-cell tumors in rats and mice. Since liraglutide’s potential to cause thyroid c-cell tumors (including medullary thyroid carcinoma) in humans is unknown, the fdA recommends that patients with thyroid nodules (noted on physical exam or neck imag-ing) be referred to an endocrinologist for further evaluation. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (mTc) or in patients with multiple endocrine neoplasia syndrome type 2 (meN 2).29

dPP-4 inhibitors, also called incretin enhancers, exert glucose regulatory actions by prolonging the effects of gLP-1 and giP, ultimately increasing glucose-mediated insulin secretion and suppressing glucagon secretion. Three dPP-4 inhibitors (sitagliptin, linagliptin, saxagliptin) are currently approved in the united States for the treatment of T2dm, and a number of other dPP-4 inhibitors are in late-stage development.24 As a class, these agents are considered small molecules that are rapidly absorbed following oral dosing, resulting in over 80% inhibition of dPP-4 and a 2- to 3-fold increase in peripheral plasma concentrations of gLP-1 and giP. in clinical studies, dPP-4 inhibitors have been shown to lower A1c levels by 0.6% to 0.9%, and have shown neutral effects on weight as well as the potential for the preservation or enhancement of b-cell function.9,24 The most compelling indication for the use of dPP-4 inhibitors appears to be in combination with metformin in patients with early T2dm who require their first combination therapy. The complemen-tary pharmacology of dPP-4 inhibition and biguanide action may lead to increased glucose-dependent insulin secretion, suppression of hepatic gluconeogenesis, and improvement in insulin sensitivity. Based on clinical evidence suggesting that a substantial proportion of patients receiving a combination of saxagliptin and metformin achieved statistically significant improvements in glycemic control (compared with either treatment alone), a fixed-dose metformin-saxagliptin product was recently approved for T2dm.30

Similar to gLP-1 analogues, dPP-4 inhibitors are unlikely to cause hypoglycemia when used as monotherapy; how-ever, combination therapy is the more common approach in T2dm and may require monitoring for hypoglycemia. Because dPP-4 is expressed in many tissues, including

immune cells, this class of compounds has the potential to influence immune function, as evidenced by an increased incidence of infection.31

Both dPP-4 inhibitors and gLP-1 analogues appear to have beneficial effects on classic cardiac risk factors by reduc-ing blood pressure, weight, triglycerides, and low-density lipo-protein cholesterol, and increasing high-density lipoprotein cholesterol.24 it is still unknown whether these surrogate out-comes will yield a clinical benefit, although human gLP-1 infusion has shown positive effects in the settings of acute myocardial ischemia, chronic heart failure, and postmyocar-dial infarction. Several large cardiovascular outcome trials are currently under way to determine the impact of incretin-based therapies on macrovascular risk.

Amylin Agonists (Amylinomimetics)Amylin, a neuroendocrine hormone cosecreted with insu-

lin in response to meals, is known to inhibit postprandial glu-cagon secretion, slow the rate of gastric emptying, enhance satiety, and reduce food intake. Amylin-mediated activity normally results in suppression of postprandial glucose excur-sions; however, in T2dm, amylin and insulin response is markedly impaired.9 Pramlintide is a synthetic analogue of the b-cell hormone amylin and is currently approved only as adjunctive therapy with insulin. Administered subcutane-ously before meals, pramlintide is known to slow gastric emp-tying and inhibit glucagon production in a glucose-dependent fashion; pramlintide predominantly decreases postprandial glucose excursions.9 Pramlintide produces A1c reductions of 0.5% to 0.7% and is associated with a relatively high rate of gastrointestinal side effects (30% of patients develop nausea) and weight loss of 1 to 1.5 kg over 6 months. Pramlintide is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in patients with T1dm. To reduce this risk, appropriate patient selection, careful patient instruction, and insulin dose adjust-ments are critical.32

New Diabetes Indication for Established Drugs

An alternative to finding new agents is to examine existing drugs for their potential utility in the management of T2dm. colesevelam and bromocriptine, which were previously approved by the fdA for other indications, have recently been granted indications for treatment of T2dm.33 colesevelam, a bile acid sequestrant traditionally used for the treatment of hyperlipidemia, is thought to delay or alter absorption of glucose from the intestines.33 in a 16-week trial of patients with baseline A1c levels of 7.5% to 9.5% who were treated with insulin (alone or in combination with oral



antidiabetic therapy), colesevelam was shown to provide an A1c reduction of 0.41% and an LdL reduction of 12.8%.34 The main associated side effects are of gastrointestinal origin (constipation, dyspepsia, nausea) as well as increased triglyc-eride levels.35

Bromocriptine, a dopamine-2 receptor agonist, was shown in a 1-year study to reduce A1c level by approximately 0.6% as monotherapy and 1.2% in combination with insulin or a sulfonylurea.33 The agent also lowered plasma triglycerides and free fatty acids by approximately 30%, and was associated with fewer cardiovascular events.33,36 The main associated side effects include nausea, vomiting, fatigue, dizziness, and hypotension.37

Sodium-Glucose Transporter 2 BlockersThe sodium-glucose transporter 2 (SgLT2) transporter

protein is located exclusively in the proximal tubule of the kidney, where 90% of glucose reabsorption takes place.33 Agents targeting SgLT2 prevent renal glucose reabsorption and lower serum glucose by increasing urinary excretion of

glucose. The resultant glucosuria leads to reduction of plasma glucose, glucotoxicity, and body weight; however, effects may be less pronounced in patients with renal impairment.38 dapagliflozin, one of the emerging agents in this class, has been shown to lower A1c by 0.58% to 0.89% in phase 2 trials; however, an fdA advisory committee voted against approval in light of safety concerns regarding its association with bladder and breast cancer, as well as hepatotoxicty.39,40

Managed Care Aspects of Diabetes Treatment

Along with the rising prevalence and economic burden of T2dm, actual spending on drugs has increased by 87% between 1994 and 2007 (from $6.7 billion to $12.5 billion; Figure).41 researchers examining national trends in T2dm reported significant shifts in treatment since 1994, includ-ing: (1) increased use of oral therapies until the early 2000s, followed by a subsequent shift back toward the use of insulin with the advent of ultra short-acting and long-acting prepa-rations, (2) rapid growth of metformin and TZds in the late 1990s, (3) rapid early growth of incretins and dPP-4 inhibi-

5000

0

500

1000

1500

2000

2500

3000

3500

4000

4500

2001 2002 2003 2004

Year

2005 2006 2007

Am

ou

nt

Sp

ent,

US

$ in

Mill

ion

s

Other

BiguanidesGlitazones(thiazolidinediones)

Sulfonylureas

Insulins

n Figure. National Trends in the Amount Spent Per Year on Diabetes Drugs, 2001 to 200741

“Other” includes secretagogues (eg, nateglinide), a-glucosidase inhibitors (eg, acarbose), dipeptidyl-peptidase-4 inhibitors (ie, sitagliptin phosphate), and incretins (ie, exenatide). Reprinted with permission from Alexander GC, Sehgal NL, Moloney RM, Randall S, Stafford RS. Arch Intern Med. 2008;168(19):2088-2094.

reports


tors in the past 2 years, (4) a continuous decrease in sulfonyl-urea use, (5) increasing use of both combination products and multiple products per patient, and (6) substantially increased

aggregate drug expenditures and price per prescription. in 2007, the most frequently used therapies included metformin,

sulfonylureas, glitazones, insulin, sitagliptin, and exenatide. Newer therapies (ie, gLP-1 agonists, dPP-4 inhibitors) have shown rapid early adoption into practice, although the use of other relatively new therapeutic classes (ie, alpha glucosidase inhibitors, meglitinides) decreased.41

As of 2007, major contributors to the increase in aggregate drug expenditures included increased utilization of TZds, combination products, ultra short-acting insulins and their combinations, and long-acting insulins.41 during this same period, decreases were seen in metformin and sulfonylurea expenditures. The mean price of a diabetes prescription increased from $56 in 2001 to $76 in 2007, due to increasing use of and increasing prescription prices for TZds ($119 in 2001 to $160 in 2007), as well as increased use of more costly newer drugs, including ultra short-acting insulins ($156 in 2007), long-acting insulins ($123 in 2007), exenatide ($202 in 2007), and sitagliptin ($160 in 2007). The cost of metfor-min ($63 to $29) and sulfonylurea ($27 to $20) prescriptions decreased during this same period.41

in more closely examining some of the trends that con-tribute to higher medication costs in T2dm, one study compared healthcare costs among patients with T2dm who added a new oral antidiabetes drug (OAd) to an initial OAd regimen with those who uptitrated their initial OAd.42 While addition of another OAd to the initial OAd regimen was associated with 9% higher medication costs, combina-tion treatment also resulted in 14% lower inpatient costs and slightly lower (but not statistically significant) total risk-adjusted healthcare costs.42 Another report debating the merits of newer agents pointed out that compared with older drugs, newer therapies produce modest A1c-lowering effects, are considerably higher in cost, and are not available in generic formulations.43 Therefore, it has been suggested that newer agents should be reserved for patients who are not adequately managed by traditional therapies with known long-term efficacy and safety profiles.

however, in patients who do require aggressive combination treatment (potentially incorporating older and newer agents) to reach glycemic goals, an increasing body of pharmacoeco-nomic evidence appears to support the additional associated costs, since reductions in A1c have been shown to decrease medical costs and healthcare utilization. in one related study, researchers found that among patients with diabetes in a large managed care organization (mcO), those who achieved a

target A1c of 7% or less incurred 32% lower costs after 1 year of follow-up than those who did not reach the target ($1171 vs $1540).44 Another study followed individuals enrolled in a minnesota health plan to determine the effect of baseline A1c, cVd, and depression in predicting subsequent health-care costs among those with diabetes.45 in their 3-year analysis, researchers found that for every 1% rise in A1c levels, there was an associated increase in costs, which were, as expected, higher in those with higher A1c levels and concomitant heart disease, hypertension, and depression.45 researchers also found that once the A1c fell to less than 7.5%, A1c ceased to be a predictor of increased costs. Therefore, it is suggested that once glycemic control is achieved, it may be more cost-effective to focus efforts on prevention of cardiovascular events.45 A more recent study that examined the timing of cost savings in rela-tion to A1c reductions found that a sustained decrease in A1c level is associated with significant cost savings, specifically within 1 to 2 years of A1c improvement (reduction of >1%).46 mean total healthcare costs were $685 to $950 less each year in the cohort with improved A1c levels; however, these cost savings were statistically significant only among those with the highest baseline A1c levels (>10%) and appeared to be unaf-fected by the presence of complications at baseline.46

despite the clear benefits of achieving and maintaining glycemic goals and the availability of newer and potentially more effective drugs for the management of T2dm, the num-ber of patients with poor glycemic control has not substan-tially decreased over the past 10 years. According to the 2007 State of Health Care report from the National committee for Quality Assurance (NcQA), 30% of patients with diabetes enrolled in mcOs (27% in medicare, 49% in medicaid) had poor glycemic control (A1c >9%).47 in a study of modestly controlled patients (A1c levels 7.9%-8.8%) who were man-aged with a sulfonylurea and/or metformin, patients spent an average of 14.5 to 25.6 months with A1c values greater than 8% before a therapeutic change was made. Less than 50% of patients treated with sulfonylurea and/or metformin mono-therapy were switched to a new regimen as soon as, or before, the A1c exceeded 8%.47 furthermore, only 18.6% of patients treated with a combination of these agents were switched upon reaching this threshold. These results indicate that patients with relatively uncontrolled hyperglycemia are not managed promptly with more aggressive therapy, and that perhaps newer therapeutic options are being underutilized or prescribed too late in the disease process.47

Summary

much of the morbidity related to T2dm may be sub-stantially reduced with interventions that achieve relatively



normal glucose levels and perhaps have beneficial effects on cVd risk factors (eg, hypertension, dyslipidemia) and other factors influencing long-term glycemic control (eg, body mass, insulin resistance, insulin secretory capacity). The increasing availability of numerous classes of medications has given clinicians and patients more therapeutic choices, and perhaps better chances of achieving glycemic goals. however, this rapidly expanding pharmacologic menu has also complicated management of the disease. Ongoing educa-tion on new and emerging therapies for T2dm is critical to simplifying treatment regimens, individualizing therapy, and ultimately, optimizing patient outcomes.

Author affiliations: college of Pharmacy and Allied health Professions, St. John’s university, Queens, Ny; and North Shore university hospital, manhasset, Ny.

Funding source: This activity is supported by an educational grant from Bristol-myers Squibb and AstraZeneca LP.

Author disclosure: dr mazzola has disclosed no relevant commercial financial relationships related to this activity.

Authorship information: Analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and supervision.

Address correspondence to: e-mail: [email protected].

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