The Kidney As a Treatment Target for Type 2 Diabetes Betsy Dokken, NP, Phd, CDE

Feature Article / Dokken

The Kidney as a Treatment Target for Type 2 Diabetes Betsy Dokken, NP, PhD, CDE

Abstract Type 2 diabetes is a complex and stages of clinical development for the progressive disease that affects 8.3% treatment of type 2 diabetes. Results of the U.S. population. Despite the from clinical trials show that these availability of numerous treatment compounds decrease plasma glucose options for type 2 diabetes, the and body weight in treatment-naive proportion of patients achieving patients and in patients receiving glycemic goals is unacceptably low; metformin or insulin and insulin therefore, new pharmacotherapies are sensitizers. Overall, SGLT2 inhibitors needed to promote glycemic control appear to be generally well tolerated, in these patients. but in some studies, signs, symptoms, The kidney normally reabsorbs and other reports of genital and 99% of filtered glucose and returns urinary tract infections have been it to the circulation. Glucose reab- more frequent in drug-treated groups sorption by the kidney is mediated than in placebo groups. by sodium-glucose co-transporters Additional clinical trials will (SGLTs), mainly SGLT2. SGLT2 determine whether this class of inhibition presents an additional compounds with a unique, insulin- option to promote glycemic control independent mechanism of action in patients with type 2 diabetes. becomes a treatment option for A number of SGLT2 inhibitors have reducing hyperglycemia in type 2 been synthesized and are in various diabetes.

Worldwide, more than 220 million Randomized, controlled people have diabetes.1 In the United clinical trials from the 1990s, States, diabetes is present in 8.3% including the Diabetes Control and of the population.2 Type 2 diabetes Complications Trial (DCCT)9 and accounts for 90–95% of all diag- the U.K. Prospective Diabetes Study nosed cases of adult diabetes.2 The (UKPDS),10,11 found that intensive prevalence of type 2 diabetes is glycemic control (achieved A1C of projected to increase further, in ~ 7%) compared to conventional parallel with obesity,3 a major risk therapy (A1C of ~ 8–9%) can reduce factor for its development.4 the risk of microvascular complica- Hyperglycemia is the hallmark tions in patients with type 1 diabetes of diabetes and a key determinant and in patients with newly diag- of microvascular complications nosed type 2 diabetes. However, (e.g., retinopathy, neuropathy, and whether intensive glycemic control nephropathy).5 Type 2 diabetes is reduces cardiovascular events is less a major risk factor for the develop- certain.12 Long-term monitoring ment of cardiovascular disease6 and of patients from the DCCT13 and chronic kidney disease.7 It is also the UKPDS14 trials found significant Address correspondence to Betsy primary cause of end-stage renal dis- reductions in cardiovascular events Dokken, NP, PhD, CDE, University ease, requiring either chronic dialysis in patients originally randomized to of Arizona Department of Medicine, or renal transplantation,8 and new receive intensive therapy compared 1656 East Mabel St., Room 412, cases of blindness among U.S. adults to patients who received standard Tucson, AZ 85724-5218. aged 20–74 years.3 therapy. Diabetes Spectrum Volume 25, Number 1, 2012 29 Feature Article / Kidney and Type 2 Diabetes

However, recent clinical tri- β-cell function can all contribute ~ 45% of ingested glucose is taken als such as the Action in Diabetes to failure in the achievement of up by the liver, and 30% is taken up and Vascular Disease: Preterax glycemic goals.26,27 Therefore, new by skeletal muscle and converted to and Diamicron Modified Release pharmacological therapies with novel glycogen.29 During an overnight fast, Controlled Evaluation (ADVANCE) mechanisms of action that are inde- glucose is released into the circula- trial, the Action to Control pendent of insulin secretion or action tion, the majority (80%) of which Cardiovascular Risk in Diabetes and have a low propensity to cause comes from the liver as the result of (ACCORD) trial, and the Veterans hypoglycemia may enhance patients’ glycogenolysis and gluconeogenesis. Affairs Diabetes Trial (VADT) ability to achieve glycemic control. The breakdown of muscle glycogen found no benefit,15–17 and possibly The deleterious effects of diabetes leads to the formation of lactate, a some harm, from intensive control.16 on the kidney are well established. gluconeogenic precursor.29 These trials were designed to test the Less appreciated is the role the However, it is now evident that effects of intensive glycemic control kidney plays in glucose homeostasis the kidney also contributes to the (achieved A1C of 6.4–6.9%) com- and the potential of the kidney as a maintenance of blood glucose levels pared to standard therapy (A1C of therapeutic target in type 2 diabetes. by taking up glucose for energy 7.3–8.4%) on cardiovascular events This article reviews the role of the needs, synthesizing glucose (through (death from cardiovascular causes, kidney in glucose regulation and the the process of gluconeogenesis), nonfatal myocardial infarction, and potential of inhibiting renal glucose and reabsorbing glucose from the nonfatal stroke) in relatively high- reabsorption as a new treatment glomerular filtrate and returning it risk patients with established type 2 option in type 2 diabetes. to the circulation. In humans, only diabetes. Recent treatment guidelines the liver and kidney possess the stress the importance of individual- Role of the Kidney in Glucose necessary gluconeogenic enzymes ized treatment goals in patients with Homeostasis to produce and release glucose.30 diabetes.4,18 For most people, the major source of Normally, the kidneys account for Lifestyle changes that include glucose is the diet. After a meal or ~ 40% of total gluconeogenesis and a healthy diet, weight loss, and glucose load, plasma glucose concen- ~ 20% of all glucose released into the increased physical activity have tration peaks at ~ 90 minutes and circulation in humans.31 The kidney many benefits in improving gly- thereafter declines over the course also takes up and metabolizes ~ 10% cemic control and cardiovascular of the ~ 4.5-hour postprandial of all glucose utilized by the body.28 28 risk factors in patients with type 2 period. During this time, ingested Because of the distribution of glucose 32,33 diabetes.19 However, weight loss and carbohydrate accounts for ~ 75% transporters and enzymes, the physical activity and their favorable of circulating glucose. After a meal, renal cortex is the primary site effects are difficult to maintain over the long term, and most patients will require pharmacotherapy to achieve and maintain their glycemic goals.20 Despite the availability of numerous treatment options for type 2 diabetes (e.g., insulin, sulfonyl- ureas, meglitinides, biguanides, α-glycosidase inhibitors, thiazoli- dinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, amylin analogs, a dopamine agonist, and a bile acid sequestrant)21–24 with a variety of mechanisms of action, the proportion of patients achieving glycemic goals is unacceptably low. A recent analysis of diabetic patients from the National Health and Nutrition Examination Survey from 1999 to 200625 found that only 57% of patients with diagnosed diabetes achieved an A1C of < 7%. Lack of treatment initiation and intensification, patient nonadher- Figure 1. Site of gluconeogenesis and glucose utilization in the kidney. The ence, the risk of hypoglycemia with kidney cortex is the primary site of renal gluconeogenesis, whereas the some commonly used antidiabetic medulla is the primary site for glucose utilization. Dashed line indicates the drugs, and progressive decline in boundary between the cortex and medulla. 30 Diabetes Spectrum Volume 25, Number 1, 2012 Feature Article / Dokken

convoluted tubule and re-enter the circulation.43,48 Therefore, the kidney may contribute to hyperglycemia in type 2 diabetes by increasing gluconeogenesis30,44 and possibly by enhanced glucose reabsorption.45

Rationale for SGLT2 Inhibition In addition to controlling cardiovascular risk factors such as hypertension and hyperlipidemia, glycemic control is a primary goal of diabetes management.4 Because renal Figure 2. Glucose reabsorption by the proximal convoluted tubule. Gray glucose reabsorption contributes to arrows represent normal glucose transport. Red arrows represent the hyperglycemia, SGLT2 inhibition pharmacological effects of SGLT2 inhibition. Adapted with permission presents an additional option for gly- from Macmillan Publishers Ltd. From ref. 62. cemic control in patients with type 2 diabetes. Inhibition of reabsorp- of glucose synthesis and release, Once taken up into the proxi- tion would be predicted to enhance whereas the medulla is the primary mal convoluted tubule cell via glucose excretion and reduce site for glucose utilization in the SGLT2, glucose exits the basolat- hyperglycemia in type 2 diabetes 33 kidney (Figure 1). eral membrane into the interstitium independently of insulin secretion or by facilitative glucose transporters action. Glucose Transport in the Kidney (GLUTs), primarily GLUT2 and, to a Moreover, SGLT2 inhibition Glucose is freely filtered by the glom- lesser extent, GLUT136,41 (Figure 2). appears to be relatively benign in erulus. Under normal conditions, Glucose then re-enters the circulation humans. Evidence supporting the ~ 180 g of glucose are filtered by the via peritubular capillaries. In normal 34,35 safety of SGLT2 inhibition as a kidney each day. More than 99% subjects, the kidneys can maximally possible therapeutic option can be of this glucose is reabsorbed by the reabsorb ~ 350–375 mg/minute 34,35 found in studies of individuals with proximal tubule, with < 0.5 g/day of glucose.35,42 In hyperglycemic familial renal glucosuria. These excreted in the urine of healthy individuals, the transport maximum 35 patients have a number of identified adults. can be exceeded, and large amounts inactivating mutations in the gene The reabsorption and return of of glucose may be excreted into the encoding SGLT249 and excrete large glucose from the glomerular filtrate urine.43 amounts of glucose (≥ 10 g/1.73 to the circulation by the kidney is m2/day) without significant clinical dependent on the function of specific Contribution of the Kidney to consequences,49,50 except for polyuria transporters. Glucose reabsorp- Hyperglycemia and possibly subclinical extracellular tion from the glomerular filtrate The release of glucose into the volume depletion.51,52 is mediated by sodium-glucose circulation is a major cause of However, there may be other 44 co-transporters (SGLTs). These hyperglycemia in type 2 diabetes. confounding or ameliorating physi- transporters rely on the inwardly Until recently, this effect was attrib- ological actions that may play a role directed electrochemical sodium gra- uted almost exclusively to the liver. in familial renal glucosuria, and dient established and maintained by However, the kidney is responsible direct pharmacological manipula- the sodium-potassium adenosine tri- for ~ 20% of total glucose release tion of SGLT2 may not have the phosphatase (ATPase) located on the in normal postabsorptive (fasting) same safety profile. The long-term 30 basolateral membrane as the driving humans. In fasting patients with safety of SGLT2 inhibition is under 36 force for glucose entry into the cell type 2 diabetes, renal glucose release investigation. (Figure 2). SGLT2 is a high-capacity, was increased by 300% compared to low-affinity SGLT located on the api- nondiabetic control patients.44 SGLT2 Inhibitors cal (luminal) membrane of the early The mechanisms of this effect SGLT2 inhibitors exhibit several proximal convoluted tubule.36,37 In are poorly understood. In addition potential benefits over other thera- animals, SGLT2 accounts for up to to increased gluconeogenesis, the peutic options for glycemic control. 90% of glucose reabsorption.38,39 diabetic kidney may play a role in These agents directly and specifi- Another member of this family, hyperglycemia by increased glucose cally target the kidney. Because their SGLT1, is a low-capacity, high- reabsorption. Evidence from studies effects are independent of insulin affinity SGLT expressed mainly in conducted in human renal tubular secretion or action, they may be the intestine but also present in the cells45 and diabetic animals45–47 effective during the later stages of the kidney. SGLT1, located in the late suggest that the expression of disease when other therapies (e.g., proximal tubule,36,37,40 accounts for SGLT2 and GLUT2 is upregulated insulin secretagogues and insulin the majority of the remainder of in diabetes, potentially allowing sensitizers) have lost their efficacy renal glucose reabsorption.35,38 more glucose to cross the proximal because of the progressive decline Diabetes Spectrum Volume 25, Number 1, 2012 31 Feature Article / Kidney and Type 2 Diabetes

in β-cell function that is character- absorbed58 and is metabolized to betes when given as monotherapy to istic of type 2 diabetes. In addition, phloretin, which is an inhibitor of patients who were treatment-naive68 because the actions of SGLT2 inhibi- GLUT1.59 GLUT1 is important for or as add-on therapy to metfor- tors are independent of insulin, there physiological glucose transport in min,69,70 glimepiride,71 pioglitazone,72 is a decreased risk of major hypogly- a variety of tissues, including the or insulin.73,74 In addition, dapa- cemia events compared to some other brain.60 Thus, phlorizin is a poor gliflozin was associated with weight agents.29 Moreover, by increasing the candidate for the treatment of type 2 loss69,71,73,74 and a modest decrease in excretion of glucose, SGLT2 inhibi- diabetes in humans. blood pressure.68,69,71,73,74 tors may promote weight loss,29,53 A number of selective SGLT2 Dapagliflozin was generally well thus ameliorating one factor related inhibitors have been synthesized to tolerated (Table 3). The most com- to the pathophysiology of type 2 address the shortcomings of phlori- mon adverse events were headache, diabetes. Finally, because SGLT2 zin.61 Preclinical data are available diarrhea, back pain, and naso- inhibitors specifically affect the for remogliflozin and sergliflozin, pharyngitis, which occurred at kidney, there is a potential for combi- early compounds that were discon- similar frequencies in the placebo nation therapy with agents targeting tinued, and for dapagliflozin. These and dapagliflozin groups.68–71 The the variety of defects associated inhibitors cause dose-dependent incidence of hypoglycemia events with type 2 diabetes to optimize increases in renal glucose excretion was low in the trials of mono- treatment.54 in a number of species. They also therapy68 and add-on therapy to Phlorizin, a natural constituent decrease plasma glucose without metformin69 and was 10-fold lower of apple and other fruit trees, was increasing insulin secretion in dia- when dapagliflozin was compared the first agent discovered to inhibit betic rat models.62–64 to glipizide.70 Hypoglycemia events SGLTs in the kidney.55 This nonse- Clinical trials are underway to were more frequent in patients lective SGLT inhibitor has been an assess the efficacy and safety of receiving dapagliflozin in the trials important tool for physiological and investigational SGLT2 inhibitors of add-on therapy to glimepiride or pharmacological research.55 Studies (Table 1). Dapagliflozin (Bristol- to insulin.71,73 However, there were in diabetic rat models demonstrated Myers Squibb, New York, and no discontinuations due to hypogly- that phlorizin promotes glucose AstraZeneca, Wilmington, Del.) is in cemia.71,73 The signs, symptoms, and excretion, normalizes plasma the most advanced stage of clinical other reports suggestive of urinary glucose levels, and reverses insulin development and is the only SGLT2 tract68,69,73,74 and genital68,69,71,73,74 resistance.56,57 inhibitor with fully published phase infections have been more frequent However, because of its non- 3 trial data. in the dapagliflozin-treated groups specificity, phlorizin inhibits Dapagliflozin caused dose- than in placebo-treated groups SGLT1 as well as SGLT2. SGLT1 dependent increases in renal glucose (Table 3). All events were of mild to is highly expressed in the intestine. excretion in normal volunteers65 and moderate intensity and responded to Subsequently, phlorizin causes in patients with type 2 diabetes.66,67 standard treatment. diarrhea because it inhibits glucose In phase 3 trials (Table 2), dapa- In the dapagliflozin study of absorption in the small intestine.40 gliflozin decreased plasma glucose > 6,000 patients, malignancies were In addition, phlorizin is poorly and A1C in patients with type 2 dia- balanced between treatment groups, Table 1. SGLT2 Inhibitors in Development Compound Phase Clinical Results Company References Dapagliflozin Filed Decreases A1C, FPG, body weight, and blood pressure as Bristol-Myers 67–69,71,74,80 monotherapy or as add-on therapy to metformin, insulin, Squibb/ or glimepiride. Treatment duration up to 52 weeks. AstraZeneca Canagliflozin 3 Decreases A1C, FPG, and body weight as monotherapy Johnson & 76,81,82 or as add-on therapy to insulin or metformin. Treatment Johnson/ duration up to 12 weeks. Mitsubishi Tanabe Empagliflozin 3 Decreases A1C, FPG, and body weight as monotherapy. Boehringer 77 (BI 10773) Treatment duration up to 12 weeks. Ingelheim/Eli Lilly Ipragliflozin 3 Decreases A1C, FPG, and body weight as monotherapy. Astellas 78 (ASP 1941) Treatment duration up to 12 weeks. LX4211* 2 Decreases A1C and FPG as monotherapy. Treatment Lexicon 79 duration of 4 weeks. Pharma FPG, fasting plasma glucose. *SGLT2/SGLT1 inhibitor.

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Table 2. Effects of Dapagliflozin on Glycemic Parameters and Body Weight in Patients with Type 2 Diabetes: Published Phase 3 Trials Mean Change from Baseline† A1C (%) FPG (mg/dl) Body Weight (kg) n Placebo Dapa‡ Placebo Dapa‡ Placebo Dapa‡ Reference Monotherapy 274 –0.23 –0.58 to –4.1 –15.2 to –2.2 –2.8 to 68 –0.89 –28.8 –3.3 Add-on 546 –0.30 –0.67 to –6.0 –17.8 to –0.9 –2.2 to 69 therapy to –0.84 –23.5 –3.0 metformin Add-on 597 –0.13 –0.58 to –2.0 –16.8 to –0.7 –1.2 to 71 therapy to –0.82 –28.5 –2.3 glimepiride Glip Dapa Glip Dapa Glip Dapa Compared to 814 –0.52 –0.52 –18.7 –22.3 +1.4 –3.2 70 glipizide Dapa, dapagliflozin; FPG, fasting plasma glucose; Glip, glipizide. †Adjusted for baseline value. ‡Data for dapa are ranges except for glipizide study. Table 3. Summary of Adverse Events With Dapagliflozin: Published Phase 3 Trials Adverse Events (%) Monotherapy Add-on Therapy Add-on Therapy Compared to Metformin to Glimepiride to Glipizide Placebo Dapa† Placebo Dapa† Placebo Dapa† Glip Dapa One or more adverse events 60 58–69 64 65–73 47 48–52 78 78 One or more serious adverse 4 0–2 4 3 5 6–7 11 9 events Hypoglycemia 3 0–3 3 2–4 5 7–8 40 3 Events suggestive of genital 1 8–13 5 8–3 1 4–7 3 12 infections Events suggestive of urinary 4 5–13 8 4–8 6 4–7 6 11 tract infections

Reference 69 70 72 71

Dapa, dapagliflozin; glip, glipizide. †Data for dapa are ranges. with a small numerical increase In preliminary reports, cana- an increase in genital and urinary for breast and bladder cancers in gliflozin (Johnson & Johnson, tract infections was found in cana- patients on dapagliflozin.75 This was New Brunswick, N.J.), a different gliflozin-treated patients.76 unexpected because there were no SGLT2 inhibitor, increased renal The SGLT2 inhibitor empa- preclinical signals that dapagliflozin glucose excretion and decreased gliflozin (BI 10773, Boehringer was genotoxic or carcinogenic, and A1C (placebo-corrected change from Ingelheim, Ingelheim, Germany, dapagliflozin has no known off-tar- baseline of –0.73%), fasting plasma and Eli Lilly, Indianapolis, Ind.) get pharmacology. The small number glucose (FPG) (–30.6 mg/dl), and increased renal glucose excretion and of events limits the ability to assess body weight (–2.3 kg) in patients decreased FPG (placebo-corrected, causality, and continued monitoring with type 2 diabetes after 12 weeks –31.1 mg/dl) and A1C (–0.72%) after is warranted. of treatment.76 As with dapagliflozin, 12 weeks of treatment in patients Diabetes Spectrum Volume 25, Number 1, 2012 33 Feature Article / Kidney and Type 2 Diabetes

with type 2 diabetes.77 Decreases in Further clinical trials will provide metformin on complications in overweight body weight (–2.0 kg) have also been needed data to assist regulatory patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 reported.77 A small increased risk of agencies in determining whether this genital infections was reported with class of compounds with a unique, 11U.K. Prospective Diabetes Study Group: 77 Intensive blood-glucose control with empagliflozin. insulin-independent mechanism sulphonylureas or insulin compared with Other inhibitors in early clinical of action becomes an available conventional treatment and risk of trials include the SGLT2 inhibitor treatment option for reducing hyper- complications in patients with type 2 diabetes ipragliflozin (ASP1941, Astellas, glycemia in type 2 diabetes. (UKPDS 33). Lancet 352:837–853, 1998 Tokyo, Japan) and the SGLT2/ 12Skyler JS, Bergenstal R, Bonow RO, Buse SGLT1 inhibitor LX4211(Lexicon J, Deedwania P, Gale EA, Howard BV, Pharmaceuticals, The Woodlands, Acknowledgments Kirkman MS, Kosiborod M, Reaven P, Tex.). Ipragliflozin treatment for Editorial support was provided Sherwin RS: Intensive glycemic control and by Richard M. Edwards, PhD, the prevention of cardiovascular events: 12 weeks lowered A1C by 0.8% implications of the ACCORD, ADVANCE, compared to an increase of 0.5% in and Janet E. Matsuura, PhD, and VA diabetes trials: a position statement the placebo group.78 Four weeks of from Complete Healthcare of the American Diabetes Association and a treatment with LX4211 reduced A1C Communications, Inc., of Chadds scientific statement of the American College Ford, Pa., and was funded by Bristol- of Cardiology Foundation and the American by 1.25% compared to a reduction Heart Association. Circulation 119:351–357, 79 Myers Squibb and AstraZeneca. of 0.53% with placebo. 2009 13Nathan DM, Cleary PA, Backlund JY, Summary References Genuth SM, Lachin JM, Orchard TJ, Raskin Hyperglycemia is a major risk factor P, Zinman B, DCCT/EDIC Study Group: 1World Health Organization: Diabetes: fact for the development of microvascular Intensive diabetes treatment and sheet no. 312 [article online]. Available from cardiovascular disease in patients with type complications in type 2 diabetes. http://www.who.int/mediacentre/factsheets/ Control rates of hyperglycemia in 1 diabetes. N Engl J Med 353:2643–2653, fs312/en/index.html. Accessed 2 June 2011 2005 type 2 diabetes are poor, and more 2Centers for Disease Control and Prevention: treatment options are needed. Under 14Holman RR, Paul SK, Bethel MA, National diabetes fact sheet: national Matthews DR, Neil HA: 10-year follow-up normal conditions, the kidney plays estimates and general information on diabetes of intensive glucose control in type 2 diabetes. an important role in glucose homeo- and prediabetes in the United States, 2011. N Engl J Med 359:1577–1589, 2008 stasis by reabsorbing virtually all Atlanta, Ga., U.S. Department of Health and Human Services, Centers for Disease Control 15Duckworth W, Abraira C, Moritz T, of the glucose that is filtered and and Prevention, 2011 Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren by synthesizing glucose. 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61Chao EC, Henry RR: SGLT2 inhibition: 70Nauck MA, Del Prato S, Meier JJ, Duran- potent and highly selective sodium-glucose a novel strategy for diabetes treatment. Nat Garcia S, Rohwedder K, Elze M, Parikh SJ: co-transporter (SGLT-2) inhibitor BI10773 Rev Drug Discov 9:551–559, 2010 Dapagliflozin versus glipizide as add-on is safe and efficacious as monotherapy therapy in patients with type 2 diabetes in patients with type 2 diabetes mellitus 62Fujimori Y, Katsuno K, Nakashima I, who have inadequate glycemic control with [abstract]. Diabetologia 53 (Suppl. 1):S351, Ishikawa-Takemura Y, Fujikura H, Isaji M: metformin: a randomized, 52-week, double- 2010 Remogliflozin etabonate, in a novel category blind, active-controlled noninferiority trial. 78 of selective low-affinity sodium glucose Diabetes Care 34:2015–2022, 2011 Kashiwagi A, Utsuno A, Kazuta K, Yoshida cotransporter (SGLT2) inhibitors, exhibits S, Kageyama S: ASP1941, selective SGLT2 antidiabetic efficacy in rodent models. 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