Home > News > Glucose Control and Cardiovascular Outcomes in Clinical Trials of Sodium Glucose Co-transporter 2 Inhibitor Treatments in Type 2 Diabetes
Cardiovascular Risk, Diabetes
Read Time: 2 mins

Glucose Control and Cardiovascular Outcomes in Clinical Trials of Sodium Glucose Co-transporter 2 Inhibitor Treatments in Type 2 Diabetes

Published Online: May 27th 2008 European Endocrinology, 2014;10(2):117–23 DOI: http://doi.org/10.17925/EE.2014.10.02.117
Authors: Rene A Oliveros, Son V Pham, Steven R Bailey, Robert J Chilton
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Currently available medications for the treatment of type 2 diabetes have limitations, and many patients do not achieve glycemic control. Recently, a new approach has emerged using sodium glucose co-transporter 2 (SGLT2) inhibitors that decrease glucose reabsorption in the kidneys, increasing urinary glucose excretion. These agents offer the potential to improve glycemic control independently of insulin pathways while avoiding hypoglycemia. Two drugs of this class, canagliflozin and dapagliflozin, have been approved by the US Food and Drug Administration (FDA); another, empagliflozin, has been filed for regulatory approval and several others are in advanced development. These drugs have been shown to effectively reduce blood glucose, fasting plasma glucose, and glycated hemoglobin (HbA1C) levels in phase III clinical trials when used as monotherapy and as add-on therapy to other diabetes medications, including insulin. Another advantage of the SGLT2 inhibitors over existing treatments is the improvement in cardiovascular risk factors, particularly in terms of reductions in blood pressure and body weight. SGLT2 inhibitors have been generally well tolerated. While more long-term safety data are required to elucidate the benefit–risk profile of SGLT2 inhibitors, the rationale for their use in type 2 diabetes therapy is strong.

Keywords

Type 2 diabetes, sodium glucose co-transporter-2 inhibitors, canagliflozin dapagliflozin, empagliflozin

Article:

Diabetes imposes a substantial burden on societies worldwide: approximately 25 million individuals in the US have diabetes, of which more than 95 % is type 2.1 Furthermore, its incidence is increasing, a further 79 million adults in the US have pre-diabetes and one in three US adults could have diabetes by 2050.1 In addition, the age of diagnosis of type 2 diabetes is decreasing.2 Lifestyle interventions remain essential to the management of type 2 diabetes; however, most patients will not reach their therapeutic goals with these interventions alone and

Diabetes imposes a substantial burden on societies worldwide: approximately 25 million individuals in the US have diabetes, of which more than 95 % is type 2.1 Furthermore, its incidence is increasing, a further 79 million adults in the US have pre-diabetes and one in three US adults could have diabetes by 2050.1 In addition, the age of diagnosis of type 2 diabetes is decreasing.2 Lifestyle interventions remain essential to the management of type 2 diabetes; however, most patients will not reach their therapeutic goals with these interventions alone and will require pharmacologic therapies.3 Diabetes is associated with substantially increased cardiovascular (CV) risk; diabetic patients requiring glucose-lowering therapy aged 30 years or over have a CV risk comparable to nondiabetics with a prior myocardial infarction.4 Therefore antidiabetic therapies should not only reduce glycated hemoglobin ( HbA1c), but also CV mortality.

Currently, there are several classes of pharmacologic agents approved for the treatment of diabetes in the US, involving numerous mechanisms of action including the stimulation of insulin production in the pancreas; decreasing sugar release from the liver; or decreasing or delaying sugar uptake from the gut. However, despite the widespread availability of these therapies, only half of patients with type 2 diabetes attain the American Diabetes Association (ADA) recommended target of HbA1c of 7.0 %, blood pressure (BP) targets of <130/80 mmHg, and low-density lipoprotein-cholesterol (LDL-C) targets of <100 mg/dl.5 Furthermore, the incidence of CV mortality in patients with type 2 diabetes has not substantially decreased in the last decade.6 The CV safety of antidiabetic medications has become an area of concern since treatment with the thiazolidinedione medication rosiglitazone was associated with an increased risk for CV events.7 As a result, the US Food and Drug Administration (FDA) now requires evidence that new treatments for diabetes do not increase CV risk.8

Uncertainty remains regarding the CV safety of existing therapies. Dipeptidylpeptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs have not been associated with increased CV risks,9,10 and the latter may be cardioprotective.10,11 Saxagliptin has been associated development with an increased risk for hospitalizations for heart failure.12 Studies investigating the CV risks associated with insulin, sulfonylureas (SU), and metformin have yielded mixed results.13,14

Since over 85 % of people with diabetes are overweight or obese,15 and excess weight is a major contributor to the development of insulin resistance and impaired glucose tolerance,16 as well as being a major CV risk,17 the impact of antidiabetic therapies on weight is also important. Most oral antidiabetic agents (OADs) have been associated either with weight gain (thiazolidinediones,18 SU,19 meglitinides20) or are weight-neutral (metformin,21 alpha-glucosidase inhibitors,22 DPP-4 inhibitors,23 bile acid sequestrants24). Treatment with insulin and insulin analogs is also associated with weight gain, which may be substantial.25 GLP-1 analogs have been associated with moderate weight loss,10 but their use is limited by the need for administration by injection and gastrointestinal side effects.26

The increasing prevalence of type 2 diabetes, in combination with limitations of current therapies, has driven the search for alternative glucose-lowering agents. This review will consider the safety and efficacy of a new class of oral drug, sodium glucose co-transporter 2 (SGLT2) inhibitors and the key clinical trial evidence supporting their use in diabetes treatment.

Introduction to Sodium Glucose Co-transporter 2 Inhibitors
A new therapeutic approach to type 2 diabetes has emerged using SGLT2 inhibitors, whose mechanism of action is independent of insulin and involves glucose reabsorption in the kidneys. The kidneys play an important role in glycemic control, filtering, and reabsorbing glucose back into the circulatory system.27 Renal glucose transport involves two types of membrane-associated carrier proteins: facilitated glucose transporters (GLUTs), which function as passive transporters, and sodium glucose co-transporters (SGLTs), which are secondary active co-transporters.27,28 Among the latter, SGLT2s, found in the early proximal tubule, are responsible for approximately 90 % of glucose reabsorption.27,29 In type 2 diabetes, SGLT2 is upregulated, resulting in reduced glucosuria and hyperglycemia, suggesting that an adaptive response to conserve glucose becomes maladaptive in diabetes.28

The concept of inhibiting glucose reabsorption arose from the discovery of inherited and acquired diseases in which SGLT2 mutations cause alterations in renal glucose handling, resulting in glucosuria.30 Selective SGLT2 inhibitors decrease glucose reabsorption in the kidneys, increasing urinary glucose excretion. Such agents may offer several advantages as antidiabetic agents: the unique potential to cause negative energy balance and the correction of the effect of hyperglycemia on insulin secretion and action.31,32 The use of SGLT2 inhibitors will, however, require a change in the perception of glucosuria. This has historically been considered to indicate poor glucose control but during SGLT2 inhibitor treatment it indicates effective removal of excess glucose from the blood to the urine.33

Phlorizin, discovered in 1835, was the first SGLT inhibitor, but is not suitable for clinical use owing to its poor bioavailability and gastrointestinal side effects, a result of its action on SGLT1, found mainly in the small intestine.27 Following the clinical failure of other SGLT inhibitors, numerous selective SGLT2 inhibitors are currently in clinical development. Canagliflozin (Invokana®, Johnson & Johnson) received approval from the FDA in March 2013,34 dapagliflozin (Farxiga®, Bristol-Myers Squibb) received FDA approval in January 2014, and empagliflozin (Boehringer Ingelheim)35 has also been submitted for FDA approval. Several other agents are in late-stage clinical development. These agents have excellent oral bioavailability allowing oncedaily administration, renal clearance, and a limited potential for drug–drug interactions,36 offering the potential for combined therapies with different classes of antidiabetic medicines to achieve tighter glycemic control.

Clinical Trials Investigating the Use of Sodium Glucose Co-transporter 2 Inhibitors in Type 2 Diabetes
Completed trials of SGLT2 inhibitors have evaluated their effects on a range of different measures of glucose control including the change in HbA1c, fasting and postprandial glucose, and the proportion of patients achieving HbA1c targets. To date, all SGLT2 inhibitors in clinical development have demonstrated benefits in these parameters, as well as demonstrating safety and tolerability.

Dapagliflozin
Clinical trial data describing the efficacy of dapagliflozin are summarized in Table 1. Reductions in fasting glucose varied with dose, ranging from around 0.8 mmol/l with 2.5 mg dapagliflozin to between 1.2 and 4.7 mmol/l with 10 mg dapagliflozin. Mean decreases in HbA1c were 0.6 % with a dose of 2.5 mg, and between 0.8 % and 2.7 % with a 10 mg dose.37 Completed and ongoing phase III clinical trials included or will include a total of over 35,000 patients with type 2 diabetes and have demonstrated that dapagliflozin treatment results in reductions in HbA1c as monotherapy, dual therapy, and triple therapy with OADs, as well as with combination therapy with insulin with or without OADs.38–42 In January 2012 the FDA declined approval of dapagliflozin, requesting additional clinical data to enable a better assessment of the benefit–risk profile following safety concerns of an enhanced risk for bladder cancer.43 However, approval was granted in January 2014.

Canagliflozin
Clinical trials demonstrating the efficacy and safety of canagliflozin are given in Table 2. Completed and ongoing phase III clinical trials included a total of over 10,000 patients and have demonstrated that canagliflozin provides better glycemic control than sitagliptin and glimepiride.44–49 In a pooled analysis of four clinical trials involving a total of over 500 patients, canagliflozin use was associated with significant mean reductions in HbA1c (absolute reductions of 0.45–0.92 %) and fasting plasma glucose (decreases ranged from 16.2 % to 42.4 %).44

Empagliflozin
Key clinical trials investigating the efficacy and safety of empagliflozin are summarized in Table 3. Completed and ongoing phase III clinical trials have included or will include a total of more than 14,000 patients with type 2 diabetes. Empagliflozin has demonstrated good efficacy, safety, and tolerability profiles when used alone or as an add-on treatment to metformin and glimepiride.50–54 A pooled analysis of data from four phase III trials involving 2,477 patients treated with empagliflozin 10 mg, 25 mg, or placebo, showed significant reductions from baseline in HbA1c of 0.70 % and 0.76 %, respectively, compared with a change of -0.08 % for placebo at week 24.55

Clinical trial data for other SGLT2 inhibitors currently in development are given in Table 4.56 These include phase III trials (tofogliflozin,57 ertugliflozin,58 ipragliflozin,59,60 and luseogliflozin61) and phase I/II trials (remogliflozin etanobate,62 sotagliflozin,63 and ISIS 38868664).

Effects on Cardiovascular Risk Factors of Sodium Glucose Co-transporter 2 Inhibitors
Several large clinical trials assessing the CV safety of SGLT2 inhibitors are ongoing (see Table 5). The most comprehensive data currently available are from a meta- analysis of data from 14 phase II/III studies involving 6,228 patients that assessed the CV safety of all doses of dapagliflozin (2.5 to >10 mg). The primary end point was a composite of time to first event of CV death, myocardial infarction (MI), stroke, or hospitalization for unstable angina. The estimated hazard ratio (HR) was 0.674 (95 % CI 0.421–1.078), suggesting that dapagliflozin was not associated with an increased risk for CV events and may confer a reduced CV risk.65 The reductions in HbA1c achieved in clinical trials of SGLT2 inhibitors are clinically meaningful in terms of CV risk: a 0.8 % reduction in HbA1c could reduce CV risk by about 8 %.66 Furthermore, SGLT2 inhibitors have demonstrated benefits in terms of other CV risk factors.

Blood Pressure
The importance of tight BP control in patients with type 2 diabetes is well established. In the UK Prospective Diabetes Study (UKPDS), patients assigned to the tight BP control arm had a clinically meaningful reduction in the risk for deaths related to diabetes and its related complications.67 Since SGLT2 reabsorbs glucose and sodium in the renal proximal tubule, it was postulated that SGLT2 inhibitors would have diuretic properties, thereby reducing BP. In phase III studies, dapagliflozin has been associated with reductions of systolic BP at week 24 of -3.6, -5.1, and -5.0 mmHg as monotherapy,39 add-on to metformin,38 and add-on to SU,41 respectively. In a recent clinical study, 75 subjects were randomized to placebo, dapagliflozin, or hydrochlorothiazide (HCTZ), a diuretic used in the treatment of hypertension. Treatment with placebo or HCTZ resulted in changes from baseline in 24-hour ambulatory mean systolic BP of -0.9, -3.3, and -6.6 mmHg, respectively, at week 12, adjusted for baseline systolic BP. Plasma volume appeared to decrease with dapagliflozin but did not change with placebo or HCTZ treatment, suggesting that dapagliflozin has a diuretic-like capacity to lower BP.68

Canagliflozin has been associated with similar reductions in systolic BP (at week 24, -3.7 mmHg -5.4 mmHg from placebo with 100 mg and 300 mg doses, respectively, p≤0.001).44

Empagliflozin has also been found to have beneficial effects on BP. In a recent pooled analysis of data from four phase III trials, at week 24, patients given empagliflozin 10 mg and 25 mg showed reductions in systolic BP of 3.9 mmHg and 4.3 mmHg, and diastolic BP of 1.8 mmHg and 2.0 mmHg, respectively, compared with reductions of 0.5 mmHg in systolic BP and 0.6 mmHg in diastolic BP in patients treated with placebo (see Figure 1).55 Empagliflozin treatment resulted in generally greater reductions in BP when baseline BP was higher.

Lipid Parameters
SGLT2 inhibitors are associated with small mean changes in lipid parameters: increases in high-density lipoprotein-cholesterol (HDL-C) have been reported but also increases in LDL-C.69 In a pooled analysis of data from 3,731 patients in 12 phase IIb/phase III trials of dapagliflozin, changes from baseline in HDL-C were +6.5 % and +5.5 % for dapagliflozin 5 and 10 mg, respectively, versus +3.8 % placebo, and in LDL-C +0.6 % and +2.7 % dapagliflozin 5 and 10 mg, respectively, versus -0.4 % placebo.70 Pooled data from four phase III trials investigating empagliflozin found small changes from baseline in LDL-C of +3.1 mg/dl and +3.9 mg/dl for empagliflozin 10 mg and 25 mg, respectively, compared with +0.8 mg/dl for placebo. Changes from baseline in HDL-C were +2.7 mg/dl for both doses versus 0.0 mg/dl for placebo. Changes from baseline in triglyceride levels of -9.7 mg/dl and -1.8 mg/dl, respectively, compared with +2.7 mg/dl for placebo.55 The significance of the increased LDL-C with SGLT2 inhibitors requires further investigation.

In some clinical trials of SGLT2 inhibitors, plasma lipid analysis has been conducted using nuclear magnetic resonance (NMR) spectroscopy. This method was used on plasma samples from the CANagliflozin Treatment and Trial Analysis – DPP-4 Inhibitor Comparator Trial (CANTATA-D, DIA3006) trial.47 The trial compared canagliflozin 100 mg and 300 mg treatment with placebo over a 26-week randomized period in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy. Increased cholesterol levels are a concern with these treatments and NMR analysis of plasma at baseline and week 26 showed slightly greater increases in LDL particle concentrations in patients treated with either canagliflozin doses compared with placebo. This pattern of increased LDL particle concentrations with canagliflozin was similar for both large and small LDL particles but there was little difference between the two cangliflozin doses in LDL particle concentrations. In the CANagliflozin Treatment and Trial Analysis – Monotherapy (CANTATA-M) trial, NMR spectroscopy showed small increases in Apo B levels during 26 weeks of treatment of type 2 diabetes patients insufficiently controlled with diet and exercise.71In placebo-treated patients Apo B levels were shown to decrease by 0.2 % but in 100 mg and 300 mg cangliflozin-treated patients these levels rose by 1.3 % and 3.2 %, respectively.

Body Weight
Other benefits of SGLT2 inhibitors include clinically meaningful body weight reduction, which give a strong rationale for their use in overweight and obese patients, as well as in addition to therapies that are associated with weight gain. The glycosuria induced by dapagliflozin monotherapy is associated with a net calorie loss of approximately 200–300 kilocalories per day.72 In phase III studies, dapagliflozin has been associated with adjusted mean change from baseline in body weight at 24 weeks of -3.2 kg as monotherapy,39 -2.9 kg as add-on to metformin,38 -2.26 kg as add-on to SU,41 and -1.61 kg as addon to insulin.42 Pooled analysis of four clinical trials showed that the use of canagliflozin was associated with weight loss ranging from 0.7 to 3.5 kg at 24 weeks.44 In a pooled analysis of four phase III trials, empagliflozin was associated with weight losses of 2.05 kg and 2.25 kg, respectively, from baseline at 24 weeks, compared with a reduction of 0.24 kg for placebo (see Figure 2).55 Since a proportion of the weight reduction observed with SGLT2s is related to reduction in visceral fat mass, this could potentially be important for CV risk reduction.

Safety of Sodium Glucose Co-transporter 2 Inhibitors
Hypoglycemia is a rare adverse event (AE) during SGLT2 inhibitor therapy.73 In an analysis from the CANagliflozin cardioVascular Assessment Study (CANVAS) study, hypoglycemic AEs were higher with canagliflozin compared with placebo only in patients taking concomitant insulin, SU, or meglitinide.74 In the pooled analysis of empagliflozin trials, hypoglycemic AEs were reported by 2.9 % of patients on placebo, 5.2 % of patients on empagliflozin 10 mg, and 4.0 % of patients on empagliflozin 25 mg; none required assistance. Most of these occurred in patients taking metformin plus SU (8.4 %, 16.1 %, and 11.5 % on placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively). Among all patients on monotherapy, metformin only or pioglitazone, the incidence of confirmed hypoglycemic AEs was much lower (0.8 %, 1.2 %, and 1.3 % of patients on placebo, empagliflozin 10 mg, or empagliflozin 25 mg, respectively).55

The key AE associated with inhibition of SGLT2 is mycotic genital infection due to elevated glucose levels in the urine. Infections affect predominantly women and mostly comprise mycotic vulvo-vaginitis; in men, mycotic balanitis is the most common infection. Clinical trial data also indicate a low risk for urinary tract infections (UTI). The rates of genito-urinary AEs rise with the duration of follow-up; between 4 and 8 % have been reported in patients treated with dapagliflozin compared with placebo.37 In a pooled analysis of more than 5,000 patients participating in trials of canagliflozin, symptomatic UTIs were observed in approximately 4 % of patients treated with canagliflozin and approximately 3 % of those treated with placebo. The rates of serious UTIs or UTIs leading to therapy discontinuation were not significantly different in the two groups.75 In a pooled analysis from 2,477 patients participating in phase III empagliflozin trials, the rates of UTI were not statistically different (8.2 %, 9.3 %, and 7.5 %) in the placebo, lower-dose, and higher-dose groups, respectively.76 Clinical trial data indicate that infections are typically mild in nature, may be circumvented with rigorous hygiene, respond well to treatment, and are unlikely to lead to discontinuation of the drug.

Dapagliflozin has been associated with a mean increase in daily urine output of 107–375 ml/day secondary to a mild osmotic diuresis.77 Study populations received counseling about symptoms of dehydration and the importance of adequate fluid consumption, and this has proven effective. One patient in a phase II study with dapagliflozin developed dehydration and renal impairment, which resolved with oral rehydration and withholding angiotensin-converting enzyme (ACE) inhibitor and diuretic treatment.78 While further research is required to ascertain the long-term safety of these effects in patients taking SGLT2 inhibitors, patients with autosomal recessive renal glucosuria resulting from a mutation in the SGLT2 have not reported clinical complications resulting from chronic elevated urinary glucose, and the condition is considered benign.30

A relatively high proportion of patients with diabetes may be treated with ACE inhibitors and diuretic therapy, and are likely to have an increased prevalence of comorbidities, such as renal impairment, CV disease, and autonomic neuropathy. Further evidence from phase III studies is therefore required to evaluate the long-term safety and efficacy of SGLT2 inhibition in these patient populations. However, recently presented data on the renal safety of SGLT2 inhibitors have been reassuring. An analysis of pooled phase III trial data of patients with CKD taking canagliflozin (n=1,085),79 as well as 52-week phase III studies of patients with CKD taking canagliflozin80 and patients with renal impairment81 and stage 2 and 3 CKD taking empagliflozin50 showed no significant association between SGLT2 inhibitor use and impairment of renal function. SGLT2 inhibitors reduced HbA1c and were well tolerated in these patients.

Reductions in serum uric acid levels have been consistent across trials and have been suggested to arise from inhibition of sodium-coupled uric acid reabsorption in the renal proximal tubule.39,82 Uric acid may be a potential CV risk factor, although its association with CV disease has not yet been fully elucidated.83,84 It is not yet known whether reductions in serum uric acid will translate into long-term beneficial effects on kidney function or CV risk.

Future Developments in Sodium Glucose Co-transporter 2 Inhibitor Treatments
A projection for 20 years based on a population simulation model (Archimedes) that includes National Health and Nutrition Examination Survey (NHANES) study data showed that patients receiving dapagliflozin were likely to experience reductions in the incidence of MI, stroke, CV death, and all-cause death of 13.8 %, 9.1 %, 9.6 %, and 5.0 %, respectively. In addition, there would be relative reductions in the incidence of end-stage renal disease, foot amputation, and diabetic retinopathy of 18.7 %, 13.0 %, and 9.8 %, respectively, compared with the current standard of care.85

Additional and larger phase III clinical trials to fully define the potential role of canagliflozin and other SGLT2 inhibitors in the management of diabetes, including studies involving the elderly, children, and patients with renal or hepatic dysfunction, are planned or currently ongoing. The diuretic effect observed with SGLT2 inhibitors may make them the preferred class of drugs to be used in conjunction with thiazolidinediones, which have been shown to cause fluid retention, especially in the presence of heart failure. However, since most antidiabetic agents have been associated with increased risk for all-cause mortality in patients with heart failure and diabetes,86 future trials should add heart failure as part of the primary endpoint.

SGLT2 inhibitors also offer potential in the treatment of type 1 diabetes. In a phase IIa trial in type I diabetes, patients taking dapagliflozin had improved glycemic control and required less insulin than those on placebo.87 In a pilot proof-of-concept trial in type 1 diabetes, empagliflozin as adjunct to insulin therapy improved glycemic control while reducing insulin requirement, weight, and episodes of hypoglycemia.88 Individuals with type 1 diabetes are at high risk for the development of hypertension, for which hyperglycemia-mediated neurohormonal activation is an important contributing factor. Mechanistic trials in type 1 diabetes indicate that empagliflozin causes an improvement in arterial stiffness and reduction in renal hyperfiltration.89,90

Summary and Concluding Remarks
SGLT2 inhibitors are novel oral antidiabetic agents that offer the potential to improve glycemic control independently of insulin secretion while avoiding hypoglycemia, offering a modest reduction in BP and promoting weight loss. Their efficacy is not affected by the extent of insulin resistance or beta-cell dysfunction and therefore they can be used at any stage in the natural history of type 2 diabetes. However, while the rationale for beneficial effects of SGLT2 inhibitors is strong, further evidence of CV safety will be necessary to ensure their widespread use in clinical practice. Evidence that will define the CV risks of this new drug class is expected within the next 1–5 years. As clinical experience with the SGLT2 inhibitors increases, following the launch of more drugs in this class, their safety profile will become clearer and will inform future treatment decisions.

Given the ever-expanding incidence of diabetes in populations worldwide and suboptimal glycemic control achieved with currently available agents, the need for novel agents, with new modes of action remains an urgent clinical and public health priority. SGLT2 inhibitors are a useful addition to the treatment armamentarium.

Article Information:
Disclosure

Rene A Oliveros, Son V Pham, Steven R Bailey and Robert J Chilton have no conflicts of interest to declare.

Correspondence

Robert J Chilton, Professor, Division of Cardiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, US. E: chilton@uthscsa.edu

Support

The publication of this article was supported by Boehringer Ingelheim. The views and opinions expressed are those of the authors and not necessarily those of Boehringer Ingelheim.

Received

2014-05-30T00:00:00

References

  1. Centres for Disease Control and Prevention (CDC), National Diabetes Fact Sheet 2011. Available at: http://www.cdc.gov/ diabetes/pubs/pdf/ndfs_2011.pdf (last accessed: May 29, 2014).
  2. Koopman RJ, Mainous AG, 3rd, Diaz VA, et al., Changes in age at diagnosis of type 2 diabetes mellitus in the United States, 1988 to 2000, Ann Fam Med, 2005;3:60–3.
  3. Inzucchi SE, Bergenstal RM, Buse JB, et al., Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), Diabetes Care, 2012;35:1364–79.
  4. Schramm TK, Gislason GH, Kober L, et al., Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people, Circulation, 2008;117:1945–54.
  5. Stark Casagrande S, Fradkin JE, Saydah SH, et al., The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010, Diabetes Care, 2013;36:2271–9.
  6. Buse JB, Ginsberg HN, Bakris GL, et al., Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association, Diabetes Care, 2007;30:162–72.
  7. Nissen SE, Wolski K, Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes, N Engl J Med, 2007;356:2457–71.
  8. FDA, Guidance for Industry. Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, 2008. Available at: http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm071627.pdf (last accessed April 30, 2014).
  9. Jose T, Inzucchi SE, Cardiovascular effects of the DPP-4 inhibitors, Diab Vasc Dis Res, 2012;9:109–16.
  10. Verges B, Bonnard C, Renard E, Beyond glucose lowering: glucagon-like peptide-1 receptor agonists, body weight and the cardiovascular system, Diabetes Metab, 2011;37:477–88.
  11. Zhao TC, Glucagon-like peptide-1 (GLP-1) and protective effects in cardiovascular disease: a new therapeutic approach for myocardial protection, Cardiovasc Diabetol, 2013;12:90.
  12. Scirica BM, Bhatt DL, Braunwald E, et al., Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N Engl J Med, 2013;369:1317–26.
  13. ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, et al., Basal insulin and cardiovascular and other outcomes in dysglycemia, N Engl J Med, 2012;367:319–28.
  14. Margolis DJ, Hoffstad O, Strom BL, Association between serious ischemic cardiac outcomes and medications used to treat diabetes, Pharmacoepidemiol Drug Saf, 2008;17:753–9.
  15. Centers for Disease Control and Prevention (CDC), Prevalence of overweight and obesity among adults with diagnosed diabetes- -United States, 1988-1994 and 1999-2002, MMWR Morb Mortal Wkly Rep, 2004;53:1066–8.
  16. Kahn SE, Hull RL, Utzschneider KM, Mechanisms linking obesity to insulin resistance and type 2 diabetes, Nature, 2006;444:840–6.
  17. Wilson PW, D’Agostino RB, Sullivan L, et al., Overweight and obesity as determinants of cardiovascular risk: the Framingham experience, Arch Intern Med, 2002;162:1867–72.
  18. Fonseca V, Effect of thiazolidinediones on body weight in patients with diabetes mellitus, Am J Med, 2003;115(Suppl. 8A):42S–8S.
  19. Kahn SE, Haffner SM, Heise MA, et al., Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, N Engl J Med, 2006;355:2427–43.
  20. Black C, Donnelly P, McIntyre L, et al., Meglitinide analogues for type 2 diabetes mellitus, Cochrane Database Syst Rev, 2007;CD004654.
  21. Saenz A, Fernandez-Esteban I, Mataix A, et al., Metformin monotherapy for type 2 diabetes mellitus, Cochrane Database Syst Rev, 2005;CD002966.
  22. Van de Laar FA, Lucassen PL, Akkermans RP, et al., Alphaglucosidase inhibitors for type 2 diabetes mellitus, Cochrane Database Syst Rev, 2005;CD003639.
  23. Karagiannis T, Paschos P, Paletas K, et al., Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis, BMJ, 2012;344:e1369.
  24. Fonseca VA, Handelsman Y, Staels B, Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence, Diabetes Obes Metab, 2010;12:384–92.
  25. Russell-Jones D, Khan R, Insulin-associated weight gain in diabetes--causes, effects and coping strategies, Diabetes Obes Metab, 2007;9:799–812.
  26. Aroda VR, Ratner R, The safety and tolerability of GLP-1 receptor agonists in the treatment of type 2 diabetes: a review, Diabetes Metab Res Rev, 2011;27:528–42.
  27. Marsenic O, Glucose control by the kidney: an emerging target in diabetes, Am J Kidney Dis, 2009;53:875–83.
  28. Basile J, A new approach to glucose control in type 2 diabetes: the role of kidney sodium-glucose co-transporter 2 inhibition, Postgrad Med, 2011;123:38–45.
  29. Bakris GL, Fonseca VA, Sharma K, et al., Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications, Kidney Int, 2009;75:1272–7.
  30. van den Heuvel LP, Assink K, Willemsen M, et al., Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2), Hum Genet, 2002;111:544–7.
  31. Meng W, Ellsworth BA, Nirschl AA, et al., Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes, J Med Chem, 2008;51:1145–9.
  32. Katsuno K, Fujimori Y, Takemura Y, et al., Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level, J Pharmacol Exp Ther, 2007;320:323–30.
  33. Rosenwasser RF, Sultan S, Sutton D, et al., SGLT-2 inhibitors and their potential in the treatment of diabetes, Diabetes Metab Syndr Obes, 2013;6:453–67.
  34. Elkinson S, Scott LJ, Canagliflozin: first global approval, Drugs, 2013;73:979–88.
  35. Grempler R, Thomas L, Eckhardt M, et al., Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors, Diabetes Obes Metab, 2012;14:83–90.
  36. Scheen AJ, Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations, Expert Opin Drug Metab Toxicol, 2014;10:647–63.
  37. FDA, FDA Briefing Document NDA 202293. Dapagliflozin tablets 5 and 10mg. Available at: http://www.fda.gov/ DOWNLOADS/ADVISORYCOMMITTEES/ COMMITTEESMEETINGMATERIALS/DRUGS/ ENDOCRINOLOGICANDMETABOLICDRUGSADVISORYCOMMITTEE/ UCM262994.PDF (last accessed May 1, 2014).
  38. Bailey CJ, Gross JL, Pieters A, et al., Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebocontrolled trial, Lancet, 2010;375:2223–33.
  39. Ferrannini E, Ramos SJ, Salsali A, et al., Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, doubleblind, placebo-controlled, phase 3 trial, Diabetes Care, 2010;33:2217–24.
  40. Nauck MA, Del Prato S, Meier JJ, et al., Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial, Diabetes Care, 2011;34:2015–22.
  41. Strojek K, Yoon KH, Hruba V, et al., Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial, Diabetes Obes Metab, 2011;13:928–38.
  42. Wilding JP, Woo V, Soler NG, et al., Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial, Ann Intern Med, 2012;156:405–15.
  43. Burki TK, FDA rejects novel diabetes drug over safety fears, Lancet, 2012;379:507.
  44. Nisly SA, Kolanczyk DM, Walton AM, Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes, Am J Health Syst Pharm, 2013;70:311–9.
  45. Bode B, Stenlof K, Sullivan D, et al., Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial, Hosp Pract (1995), 2013;41:72–84.
  46. Cefalu WT, Leiter LA, Yoon KH, et al., Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial, Lancet, 2013;382:941–50.
  47. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, et al., Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial, Diabetologia, 2013;56:2582–92.
  48. Schernthaner G, Gross JL, Rosenstock J, et al., Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial, Diabetes Care, 2013;36:2508–15.
  49. Stenlof K, Cefalu WT, Kim KA, et al., Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise, Diabetes Obes Metab, 2013;15:372–82.
  50. Barnett AH, Mithal A, Manassie J, et al., Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol, 2014;2(5):369–84.
  51. Haring HU, Merker L, Seewaldt-Becker E, et al., Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebocontrolled trial, Diabetes Care, 2013;36:3396–404.
  52. Kovacs CS, Seshiah V, Swallow R, et al., Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial, Diabetes Obes Metab, 2014;16:147–58.
  53. Ridderstrale M, Svaerd R, Zeller C, et al., Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control, Cardiovasc Diabetol, 2013;12:129.
  54. Roden M, Weng J, Eilbracht J, et al., Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Diabetes Endocrinol, 2013;1:208–19
  55. Hach T, Gerich J, Salsali A, et al., Empaglilozin improves glycaemic parameters and cardiovascular risk factors in patients with type 2 diabetes: pooled data from four pivotal phase III trials, presented at the European Association for the Study of Diabetes (EASD) 49th Annual Meeting, September 23- 27, 2013; Barcelona, Spain; abstract 943.
  56. Kojima N, Williams JM, Takahashi T, et al., Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats, J Pharmacol Exp Ther, 2013;345:464–72.
  57. Zell M, Husser C, Kuhlmann O, et al., Metabolism and mass balance of SGLT2 inhibitor tofogliflozin following oral administration to humans, Xenobiotica, 2014;44:369–78.
  58. Miao Z, Nucci G, Amin N, et al., Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF- 04971729) in healthy male subjects, Drug Metab Dispos, 2013;41:445–56.
  59. Veltkamp SA, Kadokura T, Krauwinkel WJ, et al., Effect of ipragliflozin (ASP1941), a novel selective sodium-dependent glucose co-transporter 2 inhibitor, on urinary glucose excretion in healthy subjects, Clin Drug Investig, 2011;31:839–51.
  60. Kurosaki E, Ogasawara H, Ipragliflozin and other sodiumglucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data, Pharmacol Ther, 2013;139:51–9.
  61. Seino Y, Sasaki T, Fukatsu A, et al., Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, phase 3 study, Curr Med Res Opin, 2014;Epub ahead of print.
  62. Kapur A, O Connor-Semmes R, Hussey EK, et al., First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus, BMC Pharmacol Toxicol, 2013;14:26.
  63. Zambrowicz B, Freiman J, Brown PM, et al., LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial, Clin Pharmacol Ther, 2012;92:158–69.
  64. Zanardi TA, Han SC, Jeong EJ, et al., Pharmacodynamics and subchronic toxicity in mice and monkeys of ISIS 388626, a second-generation antisense oligonucleotide that targets human sodium glucose cotransporter 2, J Pharmacol Exp Ther, 2012;343:489–96.
  65. Langkilde AM, Sugg J, Johannson P, et al., A meta-analysis of cardiovascular outcomes in clinical trials of dapagliflozin, Circulation, 2011;124:A8947.
  66. Control G, Turnbull FM, Abraira C, et al., Intensive glucose control and macrovascular outcomes in type 2 diabetes, Diabetologia, 2009;52:2288-98.
  67. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group, BMJ, 1998;317:703–13.
  68. Lambers Heerspink HJ, de Zeeuw D, Wie L, et al., Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes, Diabetes Obes Metab, 2013;15:853–62.
  69. Monami M, Nardini C, Mannucci E, Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a metaanalysis of randomized clinical trials, Diabetes Obes Metab, 2014;16:457–66.
  70. Hardy E, Ptaszynska A, de Bruin TWA, et al., Changes in lipid profiles of patients with type 2 diabetes mellitus on dapagliflozin therapy, presented at the European Association for the Study of Diabetes (EASD) 49th Annual Meeting, September 23–27, 2013; Barcelona, Spain; abstract 947.
  71. Stenlof K, Cefalu WT, Kim KA, et al., Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study, Curr Med Res Opin, 2014;30:163–75.
  72. MacEwen A, McKay GA, Fisher M, Drugs for diabetes: part 8 SGLT2 inhibitors, Br J Cardiol, 2012;19:26–9.
  73. Rosenstock J, Vico M, Wei L, et al., Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy, Diabetes Care, 2012;35:1473-8.
  74. Wysham CH, Woo VC, Mathieu C, et al., Canagliflozin (CANA) added on to dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 (GLP-1) agonists with or without other antihyperglycemic agents (AHAs) in type 2 diabetes mellitus (T2DM), presented at the American Diabetes Association 73rd Scientific Sessions, June 21–25, 2013; Chicago, Illinois, US; abstract 1080-P.
  75. Nicolle LE, Capuano G, Fung A, et al., Urinary tract infection (UTI) with canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM), presented at the American Diabetes Association 73rd Scientific Sessions, June 21–25, 2013; Chicago, Illinois, US; abstract 1139-P.
  76. Kim G, Gerich J, Salsali A, et al., Empagliflozin (EMPA) increases genital infections but not urinary tract infections (UTIs) in pooled data from four pivotal phase III trials, presented at the American Diabetes Association 73rd Scientific Sessions, June 21–25, 2013; Chicago, Illinois, US; abstract 74-LB.
  77. List JF, Woo V, Morales E, et al., Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes, Diabetes Care, 2009;32:650–7.
  78. Wilding JP, Norwood P, T’Joen C, et al., A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulinindependent treatment, Diabetes Care, 2009;32:1656–62.
  79. Woo V, Davies M, De Zeeuw D, et al., Canagliflozin (CANA) is effective and generally well tolerated in subjects with type 2 diabetes mellitus (T2DM) and stage 3 chronic kidney disease (CKD), presented at the American Diabetes Association 73rd Scientific Sessions, June 21–25, 2013; Chicago, Illinois, US; abstract 73-LB.
  80. Yale JF, Bakris GL, Cariou B, et al., Efficacy and safety of canagliflozin in subjects with type 2 diabetes mellitus and chronic kidney disease (CKD) over 52 weeks, presented at the American Diabetes Association 73rd Scientific Sessions, June 21–25, 2013; Chicago, Illinois, US; abstract 1075-P.
  81. Barnett AH, Mithal A, Manassie J, et al., Empagliflozin in patients with type 2 diabetes mellitus and renal impairment, presented at the American Diabetes Association 73rd Scientific Sessions, June 21–25, 2013; Chicago, Illinois, US; abstract 1104-P.
  82. Gilbert RE, Sodium-glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering? Kidney Int, 2013;Epub ahead of print.
  83. Palmer TM, Nordestgaard BG, Benn M, et al., Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts, BMJ, 2013;347:f4262.
  84. Levantesi G, Marfisi RM, Franzosi MG, et al., Uric acid: a cardiovascular risk factor in patients with recent myocardial infarction, Int J Cardiol, 2013;167:262–9.
  85. Dziuba J, Alperin P, Racketa J, et al., Modeling effects of SGLT-2 inhibitor dapagliflozin treatment vs. standard diabetes therapy on cardiovascular and microvascular outcomes, Diabetes Obes Metab, 2014;Epub ahead of print.
  86. Eurich DT, McAlister FA, Blackburn DF, et al., Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review, BMJ, 2007;335:497.
  87. Henry RR, Rosenstock J, Chalamandaris AG, et al., Exploring the potential of dapagliflozin in type 1 diabetes, Diabetes, 2013;62(Suppl. 1A):abstract 70-LB.
  88. Perkins BA, Cherney DZ, Partridge H, et al., Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: Results of an 8-week open-label proof-of-concept trial, Diabetes Care, 2014;37:1480–3.
  89. Cherney DZ, Perkins BA, Soleymanlou N, et al., The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus, Cardiovasc Diabetol, 2014;13:28.
  90. Cherney DZ, Perkins BA, Soleymanlou N, et al., Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus, Circulation, 2014;129:587–97.

Further Resources

Share this Article
Related Content In Diabetes
  • Copied to clipboard!
    accredited arrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-whiteticktimetranscriptup-arrowwebinar Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72