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      Blood Pressure Reduction: An Added Benefit of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes

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      Diabetes Care
      American Diabetes Association

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          Abstract

          Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a newly approved class of glucose-lowering medications with a novel mechanism of action. These agents increase glycosuria, which leads to improved glucose control. They also produce an osmotic diuresis that, in part, contributes to blood pressure reduction and calorie loss secondary to glycosuria leading to weight loss (1,2). A recent review of SGLT2 inhibitors focuses on the blood pressure–lowering effects of the two approved glucose-lowering agents, dapagliflozin and canagliflozin (3). While not approved as antihypertensive agents, they may potentially aid in lowering blood pressure in patients with diabetes. A review of studies in both hypertensive and normotensive patients with type 2 diabetes demonstrates a 4–10 mmHg reduction of systolic blood pressure (3). In this issue of Diabetes Care, Tikkanen et al. (4) investigate the effectiveness and safety of the newest agent in this class, empagliflozin, on blood pressure using 24-h ambulatory blood pressure monitoring. This study randomized over 800 subjects with type 2 diabetes, mean age of 60 years, and good kidney function (i.e., a mean estimated glomerular filtration rate [eGFR] of 84 mL/min/1.73 m2). These subjects either were normotensive (<140/90 mmHg) or had stage 1 hypertension (≥140/90 < 160/99 mmHg). They were randomized to either empagliflozin 10 mg daily, empagliflozin 25 mg daily, or placebo. The primary end point was the change in HbA1c over the 12-week study. The coprimary end point was change in mean 24-h systolic blood pressure for which the study was 90% powered to see a 4 mmHg difference from placebo. The authors demonstrated a significant reduction in 24-h systolic and diastolic blood pressures, 4/2 mmHg lower than placebo at the 25 mg dose of empagliflozin. The use of 24-h ambulatory blood pressure monitoring in the study by Tikkanen et al. is important and distinctive as it is the gold standard for assessing blood pressure (5). Moreover, it is the largest study to date to assess blood pressure lowering during both day and night with the use of SGLT2 inhibitors. Ambulatory blood pressure is recommended in the U.K. for evaluating all new patients with hypertension by the National Institute for Health and Care Excellence guidelines (5). Given the hypothesis of the study and its specific aim, it would have been more compelling if it stratified patients by level of eGFR (i.e., >45, <60, and >60 mL/min/1.73 m2) to assess the spectrum of blood pressure lowering across stages of kidney disease as was done with canagliflozin (6). This would have required substantially more subjects, however. Additionally, the study could have been powered for a blood pressure end point; however, this class of drugs is not approved as a blood pressure–lowering agent. The exact mechanism of blood pressure lowering with these agents is not completely understood; however, proposed mechanisms are listed in Table 1. Blood pressure reduction by these agents is assumed to be related to its osmotic diuretic effect, although they have very slight natriuretic effects much less than low-dose thiazide diuretics. It is curious that if osmotic diuresis was the sole mechanism, then the antihypertensive effect would wane as kidney function decreases; however, this is not the case (3). Similar levels of blood pressure reduction are seen in people with eGFR of 45 mL/min/1.73 m2 as those with 85 mL/min/1.73 m2. Also, there is no reported hyponatremia with these agents, suggesting their blood pressure lowering is not related to sodium loss (1). Last, while weight loss has been postulated as a contributing mechanism for blood pressure lowering, it is unlikely as the blood pressure–lowering effect is seen much earlier than any significant weight loss (3). Table 1 Proposed mechanisms for antihypertensive action of SGLT2 inhibitors Osmotic diuresis Weight loss after a week or so Mild natriuresis Possible indirect effects on nitric oxide release secondary to reduced oxidant stress by better glycemic control* * Observation from preliminary studies in a couple of patients. An investigation by Cherney et al. (7) studied patients with type 1 diabetes treated with empagliflozin 25 mg daily for 8 weeks. This study demonstrated significant blood pressure reductions and there was an assessment of changes in arterial stiffness and sympathetic nervous system activity. The subjects had measurements of radial artery and carotid waveforms, augmentation index, heart rate, and aortic pulse wave velocity. During euglycemic clamp conditions, there was a significant reduction in systolic blood pressure, radial augmentation index, carotid augmentation index, and aortic augmentation index in subjects treated with empagliflozin 25 mg daily. The augmentation index is commonly accepted as a measure of central aortic pressure enhancement by a reflected pulse wave and is a predictor of adverse cardiovascular events. It is defined as a ratio calculated from the blood pressure waveform; the greater the augmentation, the greater the arterial stiffness. There were no significant changes in the measurements of sympathetic nervous system activity. SGLT2 inhibitors are a unique class of medications that not only improve glucose control but also have a demonstrated impact on reducing cardiovascular risk factors (i.e., high blood pressure and excessive weight). The long-term effects of these agents on blood pressure and overall cardiovascular and kidney disease are being assessed in ongoing cardiovascular and chronic kidney disease outcome trials that should be completed within the next 3 to 5 years. The data from the study by Tikkanen et al. (4), taken together with previous studies of other agents in the class, demonstrate that SGLT2 inhibitors not only lower glucose but also have other salutary effects (i.e., blood pressure–lowering and weight-reducing effects). Moreover, they are safe as they are not associated with hypoglycemia except when used with sulfonylureas or insulin. Future studies should perhaps focus on use of these agents as antihypertensive agents and hence a potential substitute for diuretics to avoid adverse metabolic effects in patients with diabetes. It is important to treat all associated components of the abnormal metabolic profile in patients with diabetes to optimally reduce the risk of cardiovascular disease. These agents are a powerful new tool for the diabetologist and clinician in general. They should be considered for use in patients with type 2 diabetes with hypertension, where indicated. Patients should be warned of the potential side effects including polyuria, orthostatic hypotension, hypoglycemia, and genital infections. Patients on diuretics may need dose reductions to avoid some of these adverse effects.

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          Most cited references5

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          Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors.

          Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium-glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7-10 mm Hg of goal. It should be noted that the currently approved agents have side effects that include an increased incidence of genital infections, predominantly in women. The approved SGLT2 inhibitors have limited use based on kidney function and should be used only in those with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 for dapagliflozin and ≥45 mL/min/1.73 m2 for canagliflozin. Cardiovascular outcome trials are ongoing with these agents and will be completed within the next 4-5 years. Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.
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            Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes and Stage 3 Nephropathy

            Background/Aims: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m 2 . The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to 2 ). Methods: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. Results are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and 2 ) and stage 3b CKD (eGFR ≥30 and 2 ). Results: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA 1c (-0.38 and -0.47%; p 1c , body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA 1c , -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis. Conclusion: In subjects with T2DM and stage 3 CKD, canagliflozin reduced HbA 1c , body weight, and blood pressure, and was generally well tolerated.
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              Dapagliflozin: a review of its use in patients with type 2 diabetes.

              Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2 diabetes. Dapagliflozin reduces renal glucose reabsorption by inhibiting the transporter protein SGLT2 in the renal proximal tubule, thereby increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of insulin secretion or action; therefore, dapagliflozin provides complementary therapy when used in combination with other antihyperglycaemic drugs. This article updates an earlier review of dapagliflozin and focuses on longer-term efficacy and tolerability data (e.g. from extensions of earlier clinical trials), as well as data from studies in special patient populations (e.g. history of cardiovascular disease). Numerous well-designed clinical trials with dapagliflozin, primarily as add-on therapy for 24 weeks (but also as monotherapy or initial combination therapy), have consistently demonstrated reductions in glycosylated haemoglobin, fasting plasma glucose levels and bodyweight. Extensions of these trials show the effects are maintained over longer-term follow-up periods of ≈1-4 years and dapagliflozin is generally well tolerated. Dapagliflozin has a low risk of hypoglycaemia, although the incidence varies depending on background therapy, and genital mycotic infections (particularly in women) are the most common adverse events. Dapagliflozin is not recommended in patients with moderate or severe renal impairment. In view of its unique mechanism of action and now well-established efficacy and tolerability profile, dapagliflozin is a useful treatment option in the management of type 2 diabetes, although its effects on diabetic complications remain to be evaluated.
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                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                March 2015
                12 February 2015
                : 38
                : 3
                : 429-430
                Affiliations
                [1]American Society of Hypertension Comprehensive Hypertension Center, Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Chicago Medicine, Chicago, IL
                Author notes
                Corresponding author: George L. Bakris, gbakris@ 123456gmail.com .
                Article
                1596
                10.2337/dc14-1596
                4876696
                25715414
                2c48484b-c2d8-47a4-95b3-828aa00b5b32
                © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                History
                Page count
                Pages: 2
                Categories
                Evolving Tactics With Inhibition of Sodium–Glucose Cotransporters

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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