Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion

Polidori, David; Sha, Sue; Mudaliar, Sunder; Ciaraldi, Theodore P.; Ghosh, A.K.; Vaccaro, Nicole; Farrell, K.; Rothenberg, Paul; Henry, Robert R.

doi:10.2337/dc12-2391

Cited by 251 publications

(236 citation statements)

References 26 publications

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“…Inhibition of gut SGLT1 reduces absorption of glucose there, and it has been suggested that canagliflozin may have a dual action. This was reported first in healthy volunteers 53 but has since been reported in a study of people with type 2 diabetes. 54 Because these drugs act through an insulin-independent mechanism, they can be effective when other drugs that depend entirely (sulfonylureas and meglitinides) or in part (gliptins and GLP-1 analogues) on stimulating insulin release have lost effectiveness.…”

Section: Sodium-glucose Co-transporter 2 Inhibitorsmentioning

confidence: 93%

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Johnston

Uthman

Cummins

et al. 2017

Health Technol Assess

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Background Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium–glucose co-transporter 2 (SGLT2) inhibitors. Objective To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Boehringer Ingelheim, Ingelheim, Germany/Eli Lilly and Company, Indianapolis, IN, USA), in monotherapy in people who cannot take metformin. Sources MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. Methods Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. Results We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). Limitations There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. Conclusions Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Merck Sharp & Dohme Limited, Kenilworth, NJ, USA). Funding The National Institute for Health Research Health Technology Assessment programme.

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Section: Sodium-glucose Co-transporter 2 Inhibitorsmentioning

confidence: 93%

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Johnston

Uthman

Cummins

et al. 2017

Health Technol Assess

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“…The effects of SGLT2 inhibitors on renal glucose kinetics were assessed using controlled glucose infusion experiments in rats (13) and humans (14,15). These experiments showed that SGLT2 inhibition leads to a reduction in T M G and RT G while maintaining a threshold-like relationship between PG and the UGE rate (Fig.…”

Section: Role Of Sglt2 and Sglt1 In Renal Glucose Reabsorptionmentioning

confidence: 99%

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

et al. 2015

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Type 2 diabetes is a chronic disease with disabling micro-and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.It took nearly 200 years from the isolation of phlorizin, a chemical found in apple tree bark that inhibits sodium-glucose cotransporters (SGLTs) (1), to the approval of the first medications inhibiting SGLTs for treatment of type 2 diabetes (T2D). During this time, several SGLTs were discovered and the roles of SGLT1 and SGLT2 in intestinal and renal glucose reabsorption have been elucidated in studies in genetically manipulated rodents, humans with SGLT gene mutations, healthy humans, and humans with diabetes (Fig. 1). This review provides an overview of the basic and clinical research that led to the translation of the initial findings of increased glucosuria with phlorizin to the development and approval of SGLT inhibitors and a summary of the clinical trial results obtained to date. Identification, Distribution, and In Vitro Characterization of the SGLT InhibitorsIn the 1980s and 1990s, Wright and colleagues cloned SGLT1 (2) and SGLT2 (2,3) and did much of the in vitro characterization, demonstrating that SGLT1 has a higher affinity for glucose than SGLT2 (K m for glucose ;0.4 mmol/L and 2 mmol/L, respectively), whereas SGLT2 has a higher capacity (4). SGLT1 is expressed at high levels in the intestine and is also expressed in the kidney, heart, and skeletal muscle, whereas SGLT2 is expressed almost exclusively in the kidney (4). Renal SGLT2 expression is increased in hyperglycemic rodents (5,6) and in humans with T2D (7). Intestinal SGLT1 expression is regulated by diet and other factors (8) and is

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“…Approximately 180g of glucose is filtered through the renal system daily with almost 90% reabsorbed in the proximal tubule by the glucose transporter protein, SGLT-2 [7]. Canagliflozin is a selective SGLT-2 inhibitor which increases urinary excretion of glucose but is associated with an increased rate of GU infections [8].…”

Section: Discussionmentioning

confidence: 99%

Perioperative genitourinary infection associated with sodium-glucose co-transporter 2 inhibitor use

Melnick

Rajagopalan

Lynn

et al. 2018

Journal of Community Hospital Internal Medicine Perspectives

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Context: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a novel treatment approved for type 2 diabetes mellitus to lower hyperglycemia, systolic blood pressure, and promote weight loss. Commonly reported serious adverse events include increased mycotic urogenital infections, orthostatic hypotension, and normoglycemic ketoacidosis.Case report: We present a case of a 47-year old man with a history of type 2 diabetes mellitus initiated on the SGLT-2 inhibitor canagliflozin preoperatively before a penile implant, who presented with late postoperative MRSA bacteremia and scrotal abscess requiring implant extraction.Conclusion: As the SGLT-2 inhibitors are gaining in popularity, prescribers must be aware of the potential adverse genitourinary infectious outcomes. Providers should use caution and avoid initiating SGLT-2 inhibitors in the perioperative setting, and may even consider holding or discontinuing this medication in the setting of impending GU surgery.

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Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion

Cited by 251 publications

References 26 publications

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

Perioperative genitourinary infection associated with sodium-glucose co-transporter 2 inhibitor use

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