Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients

Ferrannini, Ele; Muscelli, Elza; Frascerra, Silvia; Baldi, Simona; Mari, Andrea; Heise, Tim; Broedl, Uli C.; Woerle, Hans-Juergen

doi:10.1172/jci75754

Cited by 148 publications

(266 citation statements)

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“…Most of the patients with DKA also had DKA-precipitating factors, including 6 with evidence of autoimmune diabetes (i.e., latent autoimmune diabetes of adulthood, type 1 diabetes, or positive for GAD65 antibody). We speculate that patients with type 1 or type 2 diabetes who have no or low b-cell reserve, coupled with a potential SGLT2 inhibitorassociated increase in glucagon (28)(29)(30) and other metabolic factors, such as elevated free fatty acids, may not take or may be unable to produce sufficient insulin to suppress hepatic ketogenesis (28)(29)(30), which can progress to DKA in the setting of an acute illness, inadequate carbohydrate intake, and an associated increase in insulin resistance.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

et al. 2015

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OBJECTIVEThis study assessed the efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODSThis 18-week, double-blind, phase 2 study randomized 351 patients (HbA 1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion to canagliflozin 100 or 300 mg or placebo. The primary end point was the proportion of patients achieving at week 18 both HbA 1c reduction from baseline of ‡0.4% ( ‡4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA 1c , body weight, and insulin dose, as well as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTSMore patients had both HbA 1c reduction ‡0.4% and no increase in body weight with canagliflozin 100 and 300 mg versus placebo at week 18 (36.9%, 41.4%, 14.5%, respectively; P < 0.001). Both canagliflozin doses provided reductions in HbA 1c , body weight, and insulin dose versus placebo over 18 weeks. The incidence of hypoglycemia was similar across groups; severe hypoglycemia rates were low (1.7-6.8%). Overall incidence of AEs was 55.6%, 67.5%, and 54.7% with canagliflozin 100 and 300 mg and placebo; discontinuation rates were low (0.9-1.3%). Increased incidence of ketone-related AEs (5.1%, 9.4%, 0%), including the specific AE of diabetic ketoacidosis (DKA) (4.3%, 6.0%, 0%), was seen with canagliflozin 100 and 300 mg versus placebo. CONCLUSIONSCanagliflozin provided reductions in HbA 1c , body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin.Type 1 diabetes is an autoimmune disease characterized by progressive destruction of pancreatic b-cells, resulting in loss of endogenous insulin production and hyperglycemia (1). Consequently, treatment of type 1 diabetes requires lifelong insulin therapy to maintain normal blood glucose levels. Type 1 diabetes is associated with increased morbidity and mortality related to microvascular and macrovascular

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Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

et al. 2015

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“…It should be noted that during SGLT2 inhibition, plasma ketones increase, whereas plasma lactate decreases significantly (3). The latter change could be because of the sum of decreased glucose disposal (2), increased hepatic/ renal extraction (to support the augmentation of gluconeogenic glucose production [2]), and increased renal excretion, in relative proportions that only a combined catheterization/tracer study could quantify.…”

Section: Resultsmentioning

confidence: 99%

“…The glucose excretion data for the patients with T2D have been reported (2) and are repeated in this study for comparison purposes; the circulating b-HB and lactate levels have been reported (3) and are used in this study to calculate fractional urinary excretion rates. The study (ClinicalTrials.gov identifier NCT01248364; EudraCT no.…”

Section: Populationmentioning

confidence: 99%

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Renal Handling of Ketones in Response to Sodium–Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes

et al. 2017

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OBJECTIVEPharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes. RESEARCH DESIGN AND METHODSWe measured fasting and postmeal urinary excretion of glucose, b-hydroxybutyrate (b-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ‡60 mL · min 21 · 1.73 m 22 ) and in control subjects without diabetes at baseline and following empagliflozin treatment. RESULTSWith chronic (4 weeks) sodium-glucose cotransporter 2 inhibition, baseline fractional glucose excretion (<2%) rose to 38 6 12% and 46 6 11% (fasting vs. postmeal, respectively; P < 0. ) all increased (P £ 0.001 for all) and were each positively related to glycosuria (P £ 0.001). These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal pro-B-type natriuretic peptide levels were unaltered, plasma erythropoietin concentrations increased by 31 (64)% (P = 0.0078). CONCLUSIONSWe conclude that the sodium-glucose cotransporter 2 inhibitor-induced increase in b-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.

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“…In patients with T2D, empagliflozin-induced glycosuria lowers plasma glucose and insulin levels and raises fasting and postmeal glucagon concentrations. The subtraction of large amounts of glucose from the glucose pool, coupled with the dual hormonal changes, results in a 25% restriction of glucose utilization, and a concomitant increase in lipid mobilization and usage for energy production (24). Under conditions of reduced portal insulin-to-glucagon ratio, the increased delivery of free fatty acids (FFAs) to the liver stimulates ketogenesis (25), resulting in a metabolic condition resembling a prolonged fast (26).…”

Section: Rationalementioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

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The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trialdmodest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid leveldmay be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.First among cardiovascular (CV) end point trials of glucose-lowering agents (1), the EMPA-REG OUTCOME trialdusing 10 or 25 mg/day sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin against placebo in 7,020 patients with type 2 diabetes (T2D) who were at increased CV riskdreported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years (2). Of note, all the pathologic categories of CV death (ischemic, pump failure, arrhythmic, embolic) contributed to the overall reduction in CV death in a patient cohort well treated with the use of renin-angiotensin-aldosterone inhibitors, statins, and acetylsalicylic acid. Furthermore, separation of the cumulative incidence functions between pooled-dose groups and placebo was already evident months after randomization. This unusual time course and the discrepancy between the relative risk reduction of the primary end point (nonfatal myocardial infarction, stroke, and CV mortality) and CV mortality itself suggests that active treatment affected case fatality rates more than event rates. In other words, empagliflozin treatment appeared mostly to rescue patients from impending cardiac decompensation. This interpretation is supported by the recent post hoc analyses of heart failure, documenting a large benefit in first and recurrent heart failure hospitalization across virtually every patient subgroup (3). Despite the fact that the diagnosis of heart failure was based on investigator reporting, th...

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Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients

Cited by 148 publications

References 0 publications

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

Renal Handling of Ketones in Response to Sodium–Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

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