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 trial-modest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid level-may be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, β-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.
This Review covers the rationale, physiological consequences and clinical application of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition. In patients with type 2 diabetes mellitus, ...in whom renal glucose reabsorption might be upregulated, orally active, selective SGLT2 inhibitors improve glycaemic control to a therapeutically useful extent. Chronic administration of several SGLT2 inhibitors dose-dependently lowers HbA(1c) levels by 0.5-1.5% without causing hypoglycaemia. The unique mechanism of action of SGLT2 inhibitors-which does not hinge upon β-cell function or tissue insulin sensitivity-means that they can exert their antihyperglycaemic effects in combination with any other oral antidiabetic drug as well as insulin. Available phase III studies confirm a good tolerability profile. Weight loss owing to urinary calorie leakage may be less than expected, but the negative energy balance offers a valuable clinical benefit. Offloading of sodium can assist blood pressure control. The progressive loss of efficacy in patients with reduced glomerular function will have to be balanced against the possibility of renal protection. The safety issues of genitourinary infections and cancer risk requires careful, proactive monitoring and analysis of robust exposure data, particularly in elderly, frail patients and in patients with impaired kidney function and/or high cardiovascular/cancer risk, who represent an increasing fraction of the population with diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, multiple glucose-lowering medications are commonly required to reduce and maintain plasma ...glucose concentrations within the normal range. Type 2 diabetes mellitus individuals also are at a very high risk for microvascular complications and the incidence of heart attack and stroke is increased two- to three-fold compared with non-diabetic individuals. Therefore, when selecting medications to normalize glucose levels in T2DM patients, it is important that the agent not aggravate, and ideally even improve, cardiovascular risk factors (CVRFs) and reduce cardiovascular morbidity and mortality. In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 inhibitors, and α-glucosidase inhibitors) and injectable (glucagon-like peptide-1 receptor agonists and insulin) glucose-lowering drugs on established CVRFs and long-term studies of cardiovascular outcomes. Firm evidence that in T2DM cardiovascular disease can be reversed or prevented by improving glycaemic control is still incomplete and must await large, long-term clinical trials in patients at low risk using modern treatment strategies, i.e., drug combinations designed to maximize HbA1c reduction while minimizing hypoglycaemia and excessive weight gain.
High blood pressure is reported in over two-thirds of patients with type 2 diabetes, and its development coincides with the development of hyperglycaemia. Many pathophysiological mechanisms underlie ...this association. Of these mechanisms, insulin resistance in the nitric-oxide pathway; the stimulatory effect of hyperinsulinaemia on sympathetic drive, smooth muscle growth, and sodium–fluid retention; and the excitatory effect of hyperglycaemia on the renin–angiotensin–aldosterone system seem to be plausible. In patients with diabetes, hypertension confers an enhanced risk of cardiovascular disease. A blood pressure of lower than 140/85 mm Hg is a reasonable therapeutic goal in patients with type 2 diabetes according to clinical trial evidence. People with controlled diabetes have a similar cardiovascular risk to patients without diabetes but with hypertension. A renin–angiotensin system blocker combined with a thiazide-type diuretic might be the best initial antihypertensive regimen for most people with diabetes. In general, the positive effects of antihypertensive drugs on cardiovascular outcomes outweigh the negative effects of antihypertensive drugs on glucose metabolism.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively.
...Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% 62 ± 9 mmol/mol, estimated glomerular filtration rate eGFR 89 ± 19 mL ⋅ min(-1) ⋅ 1.73 m(-2)) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes.
At week 90, weight loss averaged -3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day interquartile range (IQR) 112). However, the observed calorie loss through glycosuria (206 kcal/day IQR 90) was predicted to result in a weight loss of -11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day IQR 258) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = -0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01).
Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.
With respect to clinical phenotype and pathophysiology, prediabetes is akin to diabetes. Prediabetes is prevalent in the global population, and those affected are at high risk of progression to overt ...diabetes, and also at risk of cardiovascular disease (CVD). Progression to diabetes can occur because of worsening insulin resistance, β-cell dysfunction, or both, but the timecourse can be non-linear and, therefore, unpredictable. Intervention-by lifestyle modification, glucose-lowering drugs, or a combination-can postpone deterioration of glucose control, but effects of intervention are variable and can be transient. Furthermore, to what extent interventions can reduce cardiovascular risk is uncertain. Lifestyle intervention mainly hinges on weight loss; as such, risk of failure in the long-term is high, and implementation at the community level is difficult. The ideal candidate for intervention is an individual with prediabetes-identified by targeted screening-with many well documented cardiovascular risk factors, and who is highly motivated to initiate and maintain multifactorial risk-control using a personalised mix of lifestyle-adaptation and pharmacological treatment.
Sodium-glucose cotransporter-2 (SGLT2) is selectively expressed in the human kidney, where it executes reabsorption of filtered glucose with a high capacity; it may be overactive in patients with ...diabetes, especially in the early, hyperfiltering stage of the disease. As a therapeutic target, SGLT2 has been successfully engaged by orally active, selective agents. Initially developed as antihyperglycemic drugs, SGLT2 inhibitors have deployed a range of in vivo actions. Consequences of their primary effect, i.e., profuse glycosuria and natriuresis, involve hemodynamic (plasma volume and blood pressure reduction) and metabolic pathways (increase in lipid oxidation and ketogenesis at the expense of carbohydrate utilization); the hormonal mediation extends to insulin, glucagon, and gastrointestinal peptides. Their initial trial in high-risk patients with diabetes has provided evidence for marked reduction of cardiovascular risk. This review focuses on the quantitative pharmacology of SGLT2 inhibitors, which can be exploited to discover new physiology, in the heart, kidney, and brain.
In this review, Ferrannini discusses how sodium-glucose cotransporter inhibitors act as antidiabetic agents that exert cardioprotective and nephroprotective effects through multiple mechanisms beyond glucose control, including in humans. Their use as pharmacological tools can be exploited to discover new physiology in the heart, kidney, and brain.
It is well-established that adipose tissue accumulation is associated with insulin resistance through multiple mechanisms. One major metabolic link is the classical Randle cycle: enhanced release of ...free fatty acids (FFA) from hydrolysis of adipose tissue triglycerides impedes insulin-mediated glucose uptake in muscle tissues. Less well studied are the different routes of this communication. First, white adipose tissue depots may be regionally distant from muscle (
i.e.,
gluteal fat and diaphragm muscle) or contiguous to muscle but separated by a fascia (Scarpa’s
fascia
in the abdomen,
fascia lata
in the thigh). In this case, released FFA outflow through the venous drainage and merge into arterial plasma to be transported to muscle tissues. Next, cytosolic triglycerides can directly,
i.e.,
within the cell, provide FFA to myocytes (but also pancreatic ß-cells, renal tubular cells, etc
.
). Finally, adipocyte layers or lumps may be adjacent to, but not anatomically segregated, from muscle, as is typically the case for epicardial fat and cardiomyocytes. As regulation of these three main delivery paths is different, their separate contribution to substrate competition at the whole-body level is uncertain. Another important link between fat and muscle is vascular. In the resting state, blood flow is generally higher in adipose tissue than in muscle. In the insulinized state, fat blood flow is directly related to whole-body insulin resistance whereas muscle blood flow is not; consequently, fractional (
i.e.,
flow-adjusted) glucose uptake is stimulated in muscle but not fat. Thus, reduced blood supply is a major factor for the impairment of
in vivo
insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect.
In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established ...cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio HR 0.62 95% CI 0.49, 0.77). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin.
Effects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed.
Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA
. In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death.
In this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.
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