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| Diabetes and Role of the Kidneys On-line FAQ Library |
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Questions
1.What is the role of the kidneys in glucose metabolism?
2. What is the localization and what is the functional significance of SGLT1 and SGLT2?
3. What effect could inhibiting renal glucose reuptake have on patients with type 2 diabetes?
5. What phase III results have been published for any SGLT2 inhibitors?
6. How do SGLT2 inhibitors address unmet needs in diabetes care?
Answers
1. What is the role of the kidneys in glucose metabolism?
• The major role of the kidney in human physiology is to maintain intravascular volume and an acid-based electrolyte balance. Approximately 180 L of plasma per day pass through the kidney’s glomerular filtration system, wherein minerals such as sodium, potassium, and chloride are absorbed and returned to the bloodstream rather than passed out in the urine. Glucose is also filtered in this manner in order to retain energy essential for physiologic functioning between meals.1 [slide 1]
• With a daily glomerular filtration rate of 180 L, approximately 162 g of glucose must be reabsorbed each day to maintain a plasma glucose concentration of 5.6 mmol/L (101 mg/dL). Typically, most of this glucose is reabsorbed and only <1% is excreted in the urine.2 [slide 1]
• The amount of glucose reabsorbed by the kidneys is essentially equivalent to the amount entering the system, with reabsorption increasing with glucose concentration up to approximately 11 mmol/L (198 mg/dL). At this threshold, the system becomes saturated and the maximal reabsorption rate, or glucose transport maximum (TmG), is reached. No more glucose can be absorbed, and instead the kidneys begin excreting it in the urine.4,5 [slide 2]
• Although 11 mmol/L (198 mg/dL) represents the theoretical threshold glucose concentration, the actual concentration varies due to nephron heterogeneity, resulting in slight differences in actual glucose reabsorption levels and TmG values between individual tubules.3 Thus, the actual threshold is not a single point but a curve, where excretion begins to occur at plasma glucose levels of approximately 10 mmol/L (180 mg/dL), and increases gradually rather than sharply.4,5 [slide 2]
• Likewise, as reabsorption approaches the TmG, it tails off in parallel to the glucose concentration threshold. The difference between the actual and theoretical TmG is known as splay.4,5 [slide 2]
• The transport of glucose through the basolateral membrane and back into the peritubular capillary is mediated by glucose transporter proteins (GLUTs) and occurs by facilitated diffusion.2
• The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium glucose cotransporters (SGLTs).2
• Reabsorption of glucose occurs mainly in the proximal tubule and is mediated by 2 different transport proteins, SGLT1 and SGLT2. SGLT1, which occurs in the straight section of the tubule (S3), is responsible for approximately 10% of glucose reabsorption in the kidney. The other 90% is mediated by SGLT2, which occurs in the convoluted section on the tubule (S1).1 [slides 1, 3]
• Low-affinity/high-capacity Na+-glucose cotransporter SGLT2 mediates the bulk uptake of glucose across the apical membrane of the early proximal tubule, whereas the high-affinity/low-capacity SGLT1 further reduces luminal glucose concentrations in distal parts of the proximal tubule.6 On the other side of the cell, sodium is reabsorbed through an ATPase-mediated sodium-potassium pump into the bloodstream in order to maintain intravascular volume. This exchange alters the concentration gradient within the cell so that glucose is reabsorbed into the bloodstream via the GLUT2 transporter.7 [slides 1, 3]
• The GLUT2 transporter is present in red blood cells, the brain, and other tissues and thus is not a candidate for pharmacologic intervention. In contrast, SGLT2 is specific to the proximal tubule, so that pharmacologic inhibition will affect glucose reabsorption in the kidney but not in other tissues.7
• The most common cause of glucosuria is diabetes mellitus. In the average patient with type 2 diabetes, the glucose in the urine remains undetected until the blood glucose concentration exceeds approximately 10 mmol/L (180mg/100 dL).
• There has been a focus on reduction of the SGLT2 activity in the renal tubules in the past few years. For more informatino please refer to questions 3 and 6.
References:
1. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32-43.
2. Neumiller JJ, White JR Jr, Campbell RK. Sodium-glucose co-transporter inhibitors. Progress and therapeutic potential in type 2 diabetes mellitus. Drugs 2010; 70:377-385.
4. Ganong WF. Review of Medical Physiology. 19th ed. Stamford, CT: Appleton & Lange; 1999:667-695.
5. Abdul-Ghani MA. Inhibition of renal glucose absorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:782-790.
6. Vallon V, Platt KA, Cunard R, Schroth J, et al. SGLT2 mediates glucose reabsorption in the early proximal tube. J Am Soc Nephrol. 2010 July 8 [Epub ahead of print].
7. Hediger MA, Rhoads DB. Molecular physiology of sodium-glucose cotransporters. Physiol Rev. 1994;74:993-1026.
2. What is the localization and what is the functional significance of SGLT1 and SGLT2?
1. Where is SGLT1 expressed in the human body?
• SGLT1 is expressed in both the intestine and the proximal tubule of the kidney.1 [slide 4]
2. What is the role of SGLT1 in the human body?
• SGLT1 has high glucose affinity and low glucose transport capacity.
• SGLT1 is involved in1 [slide 4]
-dietary absorption of glucose and galactose
-renal glucose reabsorption
3. What are the consequences of SGLT1 gene mutation(s)?
• SGLT1 gene mutation can cause impaired absorption of glucose and galactose, and can result in severe diarrhea.1 [slide 4]
• Individuals with SGLT1 gene mutations must receive all carbohydrates in the form of fructose or malnutrition, and even death, may occur.1 [slide 4]
4. Where is SGLT2 expressed in the human body?
• SGLT2 is expressed in the proximal tubule of the kidney.1 [slide 4]
5. What is the role of SGLT2 in the human body?
• SGLT2 has low glucose affinity and high glucose transport capacity1 [slide 4]
• SGLT2 is involved in renal glucose reabsorption only.1 [slide 4]
6. What are the consequences of SGLT2 gene mutation(s)?
• Mutations in the SLC5A2 gene that encodes SGLT2 protein are responsible for the large majority of cases of familial renal glucosuria (FRG).2
• 44 different mutations are scattered across the SLC5A2 gene.3,4
• Individuals with SGLT2 gene mutations excrete large amounts of glucose in their urine.4 [slide 4]
• In other respects, these individuals are normal. Blood glucose concentration is neither high nor low, and blood volume remains essentially normal due to sodium reabsorption through other channels. Kidney and bladder function remain unaffected, and this group of patients does not show an increased incidence of kidney disease, diabetes, or urinary tract infections.1,4 [slide 5]
7. What is familial renal glucosuria?
• Familial renal glucosuria is a genetic condition that serves as a model for the effects of SGLT2 inhibition. Patients with this condition are asymptomatic but have impaired functioning of their SGLT2 proteins. As a result, they excrete between a few to approximately 100 g of glucose per day in their urine.1,4 [slide 5]
• There are 2 types of types of familial renal glucosuria:4 [slide 6]
-Patients with reduced SGLT2 protein, wherein glucose reabsorption TmG is lower than normal
-Patients with SGLT2 protein that has diminished affinity for glucose, but normal glucose reabsorption TmG
• The genetics of familial renal glucosuria have been studied in 23 families with the disorder, and 21 different mutations in the gene for SGLT2 were detected.4 [slide 7]
-Fourteen of 21 individuals were homozygous or compound heterozygous and had severe glucosuria of 15 to 200 g/day.
-Heterozygous family members had either no glucosuria or mild glucosuria of ≤4.4 g/day.
-Various nonsense mutations, missense mutations, and small deletions were scattered over the SGLT2 coding sequence.
• The cause of glucosuria in the 2 remaining families remains unknown, but may relate to mutations in GLUT2, the glucose transport protein residing on the basolateral membrane; HNF-1α, which regulates SGLT2 transcription; or the genes for SGLT1 or SGLT3.4 [slide 7]
References:
3. What effect could inhibiting renal glucose reuptake have on patients with type 2 diabetes?
• Paradoxically, glucose reabsorption may be increased in the presence of chronic elevation of plasma glucose concentrations as it occurs in diabetes, thus contributing to overall hyperglycemia. This maladaptive mechanism is supported by findings showing that, in type 2 diabetes, the expression and activity of renal glucose transporter is enhanced.1 [slide 8]
• In diabetes, renal glucose reabsorption may be augmented in absolute terms by an increase in the renal Tm for glucose. [slide 9] Therefore, inhibition of glucose reabsorption can reduce plasma glucose concentration by increasing glucose loss through the urine. This can be accomplished by specific inhibitors of the SGLT2.2 [slide 10]
• Pharmacologic inhibition of SGLT2 affects glucose reabsorption in the kidney but not in other tissues.3 [slide 4]
• SGLT2 inhibition can reduce plasma glucose levels by decreasing TmG, increasing the glucose excretion rate, or both.2 [slide 10]
• Reduction of plasma glucose levels through SGLT2 inhibition can reverse the negative effects of glucotoxicity, thus improving the following:4,5[slide 11]
-Insulin sensitivity in muscle
-Insulin sensitivity in the liver
-β-cell function
References:
1. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:3427-3434.
2. Abdul-Ghani MA. Inhibition of renal glucose absorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:782-790.
3. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32-43.
4. DeFronzo RA. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes. 1988;37:667-687.
5. Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86:4047-4058.
4. What are the potential concerns with inhibiting renal glucose reuptake in patients with type 2 diabetes?
• Inhibiting renal glucose reuptake in patients with type 2 diabetes may include: [slides 12, 13]
-Increase in urine volume via increased glucosuria.1 The loss of fluids is more apparent in the early phase of treatment and it may become benign with improvement of glycemic control.
-Intravascular volume depletion.2 No significant changes in hematocrit have been reported so far with the use of SGLT2. Rather, the mild depletion in the circulating volume may have a potential effect on blood pressure.
-Susceptibility to urinary tract and genital infections.2
-Nocturia.2
-Electrolyte imbalance.2
-Nephrotoxicity due to accumulation of advanced glycation end products.2
• SGLT2 inhibitors help lower excess glucose levels in an insulin-independent manner by blocking renal glucose absorption and increasing urinary glucose excretion, thereby improving glycemic control. In addition, SGLT2 inhibitors reduce HbA1c and body weight with no increase in hypoglycemia.2 [slide 13]
• SGLT2 inhibitors block SGLT2 receptors in the kidney, where 90% of the glucose is reabsorbed. Instead of being reabsorbed, glucose is excreted through the urine (glycosuria). Glycosuria provides a favorable environment for bacteria to reside and grow in the urinary tract, often leading to urinary tract infection.
• Subjects homozygous for SGLT2 gene mutations are asymptomatic despite large amounts of glycosuria (>50 g/34 h); pharmacologic inhibition of SGLT2 would not be expected to cause polyuria, nocturia, or volume contraction.
• Detailed evaluation of patients treated with SGLT2 inhibitors revealed increased reports of signs, symptoms, and events suggestive of genital infection and urinary tract infection. This is a common feature that can be seen in most/all drugs that belong to the SGLT2 inhibitor class.2 [slide 13]
• Mutations in the SLC5A2 gene that encodes SGLT2 protein are responsible for the large majority of cases of familial renal glucosuria (FRG).3
• Codominance is the pattern of gene inheritance that best fits FRG. However, increased glucose excretion was not observed in all individuals with similar or identical mutations, suggesting that epigenetic factor and other genes in renal glucose transport may contribute to FRG.3
• Establishing definitive genotype-phenotype correlation in FRG is difficult due to high variability in mutations.
• FRG can be grouped according to the amount of glucose excreted in a 24-h urine collection:3
-Mild glucosuria (<10 g/1.73 m2 per day), in people with heterozygous nonsense and missense SGLT2 mutations.
-Severe glucosuria ( ≥ 10 g/1.73 m2 per day), in people with autosomal recessive inheritance with homozygosity or compound heterozygosity for SGLT2 mutations.
• 44 different mutations are scattered across the SLC5A2 gene.4,5
• The genetics of familial renal glucosuria have been studied in 23 families with the disorder, and 21 different mutations in the gene for SGLT2 were detected.5 [slide 7]
-Fourteen of 21 individuals were homozygous or compound heterozygous and had severe glucosuria of 15 to 200 g/day.
-Heterozygous family members had either no glucosuria or mild glucosuria of ≤4.4 g/day.
-Various nonsense mutations, missense mutations, and small deletions are scattered over the SGLT2 coding sequence.
• Patients with renal glucosuria have not been shown to be affected by severe clinical consequences, and this is considered to be a clinical phenotype rather than a disease.
• Complications that may accompany this condition:
-Polyuria and enuriesis6
-Episodic dehydration and ketosis during pregnancy and starvation7
-The presence of several auto-antibodies without clinical evidence of autoimmune disease6
-An increased incidence of urinary tract infections6,8
-Activation of the renin-angiotensin-aldosterone system, secondary to natriuresis and possible extracellular volume depletion4,9
-Hypercalciuria (with renal glucosuria or with severe renal glucosuria elevated calcium/creatinine ratio)10
![[slide 13]](Diabetes_Library/Slide13.JPG){kind=link}
References:
11. Gotzsche O. Renal glucosuria and aminoaciduria. Acta Med Scand. 1977;202:65-67.
5. What phase III results have been published for any SGLT2 inhibitors?
Two phase III studies investigating the efficacy and safety of dapagliflozin were published in June 2010, one in The Lancet and one in Diabetes Care.1,2
Lancet Study1
• The study published in The Lancet assessed the efficacy and safety of dapagliflozin (DAPA) in patients with type 2 diabetes mellitus who cannot reach adequate glucose control with metformin. In this phase III, multicenter, double-blind, parallel-group trial, 546 patients with type 2 diabetes who received metformin (≥1500 mg/day) and had inadequate glycemic control for at least 8 weeks prior to the study enrollment were randomly assigned to receive 2.5 mg, 5 mg, or 10 mg DAPA or placebo. The primary outcome of the study was change from baseline in HbA1c at 24 weeks.
• After 24 weeks, mean change in baseline HbA1c was -0.67 for 2.5 mg DAPA (P=0.0002), -0.7 for 5 mg DAPA (P<0.0001), and -0.87 of 10 mg DAPA (P<0.0001) compared to -0.30 for placebo (n=134). More patients achieved HbA1c ≤7% on 10 mg DAPA vs placebo (40% vs 25.9%, respectively; P=.0062). Reduction in body weight was more prominent in patients treated with DAPA vs placebo (2.5 mg DAPA: -2.2 kg, P<0.0001; 5 mg DAPA: -3.0 kg, P<0.0001; 10 mg DAPA: -2.9 kg, P<0001; vs placebo:-0.9 kg). 18.1%, 19.5%, and 22.1% of patients lost more than 5% of total body weight in the 2.5 mg, 5 mg, and 10 mg groups respectively.
• DAPA was well tolerated by patients. Symptoms of hypoglycemia occurred in similar proportions of patients in the DAPA groups (2%-4%) and in the placebo group (3%). Urinary tract infection (UTI) was not more prominent in patients in different DAPA groups than placebo (2.5 mg DAPA: 4% or 6 patients; 5 mg DAPA: 7% or 10 patients; 10 mg DAPA: 8% or 11 patients; vs placebo: 8% or 11 patients). Genital infection was higher in the DAPA groups than in placebo (2.5 mg DAPA: 8% or 11 patients; 5 mg DAPA: 13% or 18 patients; 10 mg DAPA: 9% or 12 patients; vs placebo: 5% or 7 patients). Seventeen patients experienced serious adverse events, including rotator cuff syndrome, chest pain, atrial fibrillation, and myocardial infarction. These cardiovascular events were observed in 4 patients taking 2.5 mg DAPA, 4 patients taking 5 mg DAPA, 4 patients taking 10 mg DAPA, and 5 patients in the placebo group.1
Diabetes Care Study2
• The study published in Diabetes Care examined the role of DAPA monotherapy in treatment-naïve patients with type 2 diabetes. This was a 24-week, parallel-group, double-blind, placebo-controlled phase III trial. A total of 485 patients with type 2 diabetes with baseline HbA1c 7.0%-10% were randomized to 1 of the 7 groups to receive once-daily placebo or once-daily 2.5 mg, 5 mg, or 10 mg of DAPA, receiving the drug either in the morning (main cohort) or at night (exploratory cohort) only. Patients with high baseline HbA1c 10%-12% (n=73) were randomly assigned 1:1 to receive a morning 5 mg or 10 mg DAPA dose. The primary endpoint of the study was change from baseline HbA1c at 24 weeks.2
• In the main morning dose cohort, at 24 weeks, the mean change in baseline HbA1c was -0.23% with placebo; -0.58% with 2.5 mg of DAPA; -0.77% with 5 mg of DAPA (P=0.0005 vs placebo); and -0.89% with 10 mg of DAPA (P<0.0001 vs placebo). In the main night dose cohort, at 24 weeks, the mean change in HbA1c was -0.83% in 2.5 mg of DAPA; -0.79% in 5 mg of DAPA; and -0.79% in 10 mg of DAPA. In the “high” HbA1c (HbA1c ≤10.1) morning dose group, the mean change in HbA1c at 24 weeks was -2.88% in 5 mg of DAPA and -2.66 mg in 10 mg of DAPA.2
• Weight change in the main cohort was -2.2 kg with placebo (n=75); -3.3 kg with 2.5 mg of DAPA (n=65); -2.8 kg with 5 mg of DAPA (n=64); and -3.2 kg with 10 mg of DAPA (n=70). Surprisingly, greater weight reduction was seen with the same doses of dapagliflozin when taken in the evening: -3.8 kg with 2.5 mg of DAPA (n=67); -3.6 kg with 5 mg of DAPA (n=68), and -3.1 kg with 10 mg of DAPA (n=76).2
• Hypoglycemia was observed in 2.7% of patients in the placebo group; 1.5%, 0%, and 2.9% of patients in the 2.5 mg, 5 mg, and 10 mg DAPA morning dose cohorts, respectively; 1.5%, 0%, and 1.3% of patients in the 2.5 mg, 5 mg, and 10 mg DAPA night dose cohorts, respectively; and 2.9% and 0 of patients in the “high” HbA1c (HbA1c ≤10.1), morning dose groups. As expected, genital and urinary tract infections (UTIs) were noted more frequently in the DAPA groups compared to placebo. Events suggestive of genital infections were observed in 1.3% of patients in the placebo group; 7.7%, 7.8%, and 12.9% of patients in the 2.5 mg, 5 mg, and 10 mg DAPA morning dose cohorts, respectively; 9.0%, 4.4%, and 2.2% of patients in the 2.5 mg, 5 mg, and 10 mg DAPA night dose cohorts, respectively; and 5.9% and 17.9% of patients in the “high” HbA1c (HbA1c ≤10.1), morning dose groups. Events suggestive of UTI were observed in 4.0% of patients in the placebo group; 4.6%, 12.5%, and 5.7% of patients in the 2.5 mg, 5 mg, and 10 mg DAPA morning dose cohorts, respectively; 7.5%, 11.8%, and 6.6% of patients in the 2.5 mg, 5 mg, and 10 mg DAPA night dose cohorts, respectively; and 8.8% and 15.4% of patients in the “high” HbA1c (HbA1c ≤10.1) morning dose groups.2
• It appears that DAPA significantly lowers HbA1c and reduces weight in patients with type 2 diabetes. In addition, there are no major events of hypoglycemia observed with the drug. Finally, increased events of UTI and genital infection can be noted with DAPA, as with any SGLT2 inhibitor.
• Please see other DAPA preclinical and phase II clinical studies results in the slide deck. [slides 12-17]
References:
6. How do SGLT2 inhibitors address unmet needs in diabetes care?
• SGLT2 inhibitors work by: [slide 18]
-Inhibiting glucose reabsorption in the renal proximal tubule, resulting in glucosuria. Glucosuria leads to a decline in plasma glucose, reversing glucotoxicity.
-Complementing the action of other anti-diabetic agents, including insulin.
• SGLT2 inhibition may provide solutions to these unresolved issues in the following ways:1 [slide 19]
-Weight management: SGLT2 inhibitors promote weight loss by increasing glucosuria, which drains glucose from the bloodstream and stimulates breakdown of fat cells for fuel.
-Multiple defects of type 2 diabetes: Increased renal glucose reabsorption has recently been identified in type 2 diabetes. SGLT2 inhibitors correct this novel defect.
-Adverse effects of therapy: Among adverse events, hypoglycemia may pose the greatest barrier to optimal glycemic control because of acute safety concerns as well as long-term risk of hypoglycemia unawareness (which develops from repeated episodes of hypoglycemia). Because their function is completely independent of insulin, SGLT2 inhibitors do not increase the risk of hypoglycemia.
-Hyperglycemia: Treating to HbA1c targets ≤7% in the years immediately following diabetes diagnosis is associated with long-term reduction in the risk of diabetic complications. The unique mechanism of action of SGLT2 inhibitors complements those of other antidiabetic agents, making them extremely suitable for combination therapy.
-CVD risk (lipid and hypertension control): The improvements in weight and glycemia achieved with SGLT2 inhibition will support treatments that more directly reduce cardiovascular risk (eg, statins and antihypertensive agents).
-SGLT2 inhibitors are suitable for patients with type 1 and type 2 diabetes.
Reference:
This programme is supported by an educational grand from Bristol-Myers Squibb and AstraZeneca.
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