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NephMadness 2017: Diabetic Nephropathy Region
- 1. Moh’d Sharshir, MD Nephrology Fellow
- 2. NephMadness 2017: Diabetic Nephropathy Region
- 3. ACEi and ARB for Nephroprotection • ACE inhibitors and angiotensin receptor blockers have been the reigning champs in diabetic nephropathy for over 2 decades. • The critical role of the renin angiotensin system (RAS) in diabetic nephropathy has been extensively studied and well-summarized in many reviews.
- 4. ACEi and ARB for Nephroprotection • Overall, since the importance of RAS inhibition in diabetic nephropathy was discovered there appears to be a slowing of the incidence of ESRD from diabetic nephropathy.
- 5. ACEi and ARB for Nephroprotection
- 6. ACEi and ARB for Nephroprotection • In type 1 DM: angiotensin-converting enzyme (ACE) inhibitors have been studied in both early and late in the course of diabetic nephropathy. • Early in the course of diabetic kidney disease, when moderately increased albuminuria is the only clinical sign of a problem, captopril decreased the rate of albuminuria excretion as well as the risk of progression to overt diabetic nephropathy when compared to placebo. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. The Microalbuminuria Captopril Study Group.Diabetologia. 1996 May;39(5):587-93
- 7. ACEi and ARB for Nephroprotection • The Collaborative Study Group found that in subjects who already had overt diabetic nephropathy, treatment with captopril: Slowed the rate of GFR decline. Decreased the risk of ESRD. and in some cases led to long term remission of nephrotic syndrome and preservation of kidney function.
- 8. ACEi and ARB for Nephroprotection
- 9. ACEi and ARB for Nephroprotection • In type 2 DM: angiotensin receptor blockers (ARBs) have been shown to have clear renoprotective effects in overt diabetic nephropathy.
- 10. ACEi and ARB for Nephroprotection • IDNT randomized 1715 subjects with hypertension and overt nephropathy to irbesartan 300 mg/day, amlodipine 10 mg/day, and placebo. • At a mean follow up of 2.6 years. • The group treated with irbesartan had a significantly lower risk of doubling serum creatinine or progression to ESRD than the other groups.
- 11. ACEi and ARB for Nephroprotection • The RENAAL trial compared losartan to placebo in 1513 subjects with overt diabetic nephropathy. • Treatment with losartan reduced the risk of doubling of serum creatinine and progression to ESRD at a mean follow up of 3.4 years.
- 12. ACEi and ARB for Nephroprotection
- 13. ACEi and ARB for Nephroprotection • ACE inhibitors have also shown benefits in type 2 DM. • The ADVANCE trial ( Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation study). • Compared the combination of perindopril-indapamide to placebo in over 11,000 subjects with type 2 DM.
- 14. ACEi and ARB for Nephroprotection
- 15. ACEi and ARB for Nephroprotection • The DETAIL trial compared the ACE inhibitor Enalapril to the ARB Telmisartan in subjects with early diabetic nephropathy. • Found that Telmisartan was not inferior to Enalapril in providing renoprotection.
- 16. Conclusions: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes.
- 17. ACEi and ARB for Nephroprotection • VA Nephron-D: Trial where the combination of treatment with losartan and lisinopril led to a significant increase in adverse events and no improvement in mortality or slowing of CKD progression when compared to treatment with losartan alone.
- 19. ACEi and ARB for Nephroprotection • ACEi or ARB are clearly indicated in the treatment of diabetic nephropathy, but are not always tolerated due to side effects of hyperkalemia or hypotension.
- 20. Glycemic Control
- 21. Glycemic Control • In diabetes there is nothing as fundamental than hyperglycemia. • If one does not have DM, one cannot develop diabetic nephropathy (even though nodular glomerulosclerosis that looks like diabetic nephropathy that has been found in metabolic syndrome without overt diabetes). • While type 1 DM and type 2 DM have different pathogenesis, the end result of both is hyperglycemia.
- 22. Glycemic Control • Hyperglycemia has been shown to activate the intrarenal RAS system which plays an important role in the development of diabetic nephropathy. • Logically, it should follow that good glycemic control is a critical part of the treatment of diabetic nephropathy.
- 23. Glycemic Control • The landmark DCCT definitively showed the importance of early glycemic control in subjects with type 1 DM. • DCCT randomized subjects to a target A1C of 7% vs 9% and included 1,365 subjects with normal albumin excretion at baseline. • The tight glycemic control group had a significant reduction in the onset of albuminuria.
- 25. Glycemic Control • The long term follow up of DCCT, the EDIC study, found that the renoprotective effects of a lower glycemic target were sustained long term. • Eight years after DCCT was completed, subjects initially assigned to the intensive glycemic control group continued to have a lower risk of development of albuminuria.
- 27. Glycemic Control • 16 years after DCCT was completed they were less likely to have developed impaired renal function. • After the completion of the study all patients had the same therapy and the hemoglobin A1c of the two groups were indistinguishable (7.9 ±1.1 for the intensive therapy group and 8.0 ±1.0 in the conventional therapy group).
- 28. Glycemic Control
- 29. Glycemic Control • Patients with type 1 DM who already have moderately increased albuminuria also appear to benefit from intensive glycemic control, although the data is less definitive given its small size. • The 73 subjects with moderately increased albuminuria at baseline in the DCCT had similar benefits to those without albuminuria at baseline.
- 30. Glycemic Control • A meta-analysis of smaller, earlier trials also suggests benefits to intensive glycemic control in the setting of already established, moderately increased albuminuria. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes, Lancet. 1993 May 22;341(8856):1306-9
- 31. Glycemic Control • Once severely increased albuminuria has developed in type 1 DM, most of the data comes in the setting of multiple small studies of subjects who have become normoglycemic after receiving pancreas transplants. • Pancreas transplant led to a reduction in albuminuria in one study at a year post transplant, and in another study led to improvement of biopsy findings in diabetic nephropathy at 10 years, but not at 5 years post- pancreas-transplant.
- 33. Glycemic Control • In type 2 DM the data is less concrete. • The UKPDS trial found that subjects with newly diagnosed type 2 DM who were treated with intensive glucose control did not have improved renal outcomes. ------> Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.
- 34. Glycemic Control • The ADVANCE trial found a reduced risk of albuminuria, but no reduction of the risk of doubling of serum creatinine in subjects who had type 2 DM for an average of 8 years.
- 35. Glycemic Control • VADT: on the other hand, found a benefit only in tight glycemic control for the risk of progression of albuminuria from moderately increased to severely increased.
- 36. Glycemic Control • Then there is the ACCORD trial, which was stopped early due to increased deaths (including increased cardiovascular deaths) in the intensive treatment arm.
- 37. Sodium Glucose Lumen Transporter 2 (SGLT2) inhibitors
- 38. Sodium Glucose Lumen Transporter 2 (SGLT2) inhibitors • 2013 was also the year canagliflozin (Invokana) was approved for sale in the United States, becoming the first of a new wave of SGLT2 inhibitors for the treatment of type 2 diabetes mellitus (DM). • SGLT2 inhibitors have the beneficial effects of promoting weight loss and avoiding hypoglycemia and hyperinsulinemia. The currently available SGLT 2 inhibitors in the U.S. are:
- 39. Sodium Glucose Lumen Transporter 2 (SGLT2) inhibitors • SGLT2 reabsorbs Na+ and glucose in the proximal convoluted tubule. • SGLT2 inhibitors inhibit this transporter resulting in glycosuria, decreased serum glucose, and increased sodium delivery to the macula densa.
- 40. Sodium Glucose Lumen Transporter 2 (SGLT2) inhibitors • SGLT2 inhibitors may slow the progression of diabetic nephropathy by decreasing hyperfiltration and by decreasing the inflammatory and fibrotic response to hyperglycemia. This is supported by data from animal and in vivo models. • In vitro studies show that empagliflozin attenuates the inflammatory and fibrotic effects of high glucose including expression of toll-like receptor-4, nuclear deoxyribonucleic acid binding to NF-κB and activator protein 1, collagen IV expression, and interleukin-6 secretion in human proximal tubule cells.
- 41. Sodium Glucose Lumen Transporter 2 (SGLT2) inhibitors • The recently completed EMPA-REG OUTCOME trial compared empagliflozin to placebo in subjects with type 2 DM with a history of CVD and a eGFR≥30 ml/min/1.73 m2.
- 42. Glucagon-like Peptide 1 (GLP-1) Receptor Agonists
- 43. Glucagon-like Peptide 1 (GLP-1) Receptor Agonists • GLP-1 is an incretin produced in the L-cells of the small intestine in response to ingestion of food. • GLP-1 lowers glucose through its actions on the GLP-1 receptor by stimulating pancreatic beta-cells to secrete insulin, which in turn reduces plasma glucagon, slows gastric emptying, and suppresses appetite.
- 44. Glucagon-like Peptide 1 (GLP-1) Receptor Agonists • The LEADER trial is a large, recently completed study assessing cardiovascular outcomes in subjects with type 2 DM treated with liraglutide vs placebo. • CONCLUSIONS: -----> The rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. -----> Subjects treated with liraglutide had a decreased risk of new onset macroalbuminuria, although time to persistent doubling of creatinine, ESRD, and death due to renal disease were similar in both groups.
- 45. THANK YOU……..
Hinweis der Redaktion
- In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 or 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p = 0.004) with a risk reduction of 69.2% (95% confidence interval (CI):31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1-83.6%], p = 0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1-26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [-18.6-0.4%] per year in the captopril-treated group (p = 0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (-6.4 [-10.2- -2.5] vs -1.4 [-5.3-2.6] ml.min-1.1.73m-2, p = 0.07). Baseline albumin excretion rate (p < 0.0001) and glycated haemoglobin (p = 0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p = 0.02) and serum cholesterol level (p = 0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects.
- The active therapy group had lower risk of new onset of moderately increased albuminuria, less worsening of moderately increased albuminuria and less new onset or worsening of severely increased albuminuria.
- Effect of Randomized Treatment on Renal Outcomes A total of 1243 (22.3%) patients assigned active treatment and 1500 (26.9%) patients assigned placebo developed the composite renal outcome of new-onset microalbuminuria, new-onset nephropathy, doubling of serum creatinine above 200 μmol/L, or end-stage kidney disease (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.73 to 0.85; P < 0.0001; Table 4). On this basis, one such event would be prevented among every 20 (95% CI 15 to 30) patients assigned active treatment for a 5-yr period. Active treatment also reduced the risk for progression of albuminuria among patients who had either normo- or microalbuminuria at baseline (HR 0.78; 95% CI 0.72 to 0.84; P < 0.0001) and the risk for new-onset microalbuminuria in patients with normoalbuminuria at baseline (HR 0.79; 95% CI 0.73 to 0.86; P < 0.0001; Table 4). A total of 286 patients developed overt nephropathy, as defined by macroalbuminuria, during follow-up: 114 (2.1%) patients assigned active treatment and 163 (3.0%) patients assigned placebo (HR 0.69; 95% CI 0.54 to 0.88; P = 0.003). The relative risk reductions were of comparable magnitude in patients with normoalbuminuria or microalbuminuria at baseline (P = 0.3 for heterogeneity). Regression of albuminuria was observed in more than half of all patients with micro- or macroalbuminuria at baseline, most of whom regressed to normoalbuminuria (Table 4). Proportionally more patients assigned active than assigned placebo treatment achieved restoration of normoalbuminuria (P = 0.006), with approximately similar absolute UACR declines according to treatment assignment (patients with microalbuminuria: from 55.0 to 10.6 μg/mg [active treatment] versus from 54.2 to 11.0 μg/mg [placebo]; patients with macroalbuminuria: from 490.6 to 9.0 μg/mg [active treatment] versus from 465.9 to 13.4 μg/mg [placebo]). Active treatment reduced eGFR to a greater extent than placebo (P < 0.0001) in the first 4 mo (Figure 1), but annual declines in eGFR were similar in the active and placebo treatment groups thereafter (0.5 versus 0.6 ml/min per 1.73 m2). This was true for patients with normoalbuminuria (0.1 versus 0.0 ml/min per 1.73 m2; P = 0.69), patients with microalbuminuria (1.1 versus 1.4 ml/min per 1.73 m2; P = 0.45), and patients with macroalbuminuria (1.5 versus 2.7 ml/min per 1.73 m2; P = 0.34). Both end-stage kidney disease and doubling of serum creatinine to a level >200 μmol/L were infrequently observed in ADVANCE, and the occurrence of these two outcomes was not significantly different between randomly assigned groups (Table 4).
- In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II–receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of end-stage renal disease and cardiovascular events; and the rate of death from all causes.
- Background Combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m2 of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥30 ml per minute per 1.73 m2 if the initial estimated GFR was ≥60 ml per minute per 1.73 m2 or a decline of ≥50% if the initial estimated GFR was
- Will this be the year that the reigning champ in diabetic nephropathy cruises through the Filtered Four to sit at the top of the dance, or will the king be dethroned?
- BACKGROUND Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. Full Text of Background... METHODS A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. Full Text of Methods... RESULTS In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of ≥ 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of ≥ 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Full Text of Results... CONCLUSIONS Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
- BACKGROUND Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. Full Text of Background... METHODS A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. Full Text of Methods... RESULTS In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of ≥ 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of ≥ 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Full Text of Results... CONCLUSIONS Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
- Patients with type 1 DM who already have moderately increased albuminuria also appear to benefit from intensive glycemic control, although the data is less definitive given its small size. The 73 subjects with moderately increased albuminuria at baseline in the DCCT had similar benefits to those without albuminuria at baseline. A meta-analysis of smaller, earlier trials also suggests benefits to intensive glycemic control in the setting of already established, moderately increased albuminuria. Once severely increased albuminuria has developed in type 1 DM, most of the data comes in the setting of multiple small studies of subjects who have become normoglycemic after receiving pancreas transplants. Pancreas transplant led to a reduction in albuminuria in one study at a year post transplant, and in another study led to improvement of biopsy findings in diabetic nephropathy at 10 years, but not at 5 years post-pancreas-transplant.
- Tight blood glucose control has been speculated to reduce late complications in insulin-dependent diabetics but results from individual studies have been inconsistent. We have done a meta-analysis of sixteen randomised trials of intensive therapy to estimate its impact on the progression of diabetic retinopathy and nephropathy and the risks of severe side-effects. In the intensive therapy group, the risk of retinopathy progression was insignificantly higher after 6-12 months of intensive control (odds ratio [OR] 2.11). After more than two years of intensive therapy the risk of retinopathy progression was lower (OR 0.49 [95% confidence interval 0.28-0.85], p = 0.011). The risk of nephropathy progression was also decreased significantly (OR 0.34 [0.20-0.58], p < 0.001). The incidence of severe hypoglycaemia increased by 9.1 episodes per 100 person-years (95% Cl -1.4 to +19.6) in the intensively treated patients. The incidence of diabetic ketoacidosis increased by 12.6 episodes per 100 person-years (95% Cl, 8.7-16.5) in the patients on continuous subcutaneous insulin infusion. Long-term intensive blood glucose control significantly reduces the risk of diabetic retinopathy and nephropathy progression but long-term continuous subcutaneous insulin infusion was associated with an increased incidence of diabetic ketoacidosis, and intensive therapy may cause more severe hypoglycaemic reactions.
- Figure 2—Urinary protein excretion (A, C, E) and creatinine clearance (B, D, F) in pancreas transplant alone type 1 diabetic patients at baseline (pre-tx) and after 1 year (post-tx), subdivided in normoalbuminuric (A and B), microalbuminuric (C and D), and macroproteinuric (E and F) according to urinary protein at baseline. Full circles indicate albumin excretion rate before and after pancreas transplant alone in four microalbuminuric (C) and three macroalbuminuric (E) patients, and the respective creatinine clearance values (D and F). Figure 1. Thickness of the Glomerular Basement Membrane, Thickness of the Tubular Basement Membrane, Mesangial Fractional Volume, and Mesangial-Matrix Fractional Volume at Base Line and 5 and 10 Years after Pancreas Transplantation. The mesangial fractional volume is the proportion of the glomerulus occupied by the mesangium; the mesangial-matrix fractional volume is the proportion of the glomerulus occupied by mesangial matrix. The shaded areas represent the normal ranges obtained in the 66 age- and sex-matched normal controls (means ±2 SD). Data for individual patients are connected by lines.
- BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)
- Background In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. Methods We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. Results After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P
- Background The effects of intensive glucose control on cardiovascular events in patients with longstanding type 2 diabetes mellitus remain uncertain. Methods We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. Results The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group. Conclusions Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications, with the exception of progression of albuminuria (P=0.01).
- Design—ACCORD is a parallel group, randomized trial designed to investigate whether intensive glycemic therapy with a target HbA1c of 291.7 micromol/L, or retinal photocoagulation or vitrectomy, and 2) these plus peripheral neuropathy. Thirteen prespecified secondary measures of kidney, eye, and peripheral nerve function were also evaluated. Randomization was performed at clinical sites using a central randomization routine available on the study website. Both investigators and participants were unmasked to treatment arm assignment. Results—A total of 10,251 participants were randomized (5,128 intensive and 5,123 standard) between January, 2001 and October, 2005. This analysis includes 10,234 patients (5,107 intensive and 5,108 standard). Intensive therapy was stopped before study end due to increased mortality, and patients were transitioned to standard therapy. Outcomes are reported at transition and at study end. At transition, the first composite outcome occurred in 443/5107 and 444/5108 participants in the intensive and standard arms, respectively (p= 0.99), and the second outcome in 1591/5107 and 1659/5108 participants in intensive and standard arms (p=0.20). Results were similar at study end. Secondary measures at study end favoring intensive therapy (p2.0 on the Michigan Neuropathy Screening Instrument, loss of ankle jerk and light touch. Conclusions—Intensive glycemic treatment did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of macroalbuminuria and some measures of eye complications and neuropathy. These benefits must be weighed against the increase in total and CVD-related mortality, increased weight gain, and higher risk for severe hypoglycemia.
- This study found that treatment with empagliflozin reduced the risk of the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarctions, and nonfatal strokes. Analysis of prespecified secondary endpoints found that treatment with empagliflozin reduced the risk of progression to macroalbuminuria, risk of incident nephropathy, and doubling of serum creatinine.
- he exact location of GLP-1 receptors in human kidneys is unclear. GLP-1 receptors have been found in rodent and porcine proximal tubular cells. In human kidneys they have only been found in hilar and intralobular arteries, but there is some methodological concern that currently available methods for detecting GLP-1 receptors are inaccurate. GLP-1 infused in obese men led to a significant increase in urinary sodium excretion, a decrease in proton excretion, and a decrease in the glomerular filtration rate suggesting an action at the level of the proximal tubule, perhaps at the level of the Na+/H+ exchanger. Rats with early type 1 diabetic nephropathy treated with the GLP-1 receptor exendin-4 had a decrease in albuminuria, glomerular hyperfiltration and a decrease in the release of pro-inflammatory cytokines. It is through these effects that GLP-1 agonists are hypothesized to have renoprotective effects in diabetic nephropathy.