Update on Diabetic Nephropathy: Core Curriculum 2018

Diabetic kidney disease and diabetic nephropathy are the leading cause of end-stage kidney disease in the United States and most developed countries. Diabetes accounts for 30% to 50% of the incident cases of end-stage kidney disease in the United States. Although this represents a significant public health concern, it is important to note that only 30% to 40% of patients with diabetes develop diabetic nephropathy. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin-angiotensin system (RAS). Recommendations for therapy include targeting a hemoglobin A1c concentration < 7% and blood pressure < 140/90 mm Hg with therapy anchored around the use of a RAS-blocking agent. The single best evidence-based therapy for diabetic nephropathy is therapy with a RAS-blocking medication. This Core Curriculum outlines and discusses in detail the epidemiology, pathophysiology, diagnosis, and management of diabetic nephropathy. Diabetic kidney disease and diabetic nephropathy are the leading cause of end-stage kidney disease in the United States and most developed countries. Diabetes accounts for 30% to 50% of the incident cases of end-stage kidney disease in the United States. Although this represents a significant public health concern, it is important to note that only 30% to 40% of patients with diabetes develop diabetic nephropathy. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin-angiotensin system (RAS). Recommendations for therapy include targeting a hemoglobin A1c concentration < 7% and blood pressure < 140/90 mm Hg with therapy anchored around the use of a RAS-blocking agent. The single best evidence-based therapy for diabetic nephropathy is therapy with a RAS-blocking medication. This Core Curriculum outlines and discusses in detail the epidemiology, pathophysiology, diagnosis, and management of diabetic nephropathy. FEATURE EDITOR:Asghar RastegarADVISORY BOARD:Ursula C. BrewsterMichael ChoiAnn O’HareManoocher SoleimaniThe Core Curriculum aims to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. FEATURE EDITOR: Asghar Rastegar ADVISORY BOARD: Ursula C. Brewster Michael Choi Ann O’Hare Manoocher Soleimani The Core Curriculum aims to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. Diabetic kidney disease occurs in patients with diabetes mellitus (DM) and reduced kidney function that can be from many diverse causes, including hypertensive nephrosclerosis and unresolved acute kidney failure. Diabetic nephropathy is a diagnosis that refers to specific pathologic structural and functional changes seen in the kidneys of patients with DM (both type 1 and type 2 [T1/T2DM]) that result from the effects of DM on the kidney. These changes result in a clinical presentation that is characterized by proteinuria, hypertension, and progressive reductions in kidney function. The risk for the development of diabetic nephropathy has a genetic component that is likely polygenetic. The prevalence of diabetic nephropathy varies among racial and ethnic groups such that African Americans (potentially by APOL1 gene variants), Native Americans, and Mexican Americans have increased risk as compared with European Americans. Although an argument can be made that barriers to care contribute to this discrepancy in prevalence, it is likely not the sole factor, such that genetic differences in these populations must also play a role. Familial studies have demonstrated clustering of diabetic nephropathy. Patients with DM with a first-degree relative with T1/T2DM and diabetic nephropathy have substantially more risk for developing diabetic nephropathy than those without an affected relative. This familial clustering has also been well documented in the Pima Indian population. Ongoing research is attempting to identify specific genetic factors and genes associated with the development of diabetic nephropathy. Although several candidate genes, including glucose transporter 2, transforming growth factor β, and endothelial nitric oxide synthase, have been identified, isolating a definitive causal pathway has proved to be elusive because there is no simple Mendelian inheritance and the interplay of several genes is likely involved and may differ between populations. ►Family Investigation of Nephropathy and Diabetes Research Group. Genetic determinants of diabetic nephropathy: the Family Investigation of Nephropathy and Diabetes (FIND). J Am Soc Nephrol. 2003;14(suppl 2):S202-S204.►Freedman BI, Bostrom M, Daeihagh P, Bowden DW. Genetic factors in diabetic nephropathy. Clin J Am Soc Nephrol. 2007;2:1306-1316.►Nelson RG, Knowler WC, Pettitt DJ, Saad MF, Bennett PH. Diabetic kidney disease in Pima Indians. Diabetes Care. 1993;16:335-341.►Seaquist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med. 1989;320:1161-1165. The pathophysiology leading to the development of diabetic nephropathy and resultant end-stage kidney disease follows from the diabetic milieu leading to the generation and circulation of advanced glycation end products, elaboration of growth factors, and hemodynamic and hormonal changes. These lead to the release of reactive oxygen species and inflammatory mediators. Collectively, these changes result in glomerular hyperfiltration, glomerular hypertension, renal hypertrophy, and altered glomerular composition, which is manifested clinically as albuminuria and hypertension. Pathologically, the kidneys undergo several changes, including deposition (in primarily the mesangium) of extracellular matrix, glomerular basement membrane thickening, proliferative changes, and tubular atrophy, ultimately resulting in interstitial fibrosis and glomerulosclerosis (the final common pathway of many kidney diseases). A schema depicting this process is shown in Figure 1. With the onset of DM, kidney size and weight increase by an average of 15%, and this size increase remains even after progressive reductions in kidney function occur. An examination of kidney tissue reveals thickening of the glomerular basement membrane and expansion of the mesangium. The classic pathologic lesion of diabetic nephropathy is nodular in nature and was first described by Kimmelstiel and Wilson in 1936. The nodules are typically acellular and positive by periodic acid–Schiff stain. Although these nodules are pathognomonic for diabetic nephropathy, they are reported in only 10% to 50% of biopsy specimens from patients with T1/T2DM. Far more common is the diffuse glomerular lesion that is characterized by diffuse mesangial matrix expansion. Arteriolar lesions involving both the afferent and efferent vessels are also prominent and common in DM. Over time, hyaline material replaces the entire vessel wall structure and this is highly specific for DM. Examples of these lesions are shown in Figure 2. It is important to note that lesions similar to both the nodular and diffuse varieties can be seen in other disease states, such as membranoproliferative glomerulonephritis, amyloidosis, and light-chain deposition disease. Specific stains, immunofluorescence staining, and electron microscopy, as well as the clinical history of the patient, will elucidate the specific diagnosis. ►Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia. 1996;39:1569-1576.►Fioretto P, Steffes MW, Sutherland DE, Mauer M. Sequential renal biopsies in insulin-dependent diabetic patients: structural factors associated with clinical progression. Kidney Int. 1995;48:1929-1935.►Schwartz MM, Lewis EJ, Leonard-Martin T, Lewis JB, Batlle D. Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy. The Collaborative Study Group. Nephrol Dial Transplant. 1998;13:2547-2552. ★ ESSENTIAL READING Case 1: A 52-year-old woman with T2DM diagnosed 1 year ago is referred to you for evaluation of proteinuria noted first 3 months ago. Family history is positive for diabetic nephropathy. Physical examination shows blood pressure (BP) of 140/95 mm Hg and normal fundal examination findings and is otherwise unremarkable. Laboratory studies show serum creatinine concentration of 0.9 mg/dL, and urinalysis shows protein (3+) with unremarkable sediment.Question 1: Which of the following statements is correct?a)The finding of proteinuria 6 months after the diagnosis of T2DM is strongly against the diagnosis of diabetic nephropathy.b)Normal fundal examination findings should strongly suggest an alternative diagnosis.c)The most likely diagnosis is diabetic nephropathy.d)Increases in BP in the majority of patients with diabetic nephropathy are seen only after decline in kidney function.For the answer to the question, see the following text. Case 1: A 52-year-old woman with T2DM diagnosed 1 year ago is referred to you for evaluation of proteinuria noted first 3 months ago. Family history is positive for diabetic nephropathy. Physical examination shows blood pressure (BP) of 140/95 mm Hg and normal fundal examination findings and is otherwise unremarkable. Laboratory studies show serum creatinine concentration of 0.9 mg/dL, and urinalysis shows protein (3+) with unremarkable sediment. Question 1: Which of the following statements is correct?a)The finding of proteinuria 6 months after the diagnosis of T2DM is strongly against the diagnosis of diabetic nephropathy.b)Normal fundal examination findings should strongly suggest an alternative diagnosis.c)The most likely diagnosis is diabetic nephropathy.d)Increases in BP in the majority of patients with diabetic nephropathy are seen only after decline in kidney function. For the answer to the question, see the following text. The natural history of diabetic nephropathy in patients with T1DM was initially characterized in the late 1970s by Kussman et al by examining death records of patients with juvenile-onset DM who were classified as having died of kidney failure. This analysis resulted in an understanding of the true untreated natural history of diabetic nephropathy due to T1DM as it was before the advent of therapy for this complication of DM. Based on this study, proteinuria appears 11 to 23 years after the T1DM diagnosis, serum creatinine concentration begins to increase after 13 to 25 years, and end-stage kidney disease develops after 18 to 30 years. With the subsequent development of more sensitive assays to detect urinary albumin excretion, small amounts of albumin in the urine (microalbuminuria; 30-300 mg/g creatinine) were noted to precede the development of overt proteinuria (macroalbuminuria; >300 mg/g creatinine) in most patients, occurring 5 to 10 years after the diagnosis of DM. Presently, microalbuminuria and macroalbuminuria are referred to as A2 and A3, respectively, by the KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease (CKD) guideline. The natural history of diabetic nephropathy in patients in longitudinally studied populations with T2DM is essentially identical to that in patients with T1DM. However, outside a study situation, the timing of DM onset in patients with T2DM is difficult to assess. Therefore, a patient may even present with proteinuria and on kidney biopsy have diabetic nephropathy before T2DM is diagnosed. Another important difference in the natural history of patients with T1 versus T2DM is that the major macrovascular complication, namely cardiac disease and death due to cardiac disease, can occur at any point along the course of a patient with T2DM from the onset of DM and early diabetic nephropathy, whereas the elevated risk for cardiovascular disease is not apparent until advanced kidney disease has developed in patients with T1DM. The classic study by Kussman et al in patients with T1DM allows one to picture a timeline of kidney disease progression that starts with microalbuminuria and proceeds sequentially through stages of overt proteinuria, kidney function decline, and ultimately end-stage kidney disease. Multiple studies of diabetic nephropathy progression over the years have confirmed this timeline and the critical role of proteinuria assessment both as a diagnostic criterion for the presence of diabetic nephropathy and for the assessment of disease severity and likelihood of progression. The single biggest predictor of kidney function deterioration and diabetic nephropathy progression is proteinuria (Fig 3). When the loss of kidney function has begun, as evidenced by an increasing serum creatinine concentration or a declining estimated glomerular filtration rate (eGFR), the patient with diabetic nephropathy begins a continual decline toward chronic kidney failure and renal replacement therapy or death. Based on studies of untreated patients with T1DM and Pima Indians with T2DM, the rate of GFR loss can be on the order of 7 to 12 mL/min/1.73 m2 per year. Treatment with renin-angiotensin system (RAS) inhibitors has reduced this rate of decline to 3 to 6 mL/min/1.73 m2 per year (data discussed in detail later in this article). Based on analysis of cohorts of patients with T2DM including those with no nephropathy, early nephropathy, and late nephropathy conducted in the 1980s and 1990s, cardiovascular death was thought to be more frequent than progression of kidney disease to end-stage kidney disease. However, a more recent analysis of participants in 2 large multinational renal clinical trials in patients with established advanced diabetic nephropathy and proteinuria, the risk for end-stage kidney disease was significantly more common than cardiovascular death (incidence rate ratio [IRR], 4.92) and all-cause mortality (IRR, 2.61). It may be that multiple therapies aimed at reducing the complications of DM or cardiovascular disease have sufficiently reduced the rate of macrovascular complications such that more patients progress to end-stage kidney disease. Recent reports have noted that up to 25% of patients with T2DM and diminished kidney function have little or no proteinuria despite having biopsy-proven diabetic nephropathy. The cause of this change in profile of diabetic nephropathy is unclear. This phenomenon may be due to the impact of long-term RAS-inhibitor therapy, underdiagnosed unresolved acute kidney injury, or other factors impacting on the traditional natural history described earlier. The patient presented here with a strong family history and proteinuria most likely has diabetic nephropathy. The timing of proteinuria is variable in T2DM and can be noted at the time of the diagnosis. Hypertension is a common finding in these patients, often preceding the increase in serum creatinine concentration. Retinopathy as noted is seen in only two-thirds of these patients. Therefore, the correct answer to Question 1 is (c). ►Dwyer JP, Lewis JB. Nonproteinuric diabetic nephropathy: when diabetics don't read the textbook. Med Clin North Am. 2013;97:53-58. ★ ESSENTIAL READING►Hovind P, Tarnow L, Rossing P, et al. Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ. 2004;328:1105-1109.►Kussman MJ, Goldstein H, Gleason RE. The clinical course of diabetic nephropathy. JAMA. 1976;236:1861-1863. ★ ESSENTIAL READING►Nelson RG, Bennett PH, Beck GJ, et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med. 1996;335:1636-1642.►Packham DK, Alves TP, Dwyer JP, et al. Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database. Am J Kidney Dis. 2012;59:75-83. ★ ESSENTIAL READING The approach to a patient with DM and evidence of kidney disease (eg, albuminuria, hematuria, or decreased eGFR) must center on the determination of whether the patient’s kidney disease is diabetic nephropathy or another kidney disease. The natural history and progression timeline discussed earlier will greatly aid the clinician in determining the likelihood that a given patient’s disease is diabetic nephropathy in individuals with T1DM. The development of significant albuminuria before 5 years’ or after 25 years’ duration of T1DM decreases the likelihood of diabetic nephropathy. Additionally, 95% of patients with T1DM and diabetic nephropathy also have diabetic retinopathy, so the absence of retinopathy may imply a diagnosis other than diabetic nephropathy. Seven-field fundus photos must be obtained to eliminate the presence of retinopathy and prompt kidney biopsy because a dilated ophthalmologic examination is insensitive. Unfortunately, patients with T2DM are more challenging because these epidemiologic clues are not as helpful. Diabetic retinopathy is concordant with diabetic nephropathy in only about 60% to 65% of cases; thus, its absence does not generate a high negative predictive value for the diagnosis of diabetic nephropathy. Also, because the onset of T2DM is generally unknown, one cannot as reliably use the natural history timeline to assist in diagnosis. Thus, it is incumbent on the practicing clinician to assess whether something other than DM is the cause of kidney disease. This evaluation will typically involve a thorough history and physical examination and selected laboratory and imaging tests to determine whether a kidney biopsy would be of benefit. There is no formal practice guideline on when to pursue kidney biopsy in patients with DM. Prospective kidney biopsy studies have illustrated that if a patient with DM has retinopathy (T1DM), onset of proteinuria in the usual timeframe (T1DM), and no evidence to support another disease (T1/T2DM), an alternative diagnosis that would substantially alter therapy is unlikely to be found. Therefore, it is not surprising that most patients with DM and reduced kidney function do not undergo kidney biopsy. ►Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia. 1996;39:1569-1576.►Orchard TJ, Dorman JS, Maser RE, et al. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes. 1990;39:1116-1124.►Schwartz MM, Lewis EJ, Leonard-Martin T, Lewis JB, Batlle D. Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy. The Collaborative Study Group. Nephrol Dial Transplant. 1998;13:2547-2552. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, BP control, and inhibition of the RAS. We take each of these in turn with case-based examples to discuss the optimal evidence-based approach to care of patients with diabetic nephropathy. Patients with diabetic nephropathy necessarily have DM and thus cardiovascular disease risk is significant and a competing risk for kidney failure. Therefore, it is important to ensure that aggressive risk factor modification is undertaken, usually in partnership with the patient’s primary care physician. Components of this therapeutic approach include tobacco cessation and lipid-lowering therapy. Evidence of cardiovascular disease risk reduction for both tobacco cessation and lipid lowering is abundant and thorough discussions can be found elsewhere. Unfortunately, because data are scant for the effects of these therapies to modify the course of kidney disease, it is outside the scope of this review. Case 2: A 48-year-old obese African-American woman with T2DM presents to your office for follow-up. She is presently using metformin, 500 mg, twice daily and lisinopril, 20 mg, daily. BP is 129/74 mm Hg and physical examination findings are otherwise unremarkable. Key laboratory values include the following: potassium, 4.7 mEq/L, serum creatinine, 0.9 mg/dL; albumin-creatinine ratio, 400 mg/g; and glycated hemoglobin (HbA1c), 9.1%.Question 2: Based on the evidence, what should the goal HbA1c concentration be for this patient?a)As close to 6% as possible.b)Around 7%.c)Between 8% and 9%.d)There is no relationship between HbA1c and microvascular outcome.For the answer to the question, see the following text. Case 2: A 48-year-old obese African-American woman with T2DM presents to your office for follow-up. She is presently using metformin, 500 mg, twice daily and lisinopril, 20 mg, daily. BP is 129/74 mm Hg and physical examination findings are otherwise unremarkable. Key laboratory values include the following: potassium, 4.7 mEq/L, serum creatinine, 0.9 mg/dL; albumin-creatinine ratio, 400 mg/g; and glycated hemoglobin (HbA1c), 9.1%. Question 2: Based on the evidence, what should the goal HbA1c concentration be for this patient?a)As close to 6% as possible.b)Around 7%.c)Between 8% and 9%.d)There is no relationship between HbA1c and microvascular outcome. For the answer to the question, see the following text. The effect of improved glycemic control on clinical outcomes, including progression of diabetic nephropathy, has been tested in multiple large clinical trials involving patients with T1/T2DM. The principal evidence regarding the benefit of glycemic control in patients with T1DM comes from the Diabetes Control and Complications Trial (DCCT). This seminal trial, conducted from 1983 to 1993 in the United States and Canada, randomly assigned 1,441 patients to intensive (goal HbA1c < 6.05%) versus conventional glycemic control with insulin with follow-up for a mean of 6.5 years. Median HbA1c concentration was 9.1% versus 7.3% for conventional versus intensive control. Intensive control resulted in a relative risk reduction of 39% for the development of microalbuminuria and relative risk reduction of 56% for overt proteinuria. Intensive glycemic control was also associated with reductions in other microvascular complications, namely retinopathy and neuropathy. After the trial ended, 1,375 participants volunteered to continue in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Given the benefits seen with the intensive control arm in the DCCT, all participants were advised to remain or convert to intensive control. Thus, glycemic control as measured by HbA1c concentration converged to 7.8% and 7.9% for the former conventional and former intensive control groups, respectively. Despite this convergence, the development of microalbuminuria and overt proteinuria was reduced (53% and 86%, respectively) by intensive control over 4 additional years of follow-up. Thus, the beneficial effects of glycemic control on microvascular complications are significant and durable in patients with T1DM. The available data for patients with T2DM are more ambiguous. In the United Kingdom Prospective Diabetes Study (UKPDS), participants were randomly assigned to intensive glycemic control using oral agents and/or insulin or to conventional therapy (diet control). The achieved mean HbA1c concentration was 7.0% in the intensive control arm compared to 7.9% in the conventional arm. Participants in the intensive control arm saw a reduction in any DM-related end point, but a reduction was not seen for specific kidney events of interest, namely the development of microalbuminuria, overt proteinuria, or doubling of serum creatinine concentration. Three more recent large trials with an aggregate enrollment of nearly 25,000 participants were conducted to assess any potential benefit of intensive glucose control in T2DM: ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), ACCORD (Action to Control Cardiovascular Risk in Diabetes), and VADT (VA Diabetes Trial). These studies targeted and achieved HbA1c concentrations of ∼6.0% relative to a control arm of ∼7.0%. Results of these studies are decidedly mixed, with either no benefits on cardiovascular effects ranging to cardiovascular risk in the intensive group and no kidney benefit, with the exception of 1 trial showing a reduction in albuminuria but no benefit on the preservation of kidney function. All 3 trials established increased risk for hypoglycemic events related to intensive glycemic control to HbA1c concentrations of near 6.0%. Intensive glycemic control to an HbA1c concentration of 7.0% prevents microvascular (not macrovascular) complications (UKPDS). However, it is unclear whether any further HbA1c concentration reduction is of utility, particularly for preventing kidney disease outcomes. Based on the available evidence (summarized in Table 1), the patient presented earlier should have her glycemic control therapy intensified, targeting a goal HbA1c concentration of 7.0% to reduce microvascular complications and diabetic nephropathy progression (thus [b] is the correct choice for Question 2). Any further reduction is of unproven benefit and would likely put the patient at risk for hypoglycemic events. This is congruent with current American Diabetes Association and KDOQI clinical practice guidelines.Table 1Summary of Key Glycemic Control TrialsTrialPopulationNIntervention TargetAchieved InterventionFindings in Intensive Care GroupCommentsDCCTT1DM1,441Intensive therapy targeting fasting and postprandial blood glucose vs conventional therapyHbA1c 7.3% vs 9.1%Decreased microvascular complications (including microalbuminuria, proteinuria, retinopathy, and neuropathy)EDICT1DM1,375 patients that completed DCCTObservational follow-up of DCCT with all getting intensive therapyHbA1c 7.8% vs 7.9%Reduction in microalbuminuria and proteinuriaUKPDSNewly Diagnosed T2DM3,867Intensive therapy targeting a fasting blood glucose vs conventional therapyHbA1c 7% vs 7.9%Reduction in any diabetes-related end point in aggregateReduction not seen in kidney-specific events (microalbuminuria, proteinuria, or doubling of Scr)ACCORDT2DM and CV event history or risk10,251HbA1c < 6.0% vs 7%-7.9%HbA1c 6.4% vs 7.5%Increased CV and total mortalityNo benefit on kidney end pointsADVANCET2DM and CV event history or risk11,140HbA1c < 6.5% vs routine careHbA1c 6.3% vs 7.0%No benefit on CV outcomes; reduction in microvascular eventsAlbuminuria reduced by 21%VADTT2DM and poor BP control1,791Reduction in HbA1c of 1.5% vs routine careHbA1c 6.9% vs 8.4%No benefitNo benefit on kidney end pointsAbbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; HbA1c, hemoglobin A1c; Scr, serum creatinine; T1(2)DM, type 1 (2) diabetes mellitus; UPKDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial. Open table in a new tab Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; HbA1c, hemoglobin A1c; Scr, serum creatinine; T1(2)DM, type 1 (2) diabetes mellitus; UPKDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial. ►Action to Control Cardiovascular Risk in Diabetes Study G; Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559. ★ ESSENTIAL READING►ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. ★ ESSENTIAL READING►Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.►Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-39. ★ ESSENTIAL READING►Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. ★ ESSENTIAL READING►Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563-2569. Case 3: A 52-year-old white man with T2DM complicated by retinopathy, neuropathy, and stage 3 CKD due to diabetic nephropathy comes in to your office for routine follow-up care. He is presently treated with insulin and lisinopril, 40 mg, daily. BP is 150/95 mm Hg and the rest of the examination findings are unremarkable. Key laboratory values include the following: serum potassium, 4.7 mEq/L; serum creatinine, 1.5 mg/dL; albumin-creatinine ratio, 800 mg/g; and HbA1c, 7.1%.Question 3: Based on the evidence, what should the goal BP be for this patient?a)Although lower BP decrea