Diabetic Nephropathy: ACE Inhibitors vs. Tight Glycemic Control
Diabetic Nephropathy: ACE Inhibitors vs. Tight Glycemic Control
Proteinuria is considered a risk factor for end-stage renal disease and coronary artery disease, secondary to diabetes (reviewed by Tan, Jaung, Gamble, & Cundy, 2014). The recommended treatment approach relies on angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB), with the goal of proteinuria remission and the control of hypertension. This strategy is effective for approximately 50% of type 2 diabetes patients suffering from microalbuminuria. The same treatment approach has been used for type 1 and type 2 diabetes patients suffering from macroalbuminuria and researchers have shown that remission is possible in a percentage of type 1 diabetes patients.
Tight glycemic control vs. regular glycemic control were compared for efficacy in reducing the risk of cardiovascular adverse events and nephropathy in several recent large randomized-controlled trials and the results were encouraging, especially for newly diagnosed patients and long-term prognosis (reviewed by Tandon, Ali, & Narayan, 2012). These results suggest that tight glycemic control may be as effective as ACE inhibitors in achieving proteinuria remission.
To better understand the relative effectiveness of the ACE inhibitors vs. tight glycemic control, a systematic review of the literature will be conducted. Medline, as accessed through the portal PubMed, and Google.com, will be the search engines used. The search strings will be "proteinuria AND tight glycemic" and "proteinuria AND ACE inhibitors."
Integration and Synthesis of the Evidence
Once considered a progressive and irreversible disease, diabetic nephropathy (DN) has since been shown to be amenable to aggressive treatment (reviewed by Tan, Jaung, Gamble, & Cundy, 2014). Tan and colleagues (2014) examined the effectiveness of ACE inhibitors or ARBs in achieving remission in New Zealand patients with type 2 diabetes and macroalbuminuria [albumin-to-creatinine ratio (ACR) ? 50 mg/mmol] in a mixed-race cohort (N = 78) and discovered that remission was possible in only a third of the patients. Of the 28% who achieved remission, a relapse was observed in 27%, while another 15% experienced a gradual increase in ACR during the study period. In addition, it took an average of 30 months from peak ACR for remission to occur, with a range between 12 and 54 months. When remission did occur it lasted anywhere from 12 months to almost a decade. When macroalbuminuria was first diagnosed in this study sample, 32% of patients had no evidence of renal disease, 24% had mild to moderate nephropathy, and 44% had severe nephropathy. The generalizability of these findings is limited because of both the small sample size and how sick these patients were, but the results appear to be validated by the larger, better controlled studies discussed below.
A large trial of cardiovascular patients (N = 10,251) with a mean glycated hemoglobin (HbA1c) of 8.1% were randomized to either intensive therapy to lower HbA1c below 6.0% or to standard therapy to lower HbA1c to between 7.0 and 7.9% (ACCORD Study Group, 2008). The study had to be stopped because all cause mortality for the intensive therapy group increased significantly above the standard therapy group, possibly due to an increased incidence of hypoglycemia; however, intensive group participants who survived enjoyed a reduction in cardiovascular risk several years later. In terms of DN, there was no difference between the intensive and standard therapy groups, except for a delay in onset of albuminuria and in the prevalence of macroalbuminuria (Ismail-Beigi et al., 2010). For the purposes of this review, this study is limited because it did not directly compare tight glycemic control with ACE inhibitors; however, it does reveal that tight glycemic control with a target HbA1c of 6.0% or less may be contraindicated in this patient population due to the risk of hypoglycemia.
An international study investigating the relative efficacy of ACE inhibitor/diuretic with usual glucose control or intensive glucose control (HbA1c ? 6.5%) versus intensive or usual glucose control alone was conducted recently (Zoungas et al., 2009). The large cohort (N = 11,140) consisted of patients with type 2 diabetes, either with a history of major microvascular or macrovascular disease or at least one other risk factor for cardiovascular disease. The combination of ACE inhibitor and intensive glucose control reduced the prevalence of microvascular events by 19% (p = .02), when compared to intensive glucose control or ACE inhibitor alone. More specifically, all renal events declined by 28% (p < .0001), new or worsening nephropathy was reduced by 33% (p = .005), macroalbuminuria was reduced by 54% (p < 0.0001), and microalbuminuria declined by 25% (p < .001). By comparison, ACE inhibitor with usual glucose control or intensive glucose alone produced intermediate risk values between placebo and combination therapy. Based on the results of this study, tight glucose control and ACE inhibitors both provide protection against DN, but the magnitude of the effect is additive when both are combined. For the purposes of this review this is the most relevant study, but the findings would be generalizable only to patients that meet the inclusion criteria of type 2 diabetes together with major microvascular or macrovascular events.
Based on the findings discussed above, both ACE inhibitors and intensive glucose control provide protection against onset or worsening of DN. The degree of success in providing reduced risk of DN or worsening DN in these studies depended on the severity of disease at the onset of the studies. In terms of safety, however, the ACCORD study revealed tight glucose control (HbA1c ? 6.0%) may not be worth the risk in patients with cardiovascular comorbidity (ACCORD Study Group, 2008). By comparison, tight glucose control (HbA1c ? 6.5%) in the ADVANCE study did not increase the risk of all cause mortality, and when combined with an ACE inhibitor/diuretic actually reduced mortality significantly (p = .04). The patient populations between the ACCORD and ADVANCE studies differed, because in the former they all had cardiovascular disease, whereas in the latter all had diabetes with or without cardiovascular disease. Based on this evidence alone, a combination of ACE inhibitors and tight glycemic control would be indicated for all diabetes patients at risk for developing microvascular events, including DN; however, tight glucose control with a target HbA1c level of 6.0% or less may be contraindicated for cardiovascular patients due to the increased risk of hypoglycemia and all cause mortality.
Comparative Evaluation of the Evidence to Practice
The use of both ACE inhibitors and tight glycemic control for preventing or controlling proteinuria associated with type 2 diabetes is essentially non-existent in my clinic; however, a diagnosis of type 2 diabetes triggers a test for albuminuria, which is repeated annually. Even if a diabetes patient with microalbuminuria is normotensive, they are given an ACE inhibitor or ARB to slow progression to macroalbuminuria. By comparison, tight control of hyperglycemia to an HbA1c level at or below 6.0% is simply not routine nor recommended for patients. In my clinic, we consider any HbA1c level below 9.0% better and below 8.0% best, depending on the disease severity and prognosis. There is thus a wide margin between what some research groups define as tight glucose control and what is considered tight glucose control in my clinic.
If my clinic were to adopt tight glucose control as best practice, with a target HbA1c level somewhere between 6.5 and 7.0%, there would be significant barriers to change. From the perspective of patients, taking multiple drugs with a risk of side effects, including drug interactions, would tend to increase the risk of noncompliance. Based on my experience, patients also tend to lack sufficient diabetes knowledge to increase their treatment self-efficacy, including making the necessary lifestyle changes and complying with aggressive treatment recommendations. From the clinician perspective, there would be some resistant to the increased time burden required to fully evaluate and follow patients who…