Heterogeneous Treatment Effects of Intensive Glycemic Control on Kidney Microvascular Outcomes and Mortality in ACCORD

Abstract

Objective: Clear criteria to individualize glycemic targets in patients with type II diabetes are lacking. In this post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD), we evaluate whether the kidney failure risk equation (KFRE) can identify patients for whom intensive glycemic control confers more benefit in preventing kidney microvascular outcomes. Research design and methods: We divided the ACCORD trial population into quartiles based on 5-year kidney failure risk using the KFRE. We estimated conditional treatment effects within each quartile and compared them to the average treatment effect in the trial. The treatment effects of interest were the 7-year restricted-mean-survival-time (RMST) differences between intensive and standard glycemic control arms on (1) time-to-first development of severely elevated albuminuria or kidney failure and (2) all-cause mortality. Results: We found evidence that the effect of intensive glycemic control on kidney microvascular outcomes and all-cause mortality varies with baseline risk of kidney failure. Patients with elevated baseline risk of kidney failure derived the most from intensive glycemic control in reducing kidney microvascular outcomes (7-year RMST difference of 114.8 (95% CI 58.1, 176.4)v. 48.4 (25.3, 69.6) days in the entire trial population) However, this same patient group also experienced a shorter time to death (7-year RMST difference of -56.7 (-100.2, -17.5) v. -23.6 (-42.2, -6.6)days). Conclusions: We found evidence of heterogenous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD as a function of predicted baseline risk of kidney failure. Patients with higher kidney failure risk experienced the most pronounced reduction in kidney microvascular outcomes but also experienced the highest risk of all-cause mortality.

Impact of the PATH Statement on Analysis and Reporting of Heterogeneity of Treatment Effect in Clinical Trials: A Scoping Review

“…Study authors claimed findings of HTE in 15 risk modeling reports (Figure 2). For six, (49,60,64,71,75,77) heterogeneity was found on the absolute but not the relative scale (i.e., benefit magnification) and for nine (36,38,43,48,50,54,58,68,73), heterogeneity was also found on the relative scale (i.e., relative treatment effects also varied across levels of baseline risk). The four remaining reports (56,57,61,76) did not find clear overall treatment effects and none claimed HTE on either scale.…”

“…Table 3 gives the decision thresholds for important subgroup differences in treatment recommendations. Reasons for concluding that credible HTE was not clinically important included lack of clarity in presentation of findings, (75) failure to identify a threshold for differing treatment choices, (64) conflicting findings across outcomes, (77) failure to add clinical value to previous risk-based selection strategies, (68) and concurrence with authors on the need for additional investigation, possibly testing additional potential effect modifiers. (44)…”

“…Several authors motivated their approaches by pointing to limitations of risk modeling. (47,65,77) Although risk scores can create patient subgroups well-matched on risk, subgroup members may be heterogeneous for the specific characteristics that contributed to their risk scores and therefore potentially heterogeneous in terms of their treatment response. (65)…”

A moderately higher time-in-range threshold improves the prognosis of type 2 diabetes patients complicated with COVID-19

“…Excessive glycemic control leading to severe hypoglycemia has been associated with increased mortality rates ( 9 ). The international consensus on TIR ( 26 ) indicated that although evidence regarding TIR for older or high-risk individuals is limited, several studies have demonstrated an elevated risk for hypoglycemia.…”

“…These associations between diabetes and worse outcomes in COVID-19 patients were incontrovertible, as blood glucose fluctuation was not conducive to the improvement of disease, and inflammation caused by hyperglycemia led to increased mortality ( 7 , 8 ). However, excessively tight glycemic control may increase the risk of hypoglycemia, which also increased mortality ( 9 ).The impact of COVID-19 on the patients and the use of glucocorticoids and nutritional support during the treatment increased blood glucose fluctuations, which had adverse effects on the prognosis ( 10 ). The UK Diabetes guidelines recommend a blood glucose target of 110 to 180mg/dL for diabetes patients with COVID-19, and a blood glucose level of less than 220mg/dL for patients with hypoglycemia and high risk factors (including the elderly, patients with low body weight, patients with severe COVID-19 and/or renal impairment) ( 11 ).…”