A paper published recently in the Clinical Journal of the American Society of Nephrology raises questions about the safety of aggressive blood glucose management strategies for type 2 diabetics. The paper, “Long-Term Effects of Intensive Glycemic and Blood Pressure Control and Fenofibrate Use on Kidney Outcomes,” showed that intensive glycemic control may increase risk for adverse kidney events.
The data come from a post hoc analysis of the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes), which was a multifactorial intervention in over 10,000 people with type 2 diabetes (T2D) who were at high risk for cardiovascular disease. The original ACCORD trial was a disappointment and came to the surprising—at least on the surface—conclusion that intensive lowering of blood glucose resulted in worse outcomes: “In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.”
As stated, this is only surprising on the surface. When you dig a little deeper, it becomes clear why the intensive glucose lowering strategy resulted in more deaths. The trial involved medications, not dietary and lifestyle changes. It would be nice if diabetes medications did nothing but lower blood glucose. Unfortunately, the mechanisms by which they do this often bring with them unwanted and even harmful side-effects. (Consider the warning recently issued by the FDA regarding increased risk for serious infection of the genital area among users of SGLT2 inhibitors.)
On the other hand, clinical trials that involve dietary changes—particularly adherence to a low-carb or ketogenic diet—consistently show dramatic improvements in fasting glucose and insulin levels, HbA1c, blood pressure, triglyceride:HDL ratio, and other cardiometabolic health indicators. In one such trial, subjects who followed a low carb diet were able to decrease or completely discontinue several medications while maintaining better blood sugar than when more heavily medicated. Carbohydrate restriction is so effective for improving T2D and metabolic syndrome, in fact, that researchers have asserted it should be “the default treatment” for these conditions.
But back to the study at hand. According to one of the authors, “These results, along with those from the primary study which showed no benefit of the interventions on heart attacks and strokes, provide evidence against aggressive targets for glucose, blood pressure, and use of fenfibrate [sic] in adults with type 2 diabetes at high risk of cardiovascular events.”
After 6.5 years of follow-up, intensive blood glucose lowering interventions (aiming for HbA1c <6%) reduced the risk for macroalbuminuria, but had no impact on serum creatinine doubling (taken to be indicative of worsening kidney function) or the need for dialysis or transplantation. Improve blood glucose levels, but still end up needing dialysis or transplant: not exactly what a patient would hope for.
The question remains: what’s the issue here? Is it that having lower blood glucose has no beneficial impact on the comorbidities of T2D, or is the confounding factor the way that lower blood glucose was achieved? A study that used a reduced carb diet that was also low in bioavailable iron and high in polyphenols delayed progression of diabetic nephropathy and reduced mortality (at least during the follow up period of 3.9 ± 1.8 years) compared to the standard low-protein control diet. (The control diet was 65% carb, 25% fat, 10% protein; the low carb diet called for 35% carbs, 30% fat, 25-30% protein, 5-10% alcohol [for the red wine polyphenols]. To be clear, most of the subjects on the lower carb diet still declined, but they declined more slowly, and there were fewer deaths during the follow-up period. The results might have been even better if this had been closer to a very low carb or ketogenic diet (perhaps 5-20% carbs). Nevertheless, these findings were promising because they show that even when a diet is still 35% carbs, a low-ish carb diet has a more favorable impact on diabetic nephropathy progression than a low protein diet, which is the typical go-to intervention for kidney disease.
If type 2 diabetes is characterized by pathologically elevated blood glucose, then it stands to reason that reducing the dietary carbohydrate load (with its major influence on blood glucose) should be a first-line therapy for controlling the progression of this illness. Doing so might induce very different effects than lowering glucose solely through pharmaceutical means which have little to no beneficial impact on disease progression and often, as demonstrated with kidney function, make overall health worse and increase mortality.
By Amy Berger, MS, CNS
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