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Glucose Control and Microvascular Complications

Big changes to affect small vessels.

Diabetes is known to have many complications associated with the disease. Among those are microvascular complications, such as diabetic retinopathy, neuropathy, nephropathy, and cardiovascular disease. While early diagnosis and treatment can lessen complications, timely control of glucose can potentially prevent these painful and disrupting problems from occurring. Previous studies concerning glucose control and prevention of diabetic complication have been individually insufficient to form treatment guidelines or guide clinical practitioners.

Due to lack of evidence, researchers from CONTROL (Collaborators on Trials of Glucose Lowering) analyzed the benefit of intensive glucose control versus less intensive control on the outcome of microvascular complications. Researchers performed a meta-analysis using data from four major trials: Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), the UK Prospective Diabetes Study (UKPDS), and the Veterans Administration Diabetes Trial (VADT). These trials were picked due to their assessment of the effects of low versus high HbA1c, fasting glucose, and post-load glucose targets in patients with type 2 diabetes. The included trials also had an average of two years follow-up with approximately 1,000 patient-years follow-up in each randomized treatment group, used intention to treat analysis, were double blind or open label, used pre-specified outcomes, and had at least a 90% follow-up on patients’ vital status. Exclusion criteria included critical care patients, patients with type 1 diabetes or under the age of 16, treatment with multifactorial interventions where effects of glycemic control could not be assessed separately, or patients with acute myocardial infarction or acute myocardial syndromes receiving invasive management strategies. Primary outcomes were kidney events, eye events, and nerve events. Kidney events were defined as composite end stage renal disease, renal death, development of estimated glomerular filtration rate of less than 30 ml/min per 1.73 m2 , or development of overt diabetic nephropathy. Eye events were outlined as a patient need for retinal photocoagulation therapy or vitrectomy, development of proliferative retinopathy, fibrous proliferations on the disc, or progression of diabetic retinopathy. Nerve events included new loss of vibratory sensation, new loss of ankle reflexes, or new loss of light touch. Secondary events were stated as: individual factors of eye events, kidney events, and nerve events as well as the development of macular edema, diabetic related blindness, vision decline, cataract extraction, development/progression of albuminuria, or maintenance/regression of normoalbuminuria. Effects of randomized treatment on the primary outcomes were assessed using cox proportional hazards models and overall estimates of effect were calculated using a random-effects model.

The final evaluation included 27,049 adults with type 2 diabetes. Patients were treated with more intensive or less intensive glucose control and followed for a median of five years. A total of 1,626 kidney events, 795 eye events, and 7,598 nerve events occurred during the follow-up period. For the composite of primary events, more intense glucose control resulted in 20% relative risk reduction in kidney events (HR 0·80, 95% CI 0·72–0·88; p<0·0001), 13% relative risk reduction in eye outcomes (HR 0·87, 95% CI 0·76–1·00; p=0·042), and no relative risk reduction in nerve outcome (HR 0·98, 95% CI 0·87–1·09; p=0·68) compared to less intensive glucose control. More intensive glucose control resulted in difference in mean HbA1c of -0.90% (95% confidence interval (CI) -1.22 to -0.58) and mean difference in fasting plasma glucose of -1.69 mmol/L (95% CI -2.12 to -1.26) in pooled data in comparison to less intensive glucose control. The number needed to treat to prevent one kidney or eye event in a patient with type 2 diabetes was calculated to be 63-73 patients.

Intensive glucose control shows modest improvement in HbA1c, which leads to significant relative risk reduction in the occurrence of kidney and eye events. Since more people are being diagnosed with diabetes every year it is important to implement proper glucose control early to reduce the occurrence of harmful kidney and eye events. Weakness of the study include the low occurrence of more serious events such as end-stage renal disease (256 events) and renal death, small number of included trials, and application to patients who do not fall within the criteria of the study.

Practice Pearls:

  • In this study, more intensive glucose control led to a 20% relative risk reduction in kidney events and 13% relative risk reduction in eye events when compared to less intensive glucose control.
  • Intensive glucose control seems to have little benefit for prevention of neuropathy.
  • Glucose lowering is pertinent for the prevention of long-term microvascular complications in adults with type 2 diabetes.

References:

About diabetes.” WHO. World Health Organization, Web. 13 Apr. 2017.

Zoungas, Sophia, Hisatomi Arima, Hertzel C. Gerstein, Rury R. Holman, Mark Woodward, Peter Reaven, Rodney A. Hayward, Timothy Craven, Ruth L. Coleman, and John Chalmers. “Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials.” The Lancet Diabetes & Endocrinology (2017)

 

Priscilla Rettman, BS, PharmD Candidate 2017, Philadelphia College of Osteopathic Medicine- GA Campus