Microvascular Complications in Diabetes: Perspectives on Glycemic Control to Prevent Microvascular Complications Discussion Outline: Glycemia and Microvascular Compliations Clinical Trials - A Brief History Intensive glucose control and microvascular disease risk A brief reminder of the Serial Position Effect Early vs. Late Intervention A Clinical Perspective EARLY =,, LATE =,, and Updates from A Rational Clinical Approach Balancing Risk Benefit with intensive glycemic control David M. Kendall, MD Chief Scientific and Medical Officer Glycemic Control for Microvascular Type 1 Diabetes N Duration of Diabetes Baseline A1C Follow Up (Yrs) Publication 11 <5 9.%.5 1993 Glycemic Control for Microvascular Stockholm () 12 ~1 9.% 7 1993 139 ~1 Varies 1+ 2+ Type 2 Diabetes 23 <1 ~7% (15 mg/dl) ~5 1971 11 2-1 9. 1995 CSDM 153 9.3 1 ½ 1995 + 512 <1 ~9% 1 199/2 1251 1.3 3 ½ 2 111 7.5 5 2 1791 11+ 9. 2 Diabetes 5 1 15 2+ The Serial Position Effect Microvascular Complications Risk in Diabetes Glycemic Control for Microvascular Primacy Effect: Recency Effect: No clearly benefit from intensive Rx No benefit from early intensive Rx Increase in mortality with selected therapies Potential for increase risk (hypo) No impact on CVD + Diabetes 5 1 15 2+
Glycemic Control for Microvascular Glycemic Control for Microvascular The Impact of Early Intervention + 5 1 15 2+ Early Intensive Diabetes Therapy: Reduction in Microvascular Complications Complications Risk in Diabetes The Impact of Intensive Glycemic Control HbA1c Retinopathy Nephropathy Neuropathy CV disease 9 7.1% 3% 5% % 9+ 7.2% 9% 7% Improved - 7% 17-29% 2-33% - 1% Relative Risk of Complications 2 Intensive glycemic control reduces the risk of microvascular complications early in the course of both type 1 and type 2 diabetes Hemoglobin A1c 7 9 1 11 12 Research Group. N Engl J Med. 1993;329:977-9. Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;2:13-117. 33: Lancet 199; 352, 37-53. eag Glucose Adapted from: Skyler JS. Endocrinol Metab Clin North Am.. 199 Jun;25(2):23-5. 5. Study Group.. N Engl J Med 329:977, 1993 35. Stratton IM. BMJ 321:5-12, 12, 2. 12 15 13 212 2 29 29 and Glycemic Control and Microvascular Risk Early Intervention Is It Truly Early? Benefit in Primary and Secondary Prevention Rate of Retinopathy (per 1 patient-years) 12 1 2 Complication Rate (%) per 1, Person-years 7 5 3 2 1 Reduction in microvascular disease risk Occurred with both primary and secondary prevention Effect observed in, and Primary Prevention Secondary Intervention 7 9 1 11 A1C (%) 5 7 9 1 11 Updated Mean HbA 1c (%) Study Group.. N Engl J Med 329:977, 1993 35. Stratton IM. BMJ. 2;321:5-12. Research Group. N Engl J Med. 1993;329:977-9.
Glycemic Control for Microvascular Enduring Impact of Early Intervention and Glycemic Control for Microvascular + Diabetes 5 1 15 2+ 2 2 1 12 The Durable Effect of Early Intervention and Follow up cohort with similar glycemic control for -1+ years Retinopathy Incidence (%) A1C achieved = ~.% Intensive (SU/Ins) vs. Conventional Conventional control Glycemic Control for Microvascular The Impact Late Intervention. 1. 2. 3.. YEAR Intensive Research Group. N Engl J Med 2;32:31-9 Holman RR. N Engl J Med.. 2;359:1577-9 Glycemic Control for Microvascular : Effect of Intensive Glucose Lowering on Microvascular Complications in T2DM 1 A1C (%) 9 7 Standard control Median A1C.%.9% + Intensive control 5 Baseline 1 2 3 5 Diabetes 5 1 15 2+ Years on Study Duckworth W et al N Engl J Med 29;3:129-39
: Effect of Intensive Glucose Lowering on Microvascular Complications in T2DM Complication Microvascular Event Impact in DIABETIC RETINOPATHY DIABETIC NEPHROPATHY DIABETIC NEUROPATHY Proliferative retinopathy Macular edema 2 step progression Doubling of serum creatinine ESRD Micro to macroalbuminuria Normal to micro/macroalbuminuria Peripheral neuropathy Autonomic neuropathy P=.7 P=.2 P=.7 Correction on Microalbuminuria On further examination of the data on albuminuria from the {[] we found that the data set that we used to evaluate the progression of disease was constructed improperly. As a result, the rates of progression to microalbuminuria and macroalbuminuria were reported [incorrectly} Both progression from normal to microalbuminuria or macroalbuminuria (P =.3) and progression from either normal or microalbuminuria to macroalbuminuria (P =.) favor intensive treatment. Any progression of albuminuria is now statistically significant (P<.1) Duckworth W et al N Engl J Med 29;3:129-39 We appreciate the opportunity to update our results Cumulative incidence (%) Treatment Effect on Microvascular Outcomes 25 2 15 1 New or worsening nephropathy / retinopathy HR=. (.77-.97).97) P=.1 Standard control Stockholm Diabetes Intervention Study How Late is too Late in T1DM? Study Design Intensive insulin therapy A1C 9. 7.2 Mean duration of diabetes at study entry = ~1 years Significant (but modest) reduction in rates of microvascular disease When do advanced complications become too advanced? 5 Intensive control 12 1 2 3 3 2 5 Follow-up (months) Reichard P. N Engl J Med 1993;329;3-39 Collaborative Group. N Engl J Med 35:25-72, 2 Intensive Glycemic Control in Diabetes Is It Safe? What are the Risks? Reducing the Risk of Complications Intensive Glycemic Control in Type 1 Diabetes Severe hypoglycemia risk Increased ~3 fold with intensive therapy? predictor of adverse outcome/mortality (, ) Increase in health care resource use Increase near-term cost of care (clinic, education, meds, technology) Increased number and type of medications used Weight gain Increase in body weight (~5-2 lbs) Unknown long term impact on CV risk, risk factors Increased mortality risk? Rate of Retin opat hy (per 1 patient -years) 12 1 2 7 9 1 11 A1C (%) 12 1 2 Seve re Hypo glyce mia (per 1 patient -years) Adapted from: Study Group.. N Engl J Med 329:977, 1993
A Final Note on Summary of Microvascular Results Through End of Study Final Results - Microvascular and Eye Study Data P ( 1 significant test) =.5 Conclusions Microvascular Intensive treatment of glycemia in the cohort did not reduce the risk of composite measures of advanced microvascular outcomes Intensive therapy delayed the onset of albuminuria and some measures of eye complications and neuropathy Microvascular benefits of intensive therapy should be weighed against the potential for increased mortality, increased body weight, and the risk for severe hypoglycemia Eye Study Design Baseline and Year comprehensive eye exams including: Visual acuity measurements Fundus photography of 7 standard stereoscopic fields Central grading of the fundus photographs using the Early Treatment Diabetic Retinopathy Study (ETDRS) Classification of diabetic retinopathy Proportion of Participants with Diabetic Retinopathy Progression at years Blood Pressure Lipid N=25 Total Glycemia Intensive Standard Feno+statin Placebo TOTALS Intensive 9.2% (29/315) Standard 11.% (3/332) TOTALS 1.% (7/7).1% (25/3) 9.% (29/3).% (5/1) 5.3% (21/) 7.1% (29/) 7.% (31/) 13.% (51/31).5% (52/) 1.2% (/77) 7.5% (1/129) 1.% (19/127).9% (253/25)
UK Prospective Diabetes Study () Group. Lancet. 199;352:5-5. Reichard P. N Engl J Med 1993;329;3-39 Holman RR. N Engl J Med. 2 Oct 9;359(15):1577-9. Research Group. N Engl J Med 329;977-9, 1993 Nathan DM, et al. N Engl J Med. 25;353:23-253. Gerstein HC, et al. N Engl J Med. 2;35:255-2559. Patel A, et al. N Engl J Med. 2;35:25-2572. Duckworth W et al N Engl J Med 29;3:129-39 UK Prospective Diabetes Study () Group. Lancet. 199;352:5-5. Reichard P. N Engl J Med 1993;329;3-39 Holman RR. N Engl J Med. 2 Oct 9;359(15):1577-9. Research Group. N Engl J Med 329;977-9, 1993 Nathan DM, et al. N Engl J Med. 25;353:23-253. Gerstein HC, et al. N Engl J Med. 2;35:255-2559. Patel A, et al. N Engl J Med. 2;35:25-2572. Duckworth W et al N Engl J Med 29;3:129-39 Eye Study Conclusions Intensive glycemia and combination of fenofibrate and simvastatin reduced the proportion whose retinopathy progressed by about one-third Effects were consistent across subgroups No statistically significant effect of intensive blood pressure No subgroup with effect Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvascular / International Diabetes Center 2 Initial Trial Long Term Follow-up Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvascular CVD Mortality * /? Treatment Considerations Risk Benefit and Intensive Therapies A few observation and much reasoning lead to error. Many observations and a little reasoning lead to truth Alexis Carrel Intensive glycemic control both early and late in diabetes Significantly reduces the risk of microvascular complications Increases the risk of severe hypoglycemia, weight gain, HCE Later intervention may limit the magnitude of these benefits on microvascular risk and should be weighed against the potential mortality risk of very intensive intervention International Diabetes Center 2 Initial Trial Long Term Follow-up Diabetes and Glycemic Control A Rational Approach to Limit Complications Conclusions As low as possible As early as possible For as long as possible As safely as possible And as rationally as possible