Does Diabetes Control Matter?

Does Diabetes Control Matter? Laurence Kennedy, MD, FRCP Endocrinology Department Cleveland Clinic, OH Disclosures None

Does Diabetes Control Matter? Generality of patients

Relative Risk Complications of Diabetes Mellitus Microvascular Complications Retinopathy Neuropathy Nephropathy Macrovascular Complications Atherosclerosis CAD Stroke PVD Hyperglycemia Hyperglycemia? A1C and Microvascular Complications: DCCT 15 13 11 9 7 5 3 Retinopathy Nephropathy Neuropathy Microalbuminuria 1 6 7 8 9 10 11 12 A1C (%) Skyler J. Endocrinol Metab Clin North Am. 1996;25:243 DCCT Research Group. N Engl J Med. 1993;329:977

Intervention Studies: DCCT Type 1 diabetes 10 9.1 Conventional therapy Intensive therapy Mean HbA 1c (%) 8 7.2 P < 0.001 6 Mean BG 231mg/dl Mean BG 155 mg/dl 0 N = 1,441 patients DCCT Research Group. N Engl J Med. 329:977, 1993 Reduction in Risk of Development and Progression of Complications 5 Compared to conventional insulin therapy, intensive insulin therapy reduced the risk of development and progression of: DCCT (Type 1 diabetes) Retinopathy 63% Nephropathy* 54% Neuropathy 60% *Urinary albumin excretion ³ 300 mg/24 h DCCT Research Group. N Engl J Med. 329:977-986, 1993

United Kingdom Prospective Diabetes Study (UKPDS) Multicenter, randomized, controlled trial N=5,102 Mean 10-year follow-up Study objectives: determine whether intensive therapy for T2D reduces the risk of complications Advantages/disadvantages of sulfonylurea, metformin (in overweight patients), or insulin UKPDS Group. Lancet. 1998;352:837-853. Glycemic Control Intensive vs Conventional Treatment 200 FPG 9 HbA 1c 180 Median 160 FPG (mg/dl) 140 8 Median HbA 1c (%) 7 120 100 6 0 0 3 6 9 12 15 Time from randomization (y) 0 3 6 9 12 15 Time from randomization (y) Patients followed for 10 years Conventional Intensive All patients assigned to regimen Conventional Intensive UKPDS Group. Lancet. 1998;352:837-853.

% Risk Reduction UKPDS: Risk Reductions With Intensive Therapy (Median HbA 1c = 7.0%) 0-5 -10-15 -20-25 -30-35 -40-45 -50 Any Diabetes Microvascular Related Endpoints Endpoint P = 0.029-12 P = 0.0099-25 Laser Rx Cataract Albuminuria Myocardial Infarction P = 0.0031-29 P = 0.046-24 P = 0.000054-33 P = 0.052-16 Sudden Death P < 0.047-46 UKPDS Group. Lancet 1998;352:837-853. Cardiovascular disease

ACCORD Trial Large U.S. trial in type 2 DM to investigate cardiovascular protection Intensive blood glucose management Intensive BP management (120 mm Hg systolic vs. 140) Randomization to fibrate or placebo in addition to statin therapy Blood glucose protocol 10,000 plus high risk patients with type 2 DM - mean age 62, many with prior CVD Starting A1C 8.1% - randomized to target A1C <6% vs. >7% Final A1C 6.4% vs. 7.5% High use of TZDs (92%) and insulin (77%) ACCORD Study Group. NEJM. 2008;358:2545-2559. ACCORD: A1C Bars are interquartile ranges

ACCORD: primary outcome and death Death from any cause P = 0.04 Primary outcome: Nonfatal MI, Nonfatal stroke, CVD death NS ACCORD: primary and secondary outcomes rate of one-year change in A1C showed that a greater decline in A1C was associated with a lower risk of death 20% higher risk of death for every 1% higher A1C level above 6% Riddle M, for the investigators ADA meeting 2009

ACCORD - hypoglycemia Hypoglycemia: the flip side of intensified glycemic control ADVANCE Trial Large international trial in type 2 DM to investigate cardiovascular protection. 11,000 plus high-risk patients with type 2 DM. In comparison to ACCORD study Older - 66 year-old (vs. 62) Thinner - BMI 28 kg/m2 (vs. 32) Shorter duration of diabetes 8 years (vs. 10 years) Lower starting A1C 7.5% (vs. 8.1%) Less baseline medication - insulin 1.5% (vs. 35%) Less intensive protocol (A1C goal <6.5% vs. <7.0%) although FINAL A1C the same (6.4%) Forced use of sulfonylurea diamicron Less use of drugs - TZDs (17%) and insulin (41%) ADVANCE Collaborative Group. NEJM. 2008;358:2560-2572.

ADVANCE: glycemic control New England Journal of Medicine 358:2560-2572; 2008 ADVANCE: Macro- and Microvascular events p = 0.01 NS p = 0.006 NS

ADVANCE: outcomes * * All microvascular effect can be attributed to nepropathy VADT: Veterans Affairs Diabetes Trial USA, multicenter, type 2 diabetes 1791 veterans, mean age 60.4y Mean duration of diabetes 11.5y 40% of subjects already had a CV event Randomization to intensive or standard glucose treatment Mean baseline A1C 9.4% Median follow up 5.6y New Engl J Med 2009; 360:129-139

VADT: A1C achieved 8.4% 6.9% New Engl J Med 2009; 360:129-139 VADT: survival outcomes: NS New Engl J Med 2009; 360:129-139

VADT: CVD Deaths: NS New Engl J Med 2009; 360:129-139 VADT: Hypoglycemia New Engl J Med 2009; 360:129-139

VADT: Investigators comment Overall, the benefit of decreasing the Glycated hemoglobin level from 8.4% to 6.9% appeared to be minimal N Engl J Med 2009;360:129-139 Start early!

UKPDS MI and Death 10y after study end SU/INSULIN METFORMIN UKPDS longterm follow-up data Good glycemic control EARLY in the course of type 2 diabetes leads to: reduced risk of microvascular disease that emerges within 2-3 years reduced risk of cardiovascular disease and death that emerges after ~ 15 years

Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) DCCT Recruitment 1983-1989 1,441 participants DCCT closeout 1993 Mean follow-up 6.5 years EDIC initiated 1994 1,388 participants (96%) EDIC data reports 2006 Mean follow-up 12 years

A1C and CVD Outcomes DCCT: Lower risk of CVD events with intensive control EDIC: 57% reduction in risk of nonfatal MI, stroke, or CVD death Benefit of intensive glycemic control persists for decades and is associated with a modest reduction in all-cause mortality. ACCORD, ADVANCE, VADT suggested no significant reduction in CVD outcomes with intensive glycemic control. Care.DiabetesJournals.org American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2016; 39 (Suppl. 1): S39-S46

Special populations The Elderly Renal transplant Pregnancy Consensus Development Conference on Diabetes in Older Adults ( 65yo) A Framework for Considering Treatment Goals Health Status Rationale A1C% FBG HS BG Healthy (few illnesses, intact cognitive and fxnl status) Longer life expectancy Complex/intermed Intermed life expectancy, high tx burden, risk of hypos, fall risk Very complex/poor health (Long-term care or end-stage chronic illnesses) Ltd remaining life expectancy makes benefit uncertain <7.5% 90-130 90-150 <8.0% 90-150 100-180 <8.5% 100-180 110-200 Kirkman etal. JAGS. Special Report-Diabetes in Older Adults: A Consensus Report 2012, 1-15.

DM Control and Kidney Transplant Outcome A Randomized Controlled Trial to Evaluate the Effect of Glycemic Control on Renal Transplantation Outcomes Objective: Determine the optimal management of hyperglycemia in patients with diabetes or impaired glucose tolerance receiving renal transplantation. Methods: RCT with patients (n=93) undergoing renal transplantation randomized to either iv insulin therapy (intensive) or standard sc insulin therapy while the patients were admitted to the hospital. Interventions: The study consisted of a 3-day postrenal transplant group treated with intensive iv insulin (n= 44, BG 70 110 mg/dl) or a control group treated with sc insulin (n= 49, BG 70 180 mg/dl). Primary endpoint: delayed graft function (DGF). Secondary endpoints: glycemic control, graft survival, and acute rejection episodes. Hermayer et al. J Clin Endocrinol Metab 97, 2012

Association of Pretransplant Glycemic Control With Posttransplant Outcomes in Diabetic Kidney Transplant Recipients All Cause Mortality Graft Failure HR (95% CI) of posttransplant, graft failure censored all-cause death (A), posttransplant, all-cause death (B), posttransplant, graft failure censored cardiovascular death Changes in BG concentrations in patients treated with iv insulin (intensive group) vs. insulin (control group). Hermayer et al. J Clin Endocrinol Metab 97, 2012

Kaplan-Meier survival curves modeling the time to nephrectomy or biopsy-confirmed rejection Hermayer et al. J Clin Endocrinol Metab 97, 2012 Summary and Conclusion First prospective RCT that compared the effects of BG control, using iv insulin (BG target 70 110 mg/dl) or sc insulin (BG target 70 180 mg/dl) in patients with impaired glucose tolerance or DM undergoing renal transplantation. Despite improved glycemic control, participants on intensive therapy experienced increased risk for rejection episodes and hypoglycemic events. In conclusion, BG target < 180 mg/dl resulted in a lower incidence of kidney rejection than a BG target of 70 110 mg/dl. Due to these results, intensive glycemic control at the time of kidney transplantation is not recommended. Hermayer et al. J Clin Endocrinol Metab 97, 2012

Pregestational Diabetes in Pregnancy High HbA1c in first trimester shown to be associated with increased risk of miscarriage and increased congenital malformation rate Increased red blood cell turnover: A1C is lower in normal pregnancy than in nonpregnant women. A1C target in pregnancy is 6 6.5% <6% if achievable without significant hypoglycemia may be <7% if necessary to prevent hypoglycemia. Intensive use of per and post meal glucose monitoring American Diabetes Association. Management of diabetes in pregnancy. Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(Suppl. 1):S94 S98 So, does diabetic control matter? a definite yes Lowering A1C to <7% reduces microvascular complications and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease. Consider more stringent goals (e.g. <6.5%) for select patients if achievable without significant hypos or other adverse effects. Consider less stringent goals (e.g. <8%) for patients with a hx of severe hypoglycemia, limited life expectancy, or other conditions that make <7% difficult to attain. But remember BP, lipid, weight management all just as important, and maybe more so