Diabetes and Hypertension William C. Cushman, MD, FAHA, FACP, FASH Chief, Preventive Medicine, Veterans Affairs Medical Center Professor, Preventive Medicine, Medicine, and Physiology University of Tennessee Memphis, Tennessee, USA Ele Ferrannini, William C Cushman. Diabetes and Hypertension: the bad companions. Lancet 2012; 380:601 10.
Disclosures William C. Cushman, MD Grant/Research Support: NHLBI/NIH, Merck Consultant: Takeda, Merck, Omron, Daiichi- Sankyo, Astra Zeneca
Disclaimer Although I was a member of JNC 7 and am a member of the NHLBI JNC 8 expert panel, this presentation is based on my review and interpretation of the literature/my opinions, and not to be construed as reflective of what JNC 8 will recommend.
Phenotypic characteristics associated with BP in people without hypertension or diabetes: multiple regression model Sex (female) Menopause Familial HTN Age (+8 yrs) BMI (+4 kg/m 2 ) Waist +(13 cm) HR (+10 bpm) IGT/DM Smoking -4-3 -2-1 0 1 2 3 4 Mean BP (mmhg) RISC: Relationship between Insulins Sensitivity and Cardiovascular Disease n=1308 Ferrannini, Cushman. Lancet 2012; 380:601 10
Phenotypic characteristics associated with hypertension in patients with type 2 diabetes: multiple logistic model Gender (male) Familial HT Age (10 years) BMI (5 kg/m 2 ) Duration (10 years) egfr (20 ml. min -1. 1.73m 2 ) Microalbuminuria Macroalbuminuria Background retinopathy Advanced retinopathy Myocardial infarction Stroke 0.5 1 6.5 Odds ratio (95% C.I.) RIACE: Renal Insufficiency And Cardiovascular Events, n=15,773 Ferrannini, Cushman. Lancet 2012; 380:601 10
Cardiovascular Mortality Rate per 10,000 Patient-Years Elevated SBP in Type 2 Diabetes Increases Cardiovascular Risk 250 200 Elevated SBP increases risk of CV death almost twofold in diabetic vs nondiabetic patients Nondiabetic patients Diabetic patients 150 100 50 0 <120 120 139 140 159 160 179 180 199 200 Stamler J et al. Diabetes Care. 1993;16:434-444. SBP (mm Hg) MRFIT
Schematic representation of the intracellular insulin signaling pathways Hyperinsulinaemia Cell membrane Receptor Insulin secretion Intracellular signalling pathways Insulin resistance feedback Glucose disposal B C Effector systems B,C: non-glucose effectors
Vascular Actions of Insulin Potentially positive Potentially negative Stimulation of nitric oxide synthase Inhibition of nuclear factor kappa B Inhibition of platelet aggregation Anti-inflammatory Antithrombotic Hypertrophy vis mitogen-activated protein kinase Stimulation of endothelin-1 Membrane hyperpolarization Adrenergic activation Antinatriuresis Stimulation of plasminogen activator inhibitor- 1 Reactive oxygen species generation Smooth muscle cell proliferation Vasoconstriction Extended QTc interval Fluid retention Prothrombotic
Why is it important not to intensify medications to reduce BP below the level proven in trials? It identifies a much larger proportion of the population as having hypertension and presumably needing drug therapy. Those previously classified as HTN require more drugs to achieve lower BP goals. Treating to lower BP levels may be harmful (J-curve?). If neither beneficial nor harmful, resources would be wasted and patient adherence may suffer.
RCTs Testing BP Goals In Hypertensive Diabetic Patients Trial n Duration (years) SBP goal, mmhg DBP goal, mmhg Mean BP, less intense, mmhg Mean BP, more intense, mmhg Outcome Risk Reduction SHEP 583 5 <148 none 155/72 146/68 Syst-Eur 492 2 <150 none 162/82 153/78 HOT 1,501 3 none <80 148/85 144/81 UKPDS 1,148 8.4 <150 <85 154/87 144/82 ABCD 470 5.3 none <75 138/86 132/78 ACCORD 4,733 4.7 <120 none 134 119 Stroke 22% (ns) CVD 34% CHD 56% Stroke 69% CVD 62% CVD 51% MI 50% Stroke 30% (ns) CV death 67% DM-related 34% deaths 32% Stroke 44% Microvasc 37% Renal (1º) nc Microvasc nc Death 49% CVD ns CVD (1º) 12% (ns) Stroke 41%
ACCORD BP Trial: Systolic BP (mean + 95% CI) Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 Average after 1 st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2 N - 4733 RZ: SBP <120 vs <140 DBP for the same time interval averaged 70 & 64 mm Hg (Delta = 6 mm Hg) Cushman, et al. N Engl J Med. 2010;362:1575-85
Intensive Events (%/yr) Standard Events (%/yr) HR (95% CI) P Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20 Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55 Cardiovascular Deaths 60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74 Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25 Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03 Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01 Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularization and unstable angina (HR=0.95, p=0.40)
Nonfatal Stroke Total Stroke 100 100 Patients with Events (%) 80 60 40 20 HR = 0.63 95% CI (0.41-0.96) P=0.03 Patients with Events (%) 80 60 40 20 HR = 0.59 95% CI (0.39-0.89) P=0.01 Stroke 1 of 8 2º CVD outcomes and relatively uncommon P values not corrected for multiple comparisons NNT = 89 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Years Post-Randomization Years Post-Randomization Cushman, et al. N Engl J Med. 2010;362:1575-85
ADVANCE BP Trial 11,140 patients with type 2 diabetes randomized to addition of indapamide + perindopril vs PBO on usual therapy. Significant 14% reduction in mortality (stopped early) and 9% reduction of combined macro- and microvascular outcomes, but neither significant alone. Mean SBP in intensive group was 135 mm Hg, similar to mean SBP in ACCORD standard BP group. Patel, et al. Lancet 2007;370:829-840
Blood Pressure Goals in Patients with Diabetes and Hypertension Clinical trial evidence suggests to me that BP <140/85 mm Hg is a reasonable therapeutic goal in patients with type 2 diabetes mellitus. This is my opinion and not to be assumed to represent what JNC 8 will say.
Treatment of Hypertension in Diabetes Mellitus Lifestyle interventions for: Prevention Treatment Drug treatment
Diabetes subgroup analyses Is there a difference in the treatment effect of commonly used blood pressure lowering regimens between patients with and without diabetes?
Heart Failure BP (mmhg) Favours first listed Favours second listed RR(95%CI) ACE-I vs. D/BB Diabetes No diabetes Overall CA vs. D/BB Diabetes No diabetes Overall ACE-I vs. CA Diabetes No diabetes Overall 2.5/0.4 1.8/0.3 0.5/-0.8 0.5/-0.5 1.6/1.2 1.3/0.9 0.94 (0.55,1.59) 1.09 (0.95,1.25) p homog =0.59 1.27 (1.01,1.61) 1.33 (1.16,1.52) p homog =0.83 0.92 (0.67,1.27) 0.86 (0.73,1.01) p homog =0.67 0.25 0.5 1 2 Risk ratio
Major CVD BP (mmhg) Favours first listed Favours second listed RR(95%CI) ACE-I vs. D/BB Diabetes No diabetes Overall CA vs. D/BB Diabetes No diabetes Overall ACE-I vs. CA Diabetes No diabetes Overall 2.2/0.3 1.4/0.2 0.7/-0.8 1.1/-0.4 1.6/1.2 1.3/0.9 0.90 (0.74,1.11) 1.04 (0.98,1.04) p homog =0.20 1.02 (0.95,1.10) 1.04 (0.99,1.10) p homog =0.83 0.92 (0.79,1.07) 0.99 (0.92,1.07) p homog =0.37 0.25 0.5 1 2 Risk ratio
Conclusions (1) Similar proportional risk reductions achieved with regimens based on ACE inhibitors, calcium antagonists and diuretics/beta-blockers (from both placebo controlled and head-to-head comparisons) More intensive blood pressure lowering regimens may, however, be of particular benefit in patients with diabetes
Conclusions (2) Little evidence from these analyses that any drug class provides special protection against macrovascular events among patients with diabetes Clinicians might reasonably use any agent for first line therapy in patients with diabetes Many patients are likely to require two or more agents
Robert E. Lamb, PharmD ACCOMPLISH Study End Points in Patients With Diabetes (n=6,946) Characteristic Favors B+A Favors B+H Hazard Ratio (95% CI) p-value Primary end point* 0.79 (0.68 0.92).003 Fatal and non-fatal MI 0.85 (0.63 1.15).283 Stroke 0.91 (0.65 1.28).607 Cardiovascular (CV) death 0.84 (0.60 1.18).312 Coronary revascularization 0.80 (0.66 0.97).024 Clinical coronary event** 0.73 (0.57 0.94).013 CV death + MI + stroke 0.84 (0.68 1.03).085 Hospitalized HF 1.11 (0.80 1.54).545 All-cause death 1.02 (0.80 1.29).887 Renal end point 0.53 (0.45 0.63) <.001 0,25 0,50 0,75 1,00 1,25 1,50 Hazard Ratio * Time to first event, defined as a composite of CV events or death from CV causes ** MI + Hospitalized unstable angina + Sudden cardiac death > 50% increase in serum creatinine with final value above normal range MI=myocardial infarction; HF=heart failure B: benazepril 40 mg/d A: amlodipine 5-10 mg/d H: HCTZ 12.5-25 mg/d Adapted from: Weber MA, et al. J Am Coll Cardiol. 2010;56:77-85
ALLHAT Diabetics & Nondiabetics (History) Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals Diabetics Nondiabetics CHD 0.99 (0.87, 1.13) Mortality 0.96 (0.87, 1.07) Stroke 0.90 (0.75, 1.08) Heart Failure 1.42 (1.23, 1.64) Combined CVD 1.06 (0.98, 1.15) ESRD 1.30 (0.98, 1.73) 0.97 (0.86,1.09) 0.95 (0.87, 1.04) 0.96 (0.81, 1.14) 1.33 (1.16, 1.52) 1.02 (0.96, 1.09) 0.86 (0.60, 1.25) 0.50 1 2 0.50 1 2 Favors Favors Favors Favors Amlodipine Chlorthal Amlodipine Chlorthal There is no difference in treatment group effect by baseline history of diabetes. JAMA 2002;288:2981-2997
ALLHAT Diabetics & Nondiabetics (History) Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals Diabetics Nondiabetics CHD 1.00 (0.87, 1.14) 0.99 (0.88, 1.11) Mortality 1.02 (0.91, 1.13) 1.00 (0.91, 1.09) Stroke 1.07 (0.90, 1.28) 1.23 (1.05, 1.44) Heart Failure 1.22 (1.05, 1.42) 1.20 (1.04, 1.38) Combined CVD 1.08 (1.00, 1.17) 1.12 (1.04, 1.19) ESRD 1.17 (0.87, 1.57) 1.05 (0.74, 1.48) 0.50 1 2 Favors Favors Lisinopril Chlorthal 0.50 1 2 Favors Favors Lisinopril Chlorthal There is no difference in treatment group effect by baseline history of diabetes. JAMA 2002;288:2981-2997
Network Meta-analysis of Diabetes Incidence with Antihypertensive Drug Classes 22 trials, n=143,153 Elliott WJ, Meyer PM. Lancet 2007; 369: 201 07.
Differences in Diabetes Incidence Between Antihypertensive Drugs Thiazide-type diuretic &/or b-blocker: diabetes incidence <1% to 2% higher vs placebo or CCB over several years. Difference doesn t worsen. ACEI or ARB: diabetes incidence 0% to 2% lower than PBO or CCB in large trials. Average difference between drugs usually no more than 2-6 mg/dl.
Do differences in glucose levels or diabetes incidence with AHT drugs produce detectable changes in CVD outcomes?
Long-Term Effects of Incident Diabetes Mellitus on Cardiovascular Outcomes in People Treated for Hypertension: The ALLHAT Diabetes Extension Study Chlorthalidone Amlodipine Lisinopril Circ Cardiovasc Qual Outcomes. 2012;5:153-162.
Initial Combinations of Antihypertensive Medications in Diabetes Mellitus* Diuretics ACE inhibitors or ARBs Calcium antagonists * Compelling indications may modify this.
Diabetes and Hypertension Hypertension is present in >2/3 of patients with type 2 diabetes. The development of hypertension can precede and predict the development of dysglycaemia, and impaired glucose tolerance can predict the development of HTN. Hypertension and diabetes confer a much enhanced risk of cardiovascular disease than either one alone. Many pathophysiological mechanisms may underlie this association, including insulin resistance, the stimulatory effect of hyperinsulinaemia on sympathetic drive, smooth muscle growth, sodium fluid retention, and the excitatory effect of hyperglycaemia on RAAS.
Diabetes and Hypertension Clinical trial evidence suggests that BP <140/85 mm Hg is a reasonable therapeutic goal in patients with type 2 diabetes mellitus. Treatment-induced CVD risk reduction in people with diabetes is not different from that of patients with HTN without diabetes. In patients with diabetes, a combination of a RAS-blocker and a thiazide-type diuretic might be the most reasonable initial antihypertensive regimen, although CCBs and CCB-ACEI combination are also effective. The effects of antihypertensive drugs on glucose metabolism should probably be a minor consideration relative to their effects on major CVD outcomes.