Thursday, August 4, 2011

Hypertension and Diabetes

James Reed, MD, Professor of Medicine at Morehouse School of Medicine, was the third speaker in the morning session and further elaborated on the relationship between hypertension and diabetes.

The Relationship Between Hypertension and Diabetes

There is an intimate relationship between diabetes mellitus (DM) and hypertension. It is estimated that if diabetic patients live long enough, approximately 75% will develop hypertension. The following mechanisms mediate the development of hypertension in diabetes:
  • Activation of the tissue-based renin-angiotensin-aldosterone axis;

  • Volume expansion secondary to hyperglycemia;

  • Reduced baroreceptor response;

  • Autonomic dysfunction (exaggerated orthostatic response and loss of circadian rhythm without the normal nighttime depression in blood pressure); and

  • Endothelial dysfunction and vascular oxidative stress.

Hypertension is more difficult to control in diabetic patients than in nondiabetic patients. Several published studies[1] corroborate the need for multiple antihypertensive agents -- on average, 3 -- to achieve target blood pressure goals in this population.
In addition, increasing systolic blood pressure portends even greater increases in mortality in diabetic patients than in nondiabetic patients, and even at normal blood pressure, the risk for cardiovascular death is 25-fold greater. The UK Prospective Diabetes Study (UKPDS) plotted the parallel increase in microvascular events, such as blindness, gastroparesis, and end-stage renal disease (ESRD), against the occurrence of myocardial infarction, a macrovascular event. The incidence of both micro- and macrovascular events increases proportionately in diabetic persons at each increasing increment of systolic blood pressure.[2] The bottom line is that to prevent both types of events, blood pressure must be aggressively managed and controlled.

Predicting Mortality and Morbidity in Diabetic Nephropathy

Diabetes and its effect on the microvasculature is well known, especially with regard to the kidney. Diabetes mellitus is the leading cause of ESRD, and the overall incidence of ESRD has been steadily increasing each year. However, these microvascular changes actually occur, on average, 8-10 years before the diagnosis. Ideally, there would be an easily administered test to measure insulin resistance or prediabetes. Unfortunately, the current methods of euglycemic insulin clamping are nonstandardized and too complex to use in everyday practice; they are used only in research studies.
Microalbuminuria, defined as urinary albuminexcretion > 4.8 micrograms/min, reflects the endothelial damage that occurs before diagnosis, and progression to macroalbuminuria predicts hypertension, renal disease, and other complications of diabetes.[3] Microalbuminuria is also a strong and independent determinant ofcoronary heart disease and death.[4] There is a positive correlation between the degree of proteinuria and cardiovascular death as well as the incidence of stroke and coronary heart disease.[5]

Treatment Recommendations in the Setting of Hypertension and Diabetic Nephropathy

The most effective first-line agent for control of blood pressure in patients with renal disease or DM is an angiotensin-converting enzyme (ACE) inhibitor, as recommended in the guidelines of both the Canadian and British Hypertension Societies, the National Kidney Foundation, the World Health Organization, and the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 6). Dr. Reed disagrees with JNC 6, however, that a diuretic should be the first-line agent if no albuminuria is present. He believes that an ACE inhibitor should be used as a first choice in this instance as well, although an average of 2-3 medications will usually be necessary to control blood pressure in most diabetic patients. Lewis and colleagues[6] were the first to demonstrate the benefit of an ACE inhibitor in patients with diabetic nephropathy. In their study, captopril compared with placebo slowed the rate of progression to dialysis and transplantation in a cohort of 409 patients who had type 1 diabetes and ESRD and were followed for 4 years (P = .006). Several later studies corroborated this renal survival benefit by using enalapril or benazepril and following patients for 3-5 years.
Despite the preponderance of evidence, many physicians still do not use ACE inhibitors in this context. Only an estimated 39% of US patients who should be taking ACE inhibitors according to current treatment guidelines are actually receiving them. This may be due to a fear of inducing an increase in serum creatinine level. Bakris and Weir[7] examined this question by reviewing 12 randomized trials to determine whether the use of ACE inhibitors or angiotensin-receptor blockers results in long-term protection against a decline in renal function in patients with renal insufficiency. They found that a limited elevation in serum creatinine level (≤ 30% above baseline) was usually seen in the first 2 weeks after initiation of therapy with an ACE inhibitor or angiotensin-receptor blocker. However, data from these studies in patients with diabetic and nondiabetic renal disease demonstrated that if an increase does occur, it stabilizes quickly and does not progressively worsen, and the effect on glomerular filtration rate is reversible. If serum creatinine level increases more than 30% on a long-term basis within the first month or if hyperkalemia occurs, the drug should be withdrawn.[7] In general, however, results indicated that use of drugs that block the renin-angiotensin system is appropriate in patients with renal insufficiency.
A second concern about using ACE inhibitors in diabetic hypertensive patients was their alleged relative ineffectiveness in the African-American population. In a study using trandolapril, Weir and colleagues[8] showed that systolic blood pressure decreased similarly in African-American patients and in white patients but at higher doses in the former group (4 mg vs 1 mg). Therefore, when proper doses are used, any disparity in effect can be eliminated.[8]
The renal protection offered by the renin-angiotensin-aldosterone blockade has multiple mechanisms, including hemodynamic effects of reduction in systemic blood pressure and glomerular capillary pressure because of efferent glomerular arteriolar dilation and proteinuria and nonhemodynamic effects of stimulation for extracellular matrix degradation and inhibition of macrophage infiltration.
Calcium-channel blockers (CCBs) are effective antihypertensive drugs, but their effects on urinary protein excretion in patients with proteinuric renal diseases and renal insufficiency has been unclear. A review of published data demonstrates that in patients with proteinuria, the dihydropyridine CCBs do not lower proteinuria, despite a reduction of blood pressure. However, information on the effects of the nondihydropyridine CCBs suggests that these agents might be just as beneficial as ACE inhibitors.[9] Subsequent studies using the combination of trandolapril (an ACE inhibitor) and verapamil (a non- dihydropyridine CCB) show a greater reduction of proteinuria than is seen with either agent alone. The reduction from the combination also occurs at lower doses of each drug and is independent of further reductions in arterial pressure.[10]
The hypertensive diabetic patient with increased capillary pressure and proteinuria has a high risk for renal disease and for coronary artery disease. Therefore, the combination of an ACE inhibitor and non-dihydropyridine CCB is recommended.[11] When taken together, these drugs reduce blood pressure, heart rate, and proteinuria as well as cardiovascular risk and renal disease progression.

References

  1. Bakris GL. Maximizing cardiorenal benefit in the management of hypertension: achieve blood pressure goals. J Clin Hypertens (Greenwich). 1999;1:141-147. Abstract
  2. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419. Abstract
  3. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med. 1997;157:1413-1418. Abstract
  4. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997. Abstract
  5. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996;27:2033-2039. Abstract
  6. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462. Abstract
  7. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685-693.
  8. Weir MR, Gray JM, Paster R, Saunders E. Differing mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. The Trandolapril Multicenter Study Group. Hypertension. 1995;26:124-130. Abstract
  9. Kloke HJ, Branten AJ, Huysmans FT, Wetzels JF. Antihypertensive treatment of patients with proteinuric renal diseases: risks or benefits of calcium channel blockers? Kidney Int. 1998;53:1559-1573. Abstract
  10. Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int. 1998;54:1283-1289. Abstract
  11. Kotchen JM, Shakoor-Abdullah B, Walker WE, et al. Hypertension control and access to medical care in the inner city. Am J Public Health. 1998;88:1696-1699. Abstract
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