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A 52-year-old overweight Caucasian male is referred to your clinic by his optician, who noted retinopathy, specifically ‘dot’ and ‘blot’ haemorrhages, on a routine eye examination. The patient complains of blurred vision, increased thirst and lethargy. You elicit the following history:
PC – blurred vision; polydipsia.
HPC – both eyes, for 2 months; becoming increasingly lethargic.
PMH – unremarkable.
DH – nil; no known drug allergies.
SH – 30 pack-years; 25 units EtOH per week.
FH – father had hypertension; mother died aged 72, stroke.
PC, presenting complaint; HPC, history of PC; PMH, previous medical history; DH, drug history; SH, smoking history; FH, family
history; EtOH, alcohol.
On examination he is comfortable at rest, there are no peripheral stigmata of cardiovascular disease, his radial pulse is 86, BP 150/95 mmHg, the JVP is not raised, nor is the apex beat displaced. On auscultation heart sounds S1 and S2 are normal. Dorsalis pedis and posterior tibialis pulses are palpable. Ophthalmoscopy reveals dot and blot haemorrhages on the retinae. The patient is 1.76 m tall and weighs 102 kg.
A lipid profile reveals HDL cholesterol to be 0.98 mmol/L (38 mg/dL) and triglyceride 1.80 mmol/L (164 mg/dL).
A random glucose tolerance test reveals a plasma glucose concentration of 14.0 mmol/L (255 mg/dL).
(a) What is your diagnosis and what do you do?
You diagnose hypertension associated with type 2 diabetes (DM2). These conditions, in addition to his low HDL, high triglycerides and obesity ( body mass index < 31 ), are consistent with a diagnosis of the metabolic syndrome. You advise him to stop smoking, reduce his alcohol intake (21 units per week is the maximum recommended intake for men; 14 units per week for women) and follow a diabetic diet, in which daily sodium intake does not exceed 6 g. You also prescribe him a statin and an antihypertensive agent.
(b) What is the target blood pressure in non-diabetic and diabetic patients?
Although antihypertensive drug therapy in non-diabetics is appropriate if the systolic reading is sustained at>160 mmHg, or the diastolic reading is >100 mmHg, in DM2 patients therapy should be commenced at lower pressures (>140 mmHg systolic and/or >90 mmHg diastolic), with the aim of reducing BP to < 130/80 mmHg.
(c) Why do as many as 75% of people with DM2 have hypertension?
There are a number of mechanisms by which the hyperinsulinaemia and insulin resistance characteristic of DM2 may cause hypertension. For example, glycosylation of proteins caused by hyperglycaemia is thought to lead to cross-linking of collagen and loss of elasticity of major arteries, which can result in systolic hypertension. Moreover, insulin resistance and hyperinsulinaemia are associated with hypertension because high insulin levels suppress renal Na+ excretion and stimulate the sympathetic nervous system (see Chapter 38).
(d) Which antihypertensive drug do you prescribe as first-line therapy and why is this class of drug preferred?
You prescribe an ACE inhibitor (ACEI). A meta-analysis (Pahor et al. (2000) Diabetes Care 23: 888–92) of four clinical trials comparing the efficacy of ACEI in DM2 versus other antihypertensives revealed ACEI to be superior. However, the long-held belief that ACEI are especially beneficial in diabetics, due to their renoprotective benefit, in addition to their blood pressure-lowering effect, is being challenged. A meta-analysis (Casas et al. (2005) Lancet 366: 2026–33) suggests ACEI do not confer renoprotection.
(e) Which is the most important prognostic indicator of a cardiovascular event: systolic, diastolic or the pulse pressure?
The pulse pressure is the most accurate predictor of a cardiovascular event. A wide pulse pressure largely reflects a high systolic level. At all ages systolic pressure is more predictive of risk than is diastolic, and this is especially important in the elderly.
(f) What additional risk of cardiovascular mortality is conferred by DM2?
Diabetics have a 2–5 times higher chance of dying from coronary heart disease (CHD) than do non-diabetics, depending on whether other risk factors are also present. About two in every three people with diabetes will die of cardiovascular disease.In the Joint British Societies’ guidelines, diabetes is judged to confer the risk equivalent to established CHD.
(g) Why should this patient now receive a diuretic, in addition to the other antihypertensive agent? And from which class?
Because his blood pressure is inadequately controlled on one antihypertensive, he needs additional therapy. He should receive a thiazide diuretic, such as bendroflumethiazide (2.5 mg/day), because thiazides are associated with reduced stroke mortality, and this benefit offsets the concerns that thiazides, at least in large doses, may reduce glucose tolerance. The combination of an ACEI with a thiazide is particularly attractive, as the ACEI will inhibit the diuretic-stimulated activation of the renin–angiotensin system and the K-sparing activity of the ACEI may protect against cardiac mortality.
(h) Which adjunct therapy should be given?
You prescribe a long-acting calcium-channel blocker (CCB). The HOT and Syst-Eur trials found that treatment of hypertension in diabetics with a CCB reduced cardiovascular mortality, and the ASCOT trial reported that the combination of the CCB amlodipine with the ACEI perindopril was more effective in reducing mortality than the combination of a beta-blocker and a thiazide diuretic.
Because he does not have proteinuria (an indicator of renal disease), you select a CCB from the dihydropyridine class: amlodipine. (If he did have < 300 mg/day proteinuria, you would select a non-dihydropyridine, such as verapamil, as some dihydropyridines worsen proteinuria.)
(i) What action do you take now?
You add in a low-dose beta-blocker, such as bisoprolol (2.5 mg/day).
(j) Which glucose-lowering drug do you prescribe?
You prescribe metformin, and if this fails to reduce blood glucose, then you add in rosiglitazone.
The patient’s blood pressure and blood glucose levels remain well controlled on this treatment regimen.
Concluding remarks - There has long been a recognized relationship between diabetes and hypertension and the metabolic syndrome encompasses these distinct conditions, along with hyperinsulinaemia, reduced HDL cholesterol, hypertriglyceridaemia and central obesity. The metabolic syndrome is defined as more than three of the following: hypertension; diabetes mellitus; body mass index >30; triglycerides >1.69 mmol/L; HDL cholesterol <1.04 mmol/L.
Hypertension is extremely common in people with DM2, affecting up to 75%. Aggressive hypertension control reduces macro- and microvascular risks, such as decreased visual acuity and end-stage renal disease. The risk reduction seen in diabetics with hypertension is substantially greater than in the general population with similar levels of blood pressure.
In the HOT study, a reduction in diastolic blood pressure of 4 mmHg resulted in a 50% decrease in cardiovascular events in patients with diabetes. Non-diabetics participating in the same trial received much less benefit after the same drop in diastolic pressure.
The priority of diabetes treatment in terms of macrovascular disease lies not in the control of blood glucose but in the control of hypertension. Glycaemic control is much more effective in reducing microvascular complications (retinopathy, nephropathy and neuropathy).