Section 1

Brian, 52 years old, has recently been diagnosed with type 2 diabetes. He has no known significant comorbidities or diabetic complications. Brian is a non-smoker who consumes around 20 units of alcohol per week and works as a plasterer.

Recent records show: BP 167/97 mmHg, BMI 30.4 kg/m², HbA_1c 64 mmol/mol, cholesterol 5.9 mmol/L, non-HDL cholesterol 3.7 mmol/L, ACR 0.8 mg/mmol, eGFR 86 mL/min/1.73 m².

Brian has been advised on lifestyle measures, prescribed metformin and statin therapy is being considered.

What else should you do to confirm the diagnosis of hypertension?

Section 2

Certainly, Brian should have a repeat BP measurement. Hypertension is defined as a sustained blood pressure of ≥140/90 mmHg (1). Ideally, for a new diagnosis of hypertension, NICE guidelines recommend offering ambulatory blood pressure monitoring (ABPM) or, if this is unsuitable, home blood pressure monitoring (HBPM) (2). HBPM can help avoid overtreatment of people with white-coat hypertension.

Important practical points about accurately measuring BP, and use of ABPM and HMBP, have been described previously in Diabetes & Primary Care (3).

A repeat clinic BP reading of 163/96 mmHg was obtained for Brian. Later, a HBPM average came back as 159/93 mmHg.

How would you interpret Brian’s BP results?

Section 3

The lower of the two clinic BP readings should be taken as the clinic BP.

An ABPM daytime average or HBPM average >135/85 mmHg indicates hypertension (2). Thus, Brian’s HBPM result confirms the diagnosis of hypertension (stage 2).

What further investigations looking for end-organ damage would you carry out for Brian?

Section 4

In parallel with HBPM, you should check a urine dipstick (for blood and protein) and send a urine sample for albuminuria (albumin–creatinine ratio; ACR) to look for renal damage (2). Brian already had results for renal function, electrolytes and lipid profile.

Brian’s fundi should be examined for the presence of diabetic/hypertensive retinopathy and cardiac auscultation performed. An ECG is recommended, looking for left ventricular hypertrophy and ischaemia in particular (2).

An assessment of Brian’s cardiovascular (CV) risk is useful in directing the need for statin therapy. QRISK2 is the recommended tool and if this is ≥10% (10-year risk of a CV event), a statin could reasonably be offered (4).

What can be the consequences of hypertension in the individual with diabetes?

Section 5

There is strong evidence that a BP >140/90 mmHg is associated with atherosclerotic CV disease (myocardial infarction [MI]/angina, stroke/TIA, peripheral vascular disease), heart failure, increased mortality and microvascular complications of diabetes (retinopathy, nephropathy) (5).

In individuals with diabetes, the frequency of hypertension is doubled (compared to no diabetes) (3) and those with both diabetes and hypertension have a CV risk approximately three times that of people with either diabetes or hypertension alone (6).

What BP target would you set for Brian?

Section 6

Brian has no accompanying diabetic complications or comorbidities and so NICE would recommend a target of <140/90 mmHg, based on evidence that treatment to this level reduces CV events and microvascular complications (1,2) (see Section 7 if you would like more details).

“Lower” may not always be better and, indeed, there is some evidence of a “J-shaped curve” describing an increase in adverse CV events if BP is lowered excessively, notably in people with established CV disease (7).

The consensus across various guidelines is moving towards a target of 135–140/85–90 mmHg, with lower BP targets reserved for those at high risk of stroke or with renal disease, and less stringent BP targets in the elderly (≥80 years of age).

For individuals with both diabetes and chronic kidney disease (CKD), latest NICE guidance suggests targets of <140/90 in adults with CKD and ACR <70 mg/mmol, and <130/80 in adults with CKD and ACR ≥70 mg/mmol (8).

Section 7 – some evidence guiding BP treatment target

UKPDS established that tighter BP control (mean BP 144/82 mmHg) versus less tight control (mean BP 154/87 mmHg) led to reductions in both macrovascular and microvascular complications in individuals with type 2 diabetes. A lower threshold of BP for benefit was not identified, and there was no legacy effect (i.e. if treatment was stopped, the risk increased) (9).

The ADVANCE trial in patients with type 2 diabetes showed that additional BP lowering (to a mean of 133/75 mmHg) using a combination of perindopril and indapamide significantly reduced CV mortality and improved renal outcomes (10).

However, an arm of the ACCORD study looking at people with type 2 diabetes and hypertension revealed that intensive lowering of systolic BP led to a small reduction in risk of stroke, but did not improve the primary outcome of CV events and deaths. Thus, a systolic BP <120 mmHg was not associated with superior outcomes compared to a systolic BP <140 mmHg. Furthermore, adverse events secondary to antihypertensive treatment (e.g. syncope, hyperkalaemia) were more common in the intensively treated group. Systolic BP <130 mmHg was associated with slower progression of proteinuria compared to systolic BP <140 mmHg, but no significant difference was found between the two groups in regard of progression to end-stage renal failure and dialysis (11).

Several meta-analyses of randomised controlled trials (RCTs) included hypertensive people with type 2 diabetes (12–14). These generally conclude that reducing BP to below 140/90 mmHg reduces the risk of atherosclerotic CV disease (ASCVD), heart failure, retinopathy, albuminuria and mortality. Lowering BP <130/80 mmHg can additionally reduce the risk of stroke, retinopathy and albuminuria, though no further benefit on ASCVD or heart failure is apparent.

A Cochrane systematic review looking at five RCTs concluded that current evidence does not support BP targets lower than standard targets in people with hypertension and diabetes (i.e. <140/90 mmHg). Whilst acknowledging that a lower systolic BP may lead to a reduction in incidence of stroke, it was judged that this was counterbalanced by an increase in adverse side-effects (8).

A more recent systematic review and meta-analysis, however, which included people with type 2 diabetes, concluded that there was further CV benefit in reducing systolic BP <130 mmHg (13), and the STEP trial supported this for older people (15). Thus, the NICE guidance for less intensive BP targets, particularly for those >80 years, has been challenged (16).

What lifestyle advice would you offer Brian in regard of his hypertension?

Section 8

There is clear evidence that lifestyle intervention can reduce BP in type 2 diabetes (17). Brian should be encouraged to lose weight. In addition to the positive effects of weight loss on diabetes control, it is estimated that a 1 kg loss in body weight is associated with a 1 mmHg reduction in BP (18).

Switching to a healthy diet can lead to a BP reduction equivalent to that of a single antihypertensive drug (19). A high fibre and low sodium diet appears to have the greatest effect on lowering both systolic and diastolic BP (20). Increased consumption of fruit and vegetables, wholegrain food and pulses, and choosing fish, lean meats and low-fat dairy products can, in addition to benefiting BP, improve glycaemic and lipid control (1). The DASH (Dietary Approaches to Stop Hypertension) eating plan has been promoted to help reduce BP (21).

Advise Brian to keep dietary salt intake low, bearing in mind the “hidden” salt in processed foods. Reducing salt intake can lower BP (22), but substitutes with potassium chloride should be avoided (especially in the elderly, CKD and those taking an angiotensin-converting enzyme-inhibitor [ACEi], angiotensin receptor blocker [ARB] or potassium-sparing diuretic).

If appropriate, advise reduced intake of alcohol (for reduction of BP and other health benefits) and smoking cessation. Excessive coffee and other caffeine-rich product consumption should be discouraged (2).

Encourage Brian to exercise regularly with an activity he can sustain, aiming for 30 minutes of brisk walking or equivalent per day (2).

All individuals newly diagnosed with type 2 diabetes should be referred to their local diabetes education programme (23).

What would be your first choice antihypertensive for Brian?

Section 9

Ultimately, selection of an antihypertensive will be an individual choice influenced by patient age, ethnicity, comorbidity and concurrent medications. Achieving the desired BP target is more important than using a specific agent. For many patients, a combination of antihypertensive drugs will be required to reach the BP goal.

ACEis (e.g. ramipril, lisinopril) and ARBs (e.g. losartan, irbesartan) are recommended by NICE as a first-line choice in treating hypertension in adults with type 2 diabetes of whatever age or family origin (2). These agents have been demonstrated to reduce CV events in people with diabetes (24).

ACEis and ARBs exert a renoprotective effect over and above their effect on BP, and this is particularly evident in individuals with proteinuria (ACR >30 mg/mmol) (25,26). This benefit extends to normotensive people with proteinuria.

Whilst the actions of ACEis and ARBs in providing BP control and renoprotection are considered interchangeable, the advantage of ARBs is a reduced propensity to induce cough and angioedema. In people with black African or African–Caribbean family origin, an ARB may be preferred over an ACEi (2). The combination of an ACEi and ARB does not appear to improve outcomes and increases the risk of acute kidney injury and hyperkalaemia, so is not recommended (26,27).

Renal function and electrolytes need to be carefully monitored after initiation or dose alteration of a RAAS blocker between 1 and 2 weeks), looking for hyperkalaemia (much more likely if starting potassium [K] level is >4.5 mmol/L or if eGFR <45 mL/min/1.73 m² (1)) and an excessive drop in eGFR (which might imply renal artery stenosis). Generally, avoid starting an ACEi or ARB if serum K >5.0 mmol/L, and stop or reduce dose of these agents if K level reaches 6 mmol/L. NICE guidance suggests a cumulative fall in eGFR of up to 25% is acceptable (28). Remember that in a situation of hypovolaemia (e.g. diarrhoea and vomiting), then ACEis and ARBs should be temporarily paused to reduce the risk of acute kidney injury (patients should be informed).

Brian was commenced on losartan 25 mg once daily and, over subsequent weeks, the dose was titrated up to 100 mg once daily. Renal function remained stable and, by this time, Brian’s BP had fallen to 149/92 mmHg.

How would you respond to Brian’s latest BP measurement?

Section 10

At this stage a second antihypertensive is indicated, aiming for a BP of 140/90 mmHg, but first check that Brian is taking the losartan as prescribed.

You should consider adding in either a dihydropyridine calcium-channel blocker (DHPCCB; e.g. amlodipine) or a thiazide-like diuretic (e.g. indapamide) (1,2). Both these classes of medication have evidence of improved CV outcomes in people with diabetes (29,30). Other factors may direct a choice between these two classes of treatment; for example, thiazide-like diuretics may be preferred in the setting of heart failure and DHPCCBs preferred in ischaemic heart disease.

If ACEis/ARBs were contraindicated or poorly tolerated, then thiazide-like diuretics or CCBs would become the first-line treatment.

If Brian’s BP was still persistently above target on dual therapy, then a third agent should be added, so that triple therapy would then consist of ACEi/ARB + DHPCCB + thiazide-like diuretic.

What side-effects would you be on the lookout for with CCBs and thiazide-like diuretics?

Section 11

Peripheral oedema is often noticed with CCBs, particularly at top dose. Flushing and headaches may be troublesome. These side-effects may be relieved by dose reduction.

Electrolyte disturbance (hypokalaemia, hyponatraemia) is relatively common with thiazide diuretics, particularly in the elderly, who are also susceptible to postural hypotension. In acute illness where dehydration is a concern, diuretics should be temporarily withheld.