The SA Journal Diabetes & Vascular Disease Vol 15 No 2 (November 2018)

VOLUME 15 NUMBER 2 • NOVEMBER 2018

REVIEW

SA JOURNAL OF DIABETES & VASCULAR DISEASE

which results in problems with interpretation. To obtain ranges for

gm/gm multiply the above ranges by 10.

Treatment and prevention of DKD and CV events require

a multifaceted approach. Healthy lifestyle remains crucial. For

example, in early DKD, physical inactivity increases mortality by

50%, smoking by 40%, excess alcohol intake by 21% and obesity

by 68%.

Blood pressure (BP) should be targeted to < 140/90

mmHg and ideally < 130/80 mmHg if well tolerated. All patients

with micro- and macroalbuminuria must receive an ACE inhibitor

or angiotensin receptor antagonist, even if normotensive, as this

prevents progression of microalbuminuria to macroalbuminuria,

the doubling of serum creatinine level and reduces end-stage

CKD.

All patients should receive statin treatment almost regardless

of serum cholesterol,

but aspirin is not routinely indicated unless

for secondary prevention of CV disease. In the early phases, tight

glucose control is recommended (HbA

< 6.5 mmol/l) as it prevents

the onset of early DKD and other microvascular complications.

In late DKD, tight glucose control has little impact and may be

harmful because of the risk of hypoglycaemia.

In the STENO-2 study this type of multifaceted approach

resulted in a 46% risk reduction in death, 59% in CV events,

61% in nephropathy and 58% in retinopathy. Importantly, these

benefits accrued only after five years of treatment.

Importance of Na

–glucose co-transport (SGLT) in

the kidney

The normal kidney filters 180 litres of plasma, approximately

24 000 mmol of Na

and 180 g or 1 000 mmol of glucose. The

sodium–glucose co-transporters (SGLT-1 and -2) completely

reabsorb glucose linked to Na

in the proximal tubule. Glucose

is reabsorbed one-to-one with Na

by SGLT-2 and one-to-two

by SGLT-1. SGLT-2 is responsible for 90% and SGLT-1 10% of

reabsorption.

Any defect in SGLT-2 results in renal glycosuria

that has no long-term harmful effects on the kidney. In diabetes,

particularly if it is suboptimally controlled, the filtration of glucose

increases and the SGLT is upregulated to counteract the increased

filtration.

However, once its threshold is exceeded, glycosuria

occurs, causing an osmotic diuresis, resulting in the typical

manifestations of uncontrolled diabetes, namely polyuria and

polydipsia.

Relationship between heart failure and DKD

These changes have a profound effect on renal autoregulation,

which potentially lies at the heart of the pathophysiology of DKD

and heart failure (HF). (Many physicians are not aware that HF is

more common than myocardial infarction in longstanding type

2 diabetics.)

Because the SGLT is upregulated by the increased

glucose load in diabetics there is both increased Na

(and glucose)

reabsorption. The resultant reduction in Na

delivery to the juxta

glomerular apparatus results in tubular glomerular feedback (TGF)

and activation of the intrarenal renin–angiotensin system (RAS).

The net result is a dilated afferent and constricted efferent arteriole,

causing increased intraglomerular pressure, hyperfiltration and

loss of autoregulation (Fig. 2). The position is compounded by the

increased systemic Na

reabsorption that stimulates atrial natriuretic

peptides, which increases renal blood flow, further exacerbating

the hyperfiltration. The glomerulus is particularly sensitive to the

effects of glomerular hypertension, hyperfiltration and loss of

autoregulation,

and is seen as a fundamental pathophysiological

mechanism for the development of nephropathy and the raised

GFR seen in early diabetes (Fig. 1). It also exposes the glomerulus

to systemic BP, and it is for this reason that both BP control and

RAS inhibitors are renoprotective. RAS inhibitors, in addition to

lowering BP, dilate the efferent arteriole and reduce glomerular

pressure, but do not fully restore autoregulation as the afferent

remains dilated

(Fig. 2). Longstanding increased Na

reabsorption

by the kidney may also be plausibly linked to development of HF

due to Na

overload and exacerbation of hypertension.

SGLT-2 inhibitors

Highly specific inhibitors of SGLT-2 have been developed

by several pharmaceutical companies. The best known are

empagliflozin, dapagliflozin and canagliflozin. Briefly, inhibition of

the co-transporter results in glucose wasting through the kidney,

resulting in insulin-independent improvement in HbA

similar to

that seen with metformin, sustained weight loss due to calorie

loss and significant reduction in BP due to natriuresis. These drugs

are now widely registered in many countries for the treatment of

type 2 diabetes.

In the kidney, SGLT-2 inhibitors increase natriuresis by blocking

glucose-mediated Na

uptake in the proximal tubule. The

resultant increased Na

delivery to the juxta glomerular apparatus

brings about constriction of the afferent arteriole through TGF,

resulting in restoration of renal autoregulation and reduction in

hyperfiltration. These effects reduce the GFR in the short term by

2–3 ml/min

but are likely to protect the kidney in the long term

in a manner similar to the effects of RAS inhibitors. Addition of

SGLT-2 inhibitors to RAS inhibitors is likely to fully restore renal

autoregulation (Fig. 2).

CV and kidney outcome studies with SGLT-2 inhibitors

Historically, although improving glycaemic control is associated

with reduction in microvascular events, the effects on improving

CV outcomes have generally been inconclusive.

It also became

apparent that some hypoglycaemia, for example rosiglitazone,

may be associated with CV harm.

For this reason in 2008 the

FDA required companies to demonstrate empirically that a

developmental drug for diabetes does not appear to increase the

rate of CV disease. As a result, a plethora of CV outcome studies

were launched. Most notably the DPP-4 inhibitors lowered glucose,

but did not improve CV outcomes.

This nihilism regarding prevention of CV outcomes was

dramatically changed when the EMPA-REG OUTCOME study was

presented at the European Association for the Study of Diabetes

congress in Stockholm in 2015.

Empagliflozin 10 and 25 mg

was compared to placebo in patients with uncontrolled diabetes

in patients with established CV disease or at very high risk for

CV disease, treated with standard of care. Both doses of

Table 1.

Interpretation of urinary albumin/creatinine ratio* (ACR) in

mg/mmol

Stage

ACR

Normoalbuminuria

< 3

Microalbuminuria

Macroalbuminuria

> 30

* For conversion of ACR to gm/gm multiply by 10.