Hypoglycaemia

Gupta et al. [1] do well in presenting the approach and management
strategy of hypoglycemia, a common clinical setting in primary care
clinic, but I think they can direct more emphasis upon renal dysfunction,
yet another common scenario which dodges our attention. When searching for
the cause of hypoglycemia, the first few ideas that flash through our mind
are usually lifestyle change, missing meals, or appetite change, but a
recent change of renal function rarely pops out in our list of
precipitating factors.

Why should we keep renal dysfunction in our mind? It can be explained
in the following two ways:

First, nephropathy is one of the most dreaded complications of
diabetes mellitus (DM). Earlier studies in 1970s have determined that
32~54% of patients with DM develop nephropathy within 15~20 years [2],
while with the renovation of treatment principle and practice,
microalbuminuria and overt proteinuria still occur in 27~39% and 7~12% of
patients with type II DM after 15 years [3]. The incidence of overt renal
failure is also estimated at roughly one event per 1000 patient-years in
UKPDS (United Kingdom Prospective Diabetes Study) [3]. From this view,
assuming that the patient in vignette has a fair glycemic control, we can
expect he has a 10% possibility of developing proteinuria and 1% risk of
renal failure over 10~15 years of disease. In addition, patients with
diabetic nephropathy [4] and diabetes per se [5] are at risk of developing
acute kidney injury, thus the index patient carries a certain risk of
chronic kidney disease (CKD) and also acute kidney injury (AKI).

Second, glycemic control can be bizarre during period of renal
function deterioration. Moren et al. have demonstrated from a large cohort
of CKD patients that estimated glomerular filtration rate (GFR) less than
60 ml/min per 1.73 square meter is a risk factor for hypoglycemia and
excessive mortality [6]. Similarly, glycemic variability and hypoglycemia
prominently increase during episode of critical patients with AKI [7]. The
evidence for hypoglycemia in renal failure, whether acute or chronic, is
thus abundant and convincing. The precise mechanism may involve impaired
endogenous or exogenous insulin degradation, and delayed excretion of most
oral hypoglycemic agents (OHA). Blunted gluconeogenesis of renal origin
likely plays a role, too.

With all of these issues in mind, we can now return to the real
world: "how often does renal dysfunction occur in the setting of newly
found hypoglycemia episodes?" This is best demonstrated by studies done in
emergency department (ED), since most episodes of hypoglycemia with
altered mental status happen outside of clinics. Sinert et al. have
performed an interesting study in EDs [8], investigating the utility of
routine laboratory testing in hypoglycemia management. They find that
about one-fourth of patients have new onset renal failure while one-third
patients have chronic renal insufficiency, verifying our prediction that
renal dysfunction is a common scenario during a newly found hypoglycemic
attack. There is also report that specifies unexplained hypoglycemia in a
diabetic patient should direct our attention to renal failure [9].

There are still other reasons that we should arrange renal function
test when dealing with hypoglycemia. Impaired renal function could
influence our choice of OHA classes, and also the dosage of insulin.
Patients with diabetic nephropathy are often given angiotensin-converting
enzyme inhibitor or angiotensin receptor blocker for halting disease
progression, and use of these agents have been reported to correlate with
reduced hypoglycemia risk in type II diabetic patients [10]. A clinical
encounter with hypoglycemic patients thus provides an excellent
opportunity for primary care physicians to check-out their patients'
diabetic progression, presence of microvascular complication, and at the
same time to revise their patients' current medication regimen. We may
find an otherwise asymptomatic patient with abnormally high creatinine
level and simultaneously receiving metformin or other potentially
nephrotoxic drugs. This population of patients should not be missed in our
clinics, I believe.

In light of the high percentage of renal dysfunction as precipitant
or contributing factors in hypoglycemia, and the potential benefit of
early detection of renal dysfunction, acute or chronic, I suggest checking
renal function routinely to rid these patients of the potential risk.
Hypoglycemia is, in itself, an opportunity to discover gaps in our
management plan, and we should all grasp this chance tightly and
efficiently.

REFERENCES

1. Gupta PS, Green AN, Chowdhury TA. 10-minute consultation: Hypoglycemia.
BMJ 2011;342:d567

2. Johnsson S. Retinopathy and nephropathy in diabetes mellitus:
Comparison of the effects of two forms of treatment. Diabetes 1960;9:1-8

3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 1998;352:837-53

4. Calvin AD, Misra S, Pflueger A. Contrast-induced acute kidney
injury and diabetic nephropathy. Nat Rev Nephrol 2010;6:679-88

5. Zhang X, Wu Z, Peng X, Wu A, Yue Y, Martin J, et al. Prognosis of
diabetic patients undergoing coronary artery bypass surgery compared with
nondiabetics: a systematic review and meta-analysis. J Cardiothorac Vasc
Anesth 2010,doi:10.1053/j.jvca.2010.09.021

6. Moen MF, Zhan M, Hsu VD, Walker LD, Einhorn LM, Seliger SL, et al.
Frequency of hypoglycemia and its significance in chronic kidney disease.
Clin J Am Soc Nephrol 2009;4:1121-7

7. Dickerson RN, Hamilton LA, Connor KA, Maish III GO, Croce MA,
Minard G, et al. Increased hypoglycemia associated with renal failure
during continuous intravenous insulin infusion and specialized nutritional
support. Nutrition 2010, doi:10.1016/j.nut.2010.08.009

8. Sinert R, Su M, Secko M, Zehtabchi S. The utility of routine
laboratory testing in hypoglycaemic emergency department patients. Emerg
Med J 2009;26:28-31

9. Jikki PN. Apparently unexplainable hypoglycemia in a diabetic
patient - clue for renal failure? J Assoc Phys India 2008;56:645

10. Akram K, Pedersen-Bjergaard U, Cartensen B, Borch-Johnsen K,
Thorsteinsson B. Frequency and risk factors of severe hypoglycaemia in
insulin-treated type 2 diabetes: a cross-sectional study. Diabet Med
2006;23:750-6

Re: Practice:
Hypoglycaemia
Piya Sen Gupta, Andrea N Green, and Tahseen A Chowdhury
BMJ 2011 342:d567; doi:10.1136/bmj.d567

The authors are to be congratulated for producing a concise review of
an important area of clinical management bridging primary and secondary
care services in the UK. However there are 3 areas that are worthy of
further comment:

1) Figure 1 suggests the use of intravenous 50% dextrose for the emergency
rescue of the unconscious patient with hypoglycaemia in the community.
Most UK hospitals guidelines now suggest avoiding anything more
concentrated than 20% dextrose. The main concern is that 50% dextrose is
caustic to tissues if it extravasates out of the vascular space, a
significant risk where cannulation is attempted out of hospital.

2) Whipple's triad is not necessarily a useful diagnostic for insulin
induced hypoglycaemia in diabetes. As partly alluded to in the review, two
of Whipple's three criteria- the presence of symptoms which are then
reversed following administration of glucose- may be absent in patients
who have lost warning symptoms of hypoglycaemia. In clinical practice, the
greater problem is arguably not so much the diagnosis of hypoglycaemia in
this situation but rather the recognition that it is problematic by
patients and/or health care providers.

3) Finally, although at face value the use of the long acting insulin
analogue, glargine, contradicts current NICE guidelines, type 2 diabetes
is a heterogeneous condition and there is an increasing realisation that
many slim, insulin-sensitive patients like this requiring exogenous
insulin therapy may actually have a "slow burning" type 1 diabetes (which
has attracted various monikers over the years including "type 1.5
diabetes"). There is a high likelihood that the patient presented here may
progress to requiring a full "basal-bolus" regimen including insulin
analogue therapy where appropriate to achieve decent glycaemic control
without hypoglycaemia, probably requiring specialist referral, something
that primary care practitioners should be aware of.