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144 Thyroid Dysfunction, Diabetes and the Cardiac Link

ical hypothyroidism and coronary heart disease there In the NHANES III the prevalence was around 3.2%
was a modest elevation of risk particularly in individ- with a TSH cut of 0.4 mIU/L. Excessive thyroid hor-
uals younger than 65 years (Figure 2). Two observa- mone has important effects on the cardiac muscle,
tional studies provide us with good insight such as peripheral circulation and the sympathetic system.
United Kingdom General Practitioner database where The main changes are increased heart rate, cardiac
50% of individualsaged 40-70 years old treated with contractility, mean pulmonary artery pressure, car-
L-thyroxine, with TSH between 4.5-10 mIU/L hazard diac output and myocardial oxygen consumption. It
ratio of cardiac events reduced (0.67, CI 0.49 – 0.92). also reduces systemic vascular resistance and dia-
The Cleveland clinic looked at high risk patients with stolic pressure.
a TSH between 6.1-10 and >10 mIU/L who were under
65 years old and patients not treated with thyroxine Metformin and thyroid function
had higher all-cause mortality.
Metformin, an oral anti-diabetic compound, is regard-
Walsh et al. (ref 38) ed as a first-line drug for treatment of type 2 diabe-
Hak et al. (ref 193) tes. It reduces mortality among overweight patients
Imaizumi et al. (ref 194)
Kvetny et al. (ref 196) with diabetes and also used for prevention of diabe-
Parle et al. (ref 229) tes in high-risk individuals.
Rodondi et al. (ref 231) Metformin acts primarily by suppressing hepatic glu-
RISK Cappola et al. (ref 230) coneogenesis via activation of AMPK, a prerequisite
50 60 70 80 90 years
for the drug’s inhibitory effect at the hepatic level.
Metformin is not metabolized but is transported by
Gussekloo et al. (ref 92)
the organic cation transporters, OCT1 and OCT2. Met-
formin has opposite effects on hypothalamic AMPK,
inhibiting activity of the enzyme. These metformin ef-
Figure 2;Sub-clinical Hypothyroidism and the risk of fects on hypothalamic AMPK activity will counteract
heart disease T3 effects at the hypothalamic level. AMPK therefore

Hyperthyroidism may complicate or exacerbate represents a direct target for dual regulation involved
pre-existing heart disease because of increased in the hypothalamic partitioning of energy homeo-
myocardial oxygen demand, increased contractility stasis[4].
and heart rate. Many patients experience exercise In rats, metformin has recently been shown to cross
intolerance and dyspnea on exertion due to inability the blood–brain barrier and its concentrations in the
of the heart to increase heart rate or lower vascular hypothalamus match the levels in plasma. Inter-
resistance. About 6 % of thyrotoxic patients develop estingly, metformin levels in the pituitary gland are
heart failure and < 1 % develop dilated cardiomyopa- substantially increased it is supposed to suppress-
thy with impaired LV systolic function due to tachy- es pituitary TSH secretion. In a small retrospective
cardia-mediated mechanisms. All these potential study, metformin suppressed TSH to subnormal lev-
mechanisms are likely to aggravate an ailing diabetic els, without signs of hyperthyroidism or changes in
heart. The most common ECG abnormality is sinus FT4 and FT3.In prospective studies of patients with
tachycardia, shortened PR interval and intra-atrial diabetes and hypothyroidism on stable thyroxine
prolongation of conduction leading to increase in P treatment, metformin administration for 3 months
wave duration. The prevalence of atrial fibrillation in lowered serum TSH concentrations with opposite ef-
overt hyperthyroidism was 13.8 % peaking up to 15 fects on metformin withdrawal. This effect was not
% in patients older than 70 years in one particular reproduced in non-diabetic controls. In another study,
study. In subjects with atrial fibrillation maintenance 1 year of metformin administration, significant TSH
of sinus rhythm is not possible until euthyroid status decrease was observed in diabetic subjects withhy-
is restored, hence it is advisable to defer cardio-ver- pothyroidism who were treated (2.37 ± 1.17 to 1.41 ± 1.21
sion until the same is achieved. mIU/l) with thyroxine. No significant change in free
Sub-clinical Hyperthyroidism is defined by low or un- T4 was observed in any group[7]. Questions remain
detectable serum TSH and normal free T4 and free T3 regarding the interaction between metformin and
concentrations. This became simpler to identify due thyroid status despite its convincing suppression of
to the availability of third generation assays that have TSH.
a functional sensitivity of 0.01- 0.2 mIU/L, discrimi-
nate between complete and incomplete suppression. Monitoring of thyroid function in Diabetes

GCDC 2017