JURISDICCIÓN CONSULTIVA DE LA INTERNACIONAL DE JUSTICIA
E, SOBRE EL ALCANCE DE LA COMPETENCIA DE LA CORTE INTERNACIONAL DE JUSTICIA EN LOS
3. PERSPECTIVAS DE LA FUNCIÓN CONSULTIVA DE LA CORTE INTERNACIONAL DE JUSTICIA
you asked me yesterday to viva you on Metformin and its usage in various clinical scenarios. I post here a few common Qs on Metformin.
This chart is impt as it shows the relationship between stress causing HIGH Glucose which cannot be cleared by low Insulin!! and with increase of shunting to lactate now made worse by poor clearance.
Dear YL,
We no longer use Phenformin. But it has unjustifiably given Metformin a bad name.
Metformin is actually a very safe drug when used mindfully.
Under what conditions does Lactic acidosis occur? You run marathons, it is impt that you understand this. Can you describe how you felt like when lactic acidosis
occured?
Do you recall not having much appetite despite running such a long distance, anorexia is common. Were you nauseated, perhaps even vomiting? You felt
deliriously happy when you finished but this altered level of consciousness could be due to metabolic cause!!! Yes you had hyperpnoea, abdominal pain and thirst. And I recall you telling me that you were anuric and had DARK urine! Please dun do it again!!!
Red blood cells produce lactic acid as a byproduct of the regeneration of ATP during anaerobic glycolysis but cannot use lactic acid
Take home that when you have a patient with tissue underperfusion and hypoxia coinciding because of illness or surgery, avoid Metformin!
Lactic acidosis is a broad-‐anion gap metabolic acidosis caused by lactic acid overproduction or underutilization. The ABG and simple maths will tell you this.
Overproduction of lactic acid occurs when the body must regenerate ATP without oxygen (tissue hypoxia). Circulatory, and pulmonary disorders are commonly responsible.
Underutilization involves removal of lactic acid by oxidation or conversion to
glucose. Liver disease, inhibition of gluconeogenesis by metformin!! are common causes. Poor renal function also makes excretion poor.
Approximately 1400 mmol of lactic acid are produced daily, which are buffered by 1400 mmol of HCO3 to form sodium lactate. The liver is responsible for oxidizing lactate to restore this amount of HCO3. The role of the liver in lactate homeostasis is considerable.
The kidneys contribute to lactate removal in three ways: excretion, gluconeogenesis, and oxidation.
Malignant cells produce more lactate than normal cells, even under aerobic
conditions. This phenomenon is enhanced if the tumor outstrips the blood supply!!
Yin ling,
Pls note the word STABLE! Problem starts when Renal function is deteriorating or is expected to deteriorate but NOT in the awareness of the HO.
No one will use it when eGFR is less than 30 or you are walking a thin line.
Tell me what common conditions can lead to a clinical deterioration of renal function?
Ninety percent of metformin is excreted unchanged by the kidneys and lactic acidosis typically occurs in patients with renal insufficiency. Even mild renal disease increases the risk of lactic acidosis.
Prof: A metformin dosage of 850mg twice a day, or 500mg three times a day, usually gives good diabetic control. There is not much point giving beyond 2000mg a day.
Caution is needed when increasing the daily dosage beyond this, especially in the elderly and those with mild renal disease.
Significant mortality ( as high as 50%) is associated with biguanide-‐induced lactic acidosis and attention should be focused on prevention through awareness of the risk factors.
Heart failure and metformin remains a bit confusing. I have seen papers which propose that it is not anymore dangerous than usual. Again the word is STABLE vs UNSTABLE.
A patient who comes in with fluid overload and low O2 sat is different from one who is comfortable at home well maintained on medicine and stable.
Someone who comes in with mild illnesses like a URTI is obviously different from another with severe pneumonia.
Someone coming for excision of an in grown toenail is different from an elderly woman going for a total hip replacement.
What will you do if you are refered such diabetic patients as above?
YL: For the short term stay in hospital for unstable patients, sliding scale will be a good choice. Until we know patient is more stable and taking orally well, we will keep them on either sliding scale or regular insulin first
PROF: Can you pls elaborate on the Sliding Scale used here?
YL: We give pt subcut short acting insulin injection based on their blood glucose level every 4 hourly. The ranges can be 2 units of insulin if glucose is 5 to 10, 4 units for 10 to 15 and so on. Sliding scale can be augmented if glucose is hard to control.
Lactic acidosis is an uncommon but potentially fatal adverse effect. The reported frequency of lactic acidosis is 0.06 per 1000 patient-‐years, mostly in patients with predisposing factors.
Examples of metformin-‐induced lactic acidosis scenarios include:
A 69-‐year-‐old man, with renal impairment and cardiac failure, was prescribed metformin due to failing glycaemic control on glibenclamide monotherapy. He was well for six weeks, then developed lactic acidosis and died within 3 days.
Tell me what should have been done if we can turn back the clock?
An elderly man had a total hip replacement. Post-‐surgical lactic acidosis caused the death of this 70-‐year-‐old man whose metformin was not withdrawn at the time of surgery.
If you are the resident, what would you have done instead?
A 56-‐year-‐old woman, with no predisposing disease, died from lactic acidosis
following major abdominal surgery for Ca Colon. Metformin was withdrawn only for the day of surgery.
What should you have done instead if asked to see this patient?
The risk factors for metformin-‐associated lactic acidosis include sepsis, high dosage, increasing age, and DEHYDRATION. The last is often forgotten! In
situations predisposing to dehydration such as FASTING for surgery, or contrast radiography, metformin should be ceased at least 48 hours prior to the procedure (or on admission for an emergency procedure). It is not restarted until the patient has fully recovered and is eating and drinking normally. The glucose levels of
patients in CATABOLIC states, e.g. sepsis or in the post-‐operative period, should be monitored and Short-‐term insulin therapy is strongly advised for Mx.
Try not to use above 70 years old, and if using be very careful with renal function.
remember that by the time biochemistry is abnormal, the renal function is already significantly affected bec of renal reserve
YL: For the first scenario, his renal impairment already stop us fr using metformin.
Pairing up with a heart failure causing increase tissue hypoxia, lactic acidosis is likely.
Glibenclamide is such a long acting SU, hypo episodes is risky. And glibenclamide which shouldnt be use in renal impairment. We can use gliclazide.. a newer gen SU, lesser hypo episodes, lssser weight gain and can be used in mild renal impairment with caution. He will also be a good candidate to start insulin. When he is being
admitted for heart failure, temporary use of sliding scale is warranted if hes unstable.
PROF: AS a rule, pls do NOT use glibenclamide in the elderly. Its long acting and even its metabolites are ACTIVE. Glicazide is excreted by the liver so its relatively safer even in renal impairment.
Despite the presence of many unique classes of drugs to treat hyperglycemia in patients with type 2 diabetes, metformin remains the Drug of Choice.
Metformin caused less weight gain compared with either the thiazolidinediones or sulfonylureas. Metformin decreased low-‐density lipoprotein levels compared with pioglitazone, sulfonylureas, and DPP-‐4 inhibitors.
Patients taking sulfonylureas had a fourfold higher risk of mild or moderate
hypoglycemia compared with metformin alone. This is a tremendous advantage of the drug.
Most importantly as far as evidenced based medicine is concerned, Metformin is unique in being not only as effective as any other oral antidiabetic therapy in
controlling blood glucose, but also having an unparalleled clinical database relating to improved clinical outcomes in pre-‐diabetic subjects, and patients with
established type 2 diabetes.
9) on DIABETES!
yin ling has asked that I continue with her Viva voce throughout the CNY period.
While it is very important that we keep the A1c level as close to normal as we safely can, this MUST vary according to the patient's clinical circumstances, age, risk for hypoglycemia, social background and many other factors.
Which patients will you be happy to have A1c levels at 10%, which, for complicated reasons, you can't get them lower or do not want it lower?
And who will you want at target of < 7% and even in some < 6.5%?
For a patient who is symptomatic and has a blood sugar level of >11.1mmol/l he clearly has diabetes. However can you diagnose with
• Measurement of the hemoglobin A1c level;
• Measurement of the fasting glucose level;
and what are its limitations?
Which is MORE Reliable; MGTT or the hemoglobin A1c level?
Please note that blood glucose levels like any laboratory assay can vary even in perfectly normal people.
We do one test to see whether a person has diabetes, and then unless the values are clearly abnormal, we need to repeat the same test to verify whether that value is true. Because lab errors can occur, its impt to repeat the same test.
The treatment of DM is more than controlling blood sugars, in any real life and exam situation, a global evaluation is essential. Blood pressure: what is the present
targets?
Every patient who has diabetes and who is older than age 40 years is somebody who will need to be on statin therapy! The occasional man who swears that the statin had caused ED is also a difficult situation as I am not sure its the DM or the drug. What is the role of fenofibrate if any?
The role of ACEI and ARBs is another common exam Q. Will you use angiotensin-‐
converting enzyme inhibitors or angiotensin receptor blockers for the prevention of nephropathy in patients who do not have elevated blood pressure levels?
How will you advise your patient regarding alcohol intake?
YL : we should individualised our HbA1c target according to a patient's age,
comorbiditis and general condition. For a young patient say 40-‐50 years old having T2DM, we would like his HbA1c to be tightly control, targeting a 6.5-‐7% to delay the onset of microvascular and macrovascular disease.
However if we are looking at an elderly, frail, 70 year old diabetic patient, we
would be happy if his HbA1c is around 8-‐10%, tightening the glucose control equals expecting more hypoglycemic events which is detrimental to the old.
DM can be diagnosed when a patient has a HbA1c of >6.5%. HbA1c of 6-‐6.5% is considered Pre Diabetes. we can also diagnose DM by fasting blood glucose of >7.0 if there is symptoms. 2 readings is needed if there is no symptoms. IFG is when FBG ranging 5.6-‐7 and IGT when 2 hours post OGTT BG 7.8-‐11.0
Be careful when using HbA1c to diagnose in patients who have high RBC turnover eg thalasemia, any hemiglobinopathies, renal disease and etc.
i would like to think that HbA1c is more reliable as it measures glucose control for over a longer period of time.
BP target is at 130/80 for patients with DM, we no longer use the 125/75 target anymore. there is no benefit in lowering BP to such level in this group of patients.
Anyone above 40 who has DM deserves a statin. after starting statins and
controlling the blood sugar, if TG is still high, fenofibrate is warranted. Fenofibrate can also be used in patients who cannot tolerate statins eg from the myopathy.
ACE-‐i and ARB is beneficial for DM patient and we are taught to use them as first line in all DM patient due to the renal protective effect. ACE can help prevent
nephropathy and reduce proteinuria. these patients commonly have deranged renal function from diabetes, it is not entirely contraindicated to use ACE/ARB as long as
renal profile are monitored, stop if there is >30% raised of creatinine during a repeat renal profile in more than 2 weeks. we would not use ACE -‐ i once creatinine is >200.
We are commonly taught to use ACE-‐i as first line and if patient cannot tolerate ACEI mostly due to an ACE induced cough we would use an ARB instead.
Alcohol : cut off units for men is 21 and women 14 per week. but of course taking many units in one setting is bad. encourage moderate alcohol intake.
Dear yin ling
Hba1c is better than MGGT. A1C captures chronic hyperglycemia better than two assessments of fasting or 2-‐h oral glucose tolerance test of plasma glucose
Diabetes has been diagnosed for decades with fasting plasma glucose or, with an oral glucose tolerance test (OGTT). Hyperglycemia as the biochemical hallmark of diabetes is unquestionable. However, fasting and 2-‐h MGTT gauge just a moment of a single day. Many2 factors affect this sample which Hba1c overcomes.
BUT Hba1c testing lacks standardization and different labs provide different values for even a same sample. This on top of haemolytic anaemia or lack of EPO or bone marrow problems. So we need to interprete mindful of these.
When there is IHD, hypoglycaemia is DANGEROUS. it can ppt arrthymias and even ACS. Hence in proven DM CHD, the target shd NOT be lower than 7%.
Serum fructosamine was something I used to test but its unreliable. In thalassaemia trait patients bld sugar profiles remain our bedrock. Same for renal failure patients.
Top secrets:
Fbs, Hba1c and 2HPP values are all correlated to retinopathy the most specific complication of dm
Fbs is poorly correlated to CHD
BUT 2hpp and Hba1c is well associated.
Bld sugars start dropping in value by 5% every hour after venesection
So if the specimen sits on a bench while the technician rests, you are not going to get anything close to reality. Worse in HOT WEATHER.
Hba1c is not affected in this way.
Dear YL,
ARB vs ACEI
In choosing between ACEI and ARB therapy for patients with type 2 diabetes diabetic nephropathy, you have to consider evidence of proven renal protective benefit for ARB treatment versus evidence of a mortality benefit for ACEI treatment shown in patients without established diabetic nephropathy.
ARB appears superior to delaying progression to renal failure.
But IN NON PROTEINURIC PATIENTS, ACEI has better results with regards to mortality.
ACEI in general HPT patients has better outcome for CHD.
There is no routine role for combining both
You recall OnTarget trial. It was a huge trial testing Telmisartan vs Ramipril and its combination. The angiotensin receptor blocker telmisartan was "noninferior" to the ACE inhibitor ramipril in patients with vascular disease or high-‐risk diabetes in this landmark trial
However, the combination of the two drugs was associated with more adverse events without an increase in benefit.
10) on Dyspnoea