Type 2 Diabetes Mellitus II The goal of therapy is to 1)prevent the chronic complications of diabetes. symptoms of diabetes (polyuria, polydipsia, …
Endocrinology 24
02/12/99
2-3:00
Dr Pasmantier
Lobina Kalam
474-7277
Type 2 Diabetes Mellitus II
The professor did not have any slides, charts, or tables to give me
Much of the lecture discussed the various research parameters which led to
the current thinking of Type 2 Diabetes management It is all very nicely
and clearly summarized in the syllabus pages 140-143
Therapy of Type 2 Diabetes Mellitus:
The goal of therapy is to 1prevent the chronic complications of diabetes
2To prevent acute metabolic complications of diabetes hyperosmolar coma,
diabetic ketoacidosis, or hypoglycemia 3To prevent symptoms of diabetes
polyuria, polydipsia, blurred vision
A 20 year study was done with 4000 newly diagnosed patients with type
2 diabetes in 23 different centers called United Kingdom Prospective
Diabetes Study UKPDS Patients were randomized to either intensive blood
glucose control with either sulfonylurea, insulin or metformin and
conventional treatment on the development of microvascular neuropathy,
retinopathy and nephropathy and macrovascular complications
atherosclerosis There are better treatments today but this is what was
available twenty
years ago and is what was studied
The mean follow up was ten years In 1987, a blood pressure control
study was instituted among patients already in the trial who had
hypertention to look at the effect of less tight vs tighter blood pressure
control The tighter control patients were using Ace inhibitors or Beta
Blockers The less tight control groups primary treatment was with diet
with a fasting blood glucose level of 270 This was the threshold for
changing someones therapy and they had to be asymptomatic polyuria,
polydipsia, losing weight The intensive therapys goal was to try to get
that fasting glucose to less than 108 There were 21 endpoints that were
used in the study-myocardial infarction, angina, sudden death, heart
failure, strokes, amputation, retinal surgery, renal failure, vitreous
hemorrhage They also used non diabetes related endpoints including deaths
from accidents and cancer
Myocardial Infarction fatal and nonfatal was decreased 16 but had
a P value of 052 A value of less than 05 is considered significant
This number means that there is clearly a role for hyperglycemia and
myocardial infraction but, it is not the only role, and it may be
less
important than some of the other factors like hyperlipidemia and blood
pressure There was no change for stroke statistically insignficant
Microvascular disease was the most significantly affected down 25
At presentation, the mean Hemoglobin A1c was 7– which means a mean
plasma glucose of 150 In the intensive treatment group, the mean plasma
glucose fell 1 or to about 120 The difference between the intensive and
conventional treatment was about 9 which correlates to 27mg/dl-which had
a good effect on microvascular disease over the course of 15 years with
both groups HemoA1c level progressively increasing as the disease
progresses But again, the change in blood sugar was pretty modest
They also had a sub-study on overweight patients 120 ideal body
weight These patients could get Metformin, sulfonylureas, or insulin
Patients who got Metformin had their mean HbA1c be 741 And the patients
who got conventional therapy had mean HbA1c of 8 over the ten years So,
Metformin reduced HbA1c by just 6 over the 10 years yet it reduced the
risk of diabetic complications The affect on macrovascular complications
was greater and this may not be solely due to glycemic
control Some
researchers say that you have to get the HbA1c to less than 6 to see a
drop in macrovascular complications Metformin reduces insulin resistance
and has a better effect on the lipid profile and fibrinolysis so that we
see a better affect on macrovascular complications This is why adjunctive
therapy is so important in patients with Type 2 diabetes If you focus
just on the glucose, youll miss the boat
The Blood pressure arm of the research gave very interesting results
The two groups had an average a B/P of 160/94 In the less tight control
group, the blood pressure was brought down to 154/87 and in the tight
control group -140/82 So they were able to drop ten systolic and five
diastolic In any diabetes related endpoint, there was a risk reduction of
24 33 reduction for diabetes related deaths No significant change in
myocardial infarctions Heart failure was significantly reduced by 56
Stroke was reduced by 44 Microvascular disease was decreased 37 This
is only with a 10/5 reduction in blood pressure
Therefore, treating blood pressure is very important in people with
Type 2 diabetes
The American Diabetes Association has set the following goals
based on this
research for glycemic control
Biochemical index Normal Goal Action suggested
Fasting plasma glucosemg/dl 110 80-120 80 or
140
Bedtime plasma glucose 120 100-140 100 or160
Hemoglobin A1c 6 7 8
Looking at the HbA1c is the gold standard biochemical index because it does
not represent a point in time but rather an integrated window backwards to
10-12 weeks
In the UKPDS study, only 5 of patients were able to reach the goal Thus,
we need better agents for glycemic control When the HbA1c gets to be
greater than 8, thats when we see the event rate go way up
Therapy:
1 First therapy is with diet and exercise Blood sugar control and lipid
profile change is done with diabetes educators, nutritionists, exercise
physiologists, social workers, and psychiatrists The current thinking
is to go with a higher carbohydrate diets 50, 30fats or lower, and 20
protein In people with Nephropathy, the protein may be reduced to 10
A sodium restricted diet -no more than 3-4 grams It may be less in
hypertensive patients or patients with nephropathy
Limited alcohol and
increasing dietary fiber which slows GI emptying and produces a smoother
glycemic excursion Everyone over the age of 35 should have a stress
test done before embarking on an exercise regimen to increase or rather
prevent a loss of lean body mass It is that muscle tissue that is the
most metabolically active and will improve insulin sensitivity You
really need a change in lifestyle to reduce central fat and increase
muscle and effectively control blood sugar
2 Pharmacological therapy is next Everyone pretty much got sulfonylureas
since they have been around since WWII They work by binding to a
potassium ATP channel and causes depolarization and Ca entry into the
cell It works by increasing insulin secretion Preferred patient type
is the insulinopenic A newer agent -Repaglonide benzoic acid
derivative binds to a different site of the potassium ATPase channel and
it increases insulin secretion as well but is given with a meal The
Sulfonylureas are pretty safe and easy to tolerate The main problem
with them is hypoglycemia in people who have elevated or adequate insulin
levels
3 Metformin is a biguanide and
works by decreasing hepatic glucose
production and increasing glucose uptake at the level of the muscle It
also decreases glucose uptake from the gut It is particularly useful in
the insulin resistant, overweight population Metformin can but rarely
does cause lactic acidosis It should not be used in patients with renal
impairment because it is cleared there
4 Acarbose is an alpha-glucosidase inhibitor and when it competitively
inhibits alpha-glucosidase, you delay the absorption of carbohydrates
It decreases post parandial hyperglycemia There are a lot of GI side
effects It is less potent than the sulfonylureas or metformin In 2,
you can see elevated liver enzymes
5 The Thiazolinediones, or Troglitazone work by binding to the PPAR gamma
receptors which are involved in glucose and lipid utilization It turns
on insulin response genes They are good in the insulin resistant state
If used with a sulfonylurea or insulin, it has about equal effectiveness
as Metformin It is not as effective as a monotherapy In 1/50-60,000
cases rare, you can see hepatocellular injury and death with
Troglitazone
You can try to use two agents in
combination and then go to a reasonable
amount of insulin 1 unit/kg/day If you have to go above that, you may
have to add an insulin sensitizer Over time with Type II diabetes, you
get beta cell exhaustion, beta cell drop-out and replacement, and beta
cell with amyloid Thus, over half the patients are eventually going to
need insulin
The risk of vascular disease is the same in diabetics and non-diabetics
Diabetes is synergistic to all the other risk factors for vascular disease
It is not additive Lipoproteins, obesity BMI30, are risk factors
The treatment of dyslipidemia will decrease myocardial infarctions and
other coronary events The Scandinavian Simvastatin Survival Study 4S
and Cholesterol and recurrent events study CARE trials have shown that
treatment of patients with diabetes with Simvastatin, and Pravastatin can
decrease coronary events and mortality Patients with diabetes and
vascular disease should definitely not smoke cigarettes as it will
increase the risk of macrovascular disease
The hypercoaguable state associated with Type 2 diabetes shows
elevated levels of PAI-1 plasminogen activator inhibitor-1 and increased
platelet
aggregability Patients are thus treated with one 325 mg
aspirin/day if there are no contraindications
Good Luck on the Exam
Source:uhmc.sunysb.edu
