Jaslok Hospital and Research Centre,
Diabetes and high blood pressure are two powerful, if independent, risk factors leading to many serious complications such as cardiovascular diseases states, renal dysfunction and many more. The occurrence of both, diabetes and hypertension, in the same patient does not merely double the chances for developing these problems, but the risk is COMPOUNDED! This is a classic example of 1+1 not equaling two but eleven!
Unfortunately, hypertension is much more frequently seen in a person with diabetes than in the patient who does not have diabetes. In fact, both along with dyslipidemias, central obesity and atherosclerosis are now grouped together in the classical metabolic syndrome, popularly referred to as "Syndrome X".
The pathology which leads to coronary artery disease, cardiac failure, periperal vascular disease, transient ischemic attacks and strokes are all increased significantly when both these risk factors are present in the same patient. Furthermore, there is ample and overwhelming evidence to suggest that microvascular diabetic complications like nephropathy and retinopathy are made worse in the presence of high blood pressure.
Retinopathy is seen earlier in hypertensive as compared to normotensive diabetics. In fact, the severity of retinal changes are closely related to the degree of the hypertension and very significantly, adequate control of the high blood pressure can retard the progression of the retinopathy! There is also considerable evidence that the presence of hypertension is an important factor in accelerating, if not initiating diabetic nephropathy. Microalbuminuria is an important diagnostic factor for the presence of incipient or early diabetic renal disease, and it has been shown that higher degrees of albumin excretion correlates with higher levels of blood pressure. Optimal control of both the blood pressure and the hyperglycemia can return the raised levels of urinary albumin excretion to normal or at the very least, slow down the progression of the disease state to a considerable extent. Even in those patients with diabetes, who have reached a more severe degree of renal dysfunction, those with high blood pressure which has not been adequately controlled, will tend to progress to the end stage at a much faster pace.
In fact, there are people who feel that once a person with diabetes develops a certain degree of dysfunction, there comes a stage of "no return" when even tight glucose control will not be able to stop the relentless progression of the disease state. Even in such circumstances, tight control of the blood pressure (120/80) does help in slowing down the progression!
Thus, patients with high blood pressure are those at greater risk of developing the full blown picture of end stage renal disease as compared to those who are normotensive, or those in whom the blood pressure is optimally controlled.
The story is similar for diabetic retinopathy.
The importance of tight blood glucose control in decreasing the long term complications has been highlighted in recent mega-trials such as the DCCT and the UKPDS and I do not intend going into details here. But there is one excellent trial which I would like to mention.
The importance of controlling hypertension in diabetes is brought about by figures given from the Joslin Clinic. Since 1939, they followed all Type 1 patients who were seen within one year of the diagnosis of the disease. This homogenous group was followed closely till 1980 or until death, which ever was earlier. Ninety percent of the patients survived 20 years, 77% survived 30 years and 46% of the patients survived the 40 years of the study. Of all the patients who died during the 40 years of the study, 48% of the mortality was from coronary artery disease whilst 31% died from renal disease. Most of the latter also had evidence of significant coronary artery disease. Most of those who died with renal disease were in the age from 30-45 years whilst those who died from the coronary episodes were spread over the full age spectrum. Hypertension was present in all the patients dying from the renal disease and in all but three patients who died from the coronary disease. Uncontrolled hypertension was RARELY seen in those who survived !
Microvascular and Macrovascular Complications of Hypertension in Patients with Diabetes
Microvascular complicationsRenal disease- hypertension contributes to the risk of renal disease in patients with diabetes.
Autonomic neuropathySexual dysfunction-hypertension and antihypertensive therapies may independently contribute to autonomic-associated sexual dysfunction in diabetes. Orthostatic hypotension--supine hypertension with orthostatic hypotension can occur in persons with diabetes because of autonomic dysfunction. Blood pressure should be measured in the supine, sitting, and standing positions.
|Eye disease-hypertension increases the risk of eye disease in patients with diabetes, including glaucoma and diabetic retinopathy with potential blindness.|
Macrovascular complicationsCardiac disease-hypertension in patients with diabetes increases the risk of coronary artery disease, congestive heart failure, and cardiomyopathy. Cerebrovascular disease--hypertension increases the incidence of stroke in patients with diabetes. Survival rates and recovery from stroke are reduced in patients with diabetes compared with patients without diabetes. Peripheral vascular disease--hypertension increases the risk of peripheral vascular disease and subsequent foot ulcers and amputations in patients with diabetes.
Thus, it is obvious that high blood pressure is detrimental to a diabetic and that efforts should be made to bring it down. This is where the initial problem arises. What levels of blood pressure constitutes a risk for the development of complications. In the past there was quite a controversy as to what constituted good blood pressure control. Fortunately this has now been laid to rest and in all patients with diabetes, one should aim to achieve a blood pressure recording of as close to 120/80 as possible.
Easier said than done! Unfortunately, the management of high blood pressure, especially the drug therapy is not simple in a person with diabetes. Many of the drugs used in the management of hypertension are themselves apt to cause problems. They may interfere with the metabolic parameters, decrease insulin sensitivity, increase the blood glucose levels, increase the lipid levels, and may worsen some of the complications.
But nothing good comes easily! Although, optimizing the blood pressure levels may be difficult in a person with diabetes, it is definitely possible especially with the recent array of drugs. A judicious approach can successfully optimise the raised blood pressure, and the benefits for the patient far out-weigh any trouble that the doctor has to take in managing the blood pressure.
Before we discuss the management of high blood pressure in a diabetic, there are certain small, but important, aspects that I would like to mention. High blood pressure may be a manifestation of hypoglycemia. Often, the sudden appearance of high blood pressure in a normotensive diabetic may be the only clue to the presence of subtle, or even subclincial hypoglycemia. Thus, its presence should always make one suspect whether the patient may be undergoing subclinical hypoglycemia. To take an example, which I have used elsewhere the presence of early morning hypertension, possibly accompanied by early morning headaches may be a clue to the presence of nocturnal hypoglycemia. As the patient would be asleep, one may not be able to experience the signs and symptoms of hypoglycemia, but the presence of high blood pressure in the early morning may point towards this possibility. The reason for this is the hypoglycemia is countered by the counter regulatory hormones like epinephrine, cortisol, growth hormone, glucagon etc. A side effect of these hormones would be seen as an increase in the blood pressure. Thus, when faced with a sudden onset high blood pressure in a patient diabetic under treatment, one should not blindly think of starting antihypertensive therapy until such possibilities have been ruled out.
Another aspect which makes the management of high blood pressure difficult is in those patients who do have hypertension but due to the presence of associated autonomic neuropathy, also have postural hypotension. Therefore, it is essential that not only the blood pressure readings be taken on both the arms (in view of the possible presence of peripheral vascular disease ) but also in the lying down, sitting and standing positions. Often, the blood pressure is taken in the lying down position and if this is seen to be high, treatment may be started which may lead to the patient getting a fainting attack when he stands up. Conversely, if the blood pressure is taken in the sitting position as often happens, then one may miss the presence of high blood pressure as the postural drop may mask the hypertension.
It is absolutely essential that all patients be made aware of the tremendous importance of keeping their blood pressures under optimal control. One way to show how important you, as the doctor, feels this is, is to check the blood pressure regularly at each visit. It should also be made clear to the patients that blood pressure control, just as it is for blood glucose, must be lifelong and therefore, complacency should not set in once they have been told that the blood pressure has been normalised. Unfortunately, many patients are under the impression that high blood pressure must be acccompanied by some symptoms, the most common being headaches. It has to be made quite clear that this is not so and that high blood pressure can, and does, occur silently. Waiting for it to manifest with signs and symptoms may mean treating the raised blood pressure at a stage when much of the damage has already been done!
I always tell my patients who have high blood pressure that it would be better for them to learn to monitor their own blood pressures regularly and that they should contact me if the pressure recordings are consistently higher than the limits I have set for them. I make it quite clear to the patients that the best way to monitor the blood pressure is to use the mercury meter or the aneroid meter with the use of a simple stethoscope. Human tendency being what it is, many patients get sophisticated measuring instruments from abroad which do not need a stethoscope and which give a audiovisual or digital readout. Many of these instruments have a microphone as the listening device and this must be correctly placed or else one could get quite wrong readings. Even when the patient uses the routine instruments, I make it a point to ask him to get this meter when he comes for a visit and I cross check the accuracy of the instrument. This also enables me to judge whether the patient is correctly measuring the blood pressure. This also enforces in the mind of the patient the importance of a correct and regular check on his blood pressure.
Another aspect, which I will discuss in more detail later when we take up the commonly used blood pressure lowering drugs, but which really is a matter of some concern is the propensity of many of these drugs to add to the dyslipidemia. As it is, diabetics have a tendency for raised lipid levels which is an important additional risk factor for the development of macrovascular disease to which diabetics are prone. Thus, it is possible that the correction of one risk factor, namely hypertension, may increase the severity of another factor!
Antihypertensive drugs affect all three lipid parameters: triglycerides, cholesterol, and HDL-cholesterol. Thiazide diuretics are known to increase the triglycerides and the cholesterol with a decrease in the HDL-cholesterol. They cause a 15 to 30% increase in the levels of the plasma triglycerides, a 5 to 10% increase in the serum cholesterol, but no significant change in the HDL-C values. But the increase in the total cholesterol means that the LDL-C levels which have serious implications for the development of atherosclerosis are increased. Furosemide treatment is associated with a small increase in the serum cholesterol and a small decrease in the HDL cholesterol levels thereby leading to an increase in the LDL-C levels.
Both the non-selective beta blockers like propranalol and the selective ones like metoprolol and atenolol, cause a 30 to 40% increase in the plasma triglycerides and a 10-15% decrease in the HDL cholesterol. The beta blockers with intrinsic sympathomimetic activity like practolol and pindolol do not seem to have any significant effect on the lipid levels. Interestingly, drugs such as verapamil have been shown to decrease plasma cholesterol and it is possible that nifedipine also has a similar action. ACE inhibitors and ARBs have not been shown to affect the lipid profile to any significant extent.
One area which most of us do not pay much attention to but which is of great concern to most male diabetics is that of erectile dysfunction. As I have discussed in a seperate chapter, male sexual dysfunction, especially impotency is very common in male patients. Whilst the figures for the prevalence vary, it is felt that after a few years of diabetes, around 50-60% of male diabetics will have some degree of impotency. This, as can be well imagined, leads to significant emotional trauma in the patients even if they do not come out with this complaint openly. But then how many doctors ask their patients specifically about this problem. Today, so much can be done about for impotency, but one point that is worth considering here is that many of the commonly used antihypertensive drugs have impotency as a side effect. Routine use of such drugs MUST be avoided when treating high blood pressure in most patients and especially in all males.
Although I accept that the optimal control of high blood pressure is of great importance, it should never be forgotten that every person has a right to sexual satisfaction and the use of drugs which lead to, or worsen, impotency is unjustified without informing the patient about this side effect. One cannot use drugs for the treatment of one problem which makes another important aspect much worse! I have seen patients refuse to take any therapy for the high blood pressure when they were told about the possibility of becoming impotent. Today, when better drugs, which not only lead to a smooth control of the blood pressure but also do not have any detrimental action on sexual function, are available, I cannot think of any valid reason why one should continue to use the older drugs! Unfortunately, many still use these drugs, possibly in completed ignorance of this side effect.
Virtually, every common drug used in the treatment of high blood pressure has been implicated in causing sexual dysfunction. Methyldopa, clonidine and guanethidine are the most common culprits in so far as impotency is concerned, although diuretics, beta blockers and hydralazine do cause some degree of impotency they are much less liable to do this as compared to the three drugs mentioned above. ACEi's and ARBs have to date not been known to lead to erectile dysfunction.
I have discussed the problem of patients having high blood pressure along with postural hypotension of a significant degree due to involvement of the autonomic nerves. This, as we shall see below, is an extremely difficult problem to treat, but one should avoid the use of drugs which may make things much worse by themselves causing additional postural hypotension! The drugs which provoke maximal peripheral vascular dilatation like prazosin, hydralazine and minoxidil are the most likely to cause severe postural hypotension. A significant volume depletion brought about by diuretics may also lead to postural hypotension. Clonidine and methyldopa although leading to less of a postural drop, should be avoided in patients with autonomic neuropathy and postural hypotension of any significant degree. Beta blockers are generally not associated with significant postural hypotension and amongst them, pindolol is the least likely to cause any problem. The newer calcium channel blockers, and the ACE inhibitors and ARB's have not been shown to lead to any significant postural drop in pressure.
The next step is to rule out other medical conditions where one may see both, raised blood glucose levels as well as high blood pressure in the same patient, as well as to rule out surgically curable forms of high blood pressure (after all, there is no reason why these should not occur in a diabetic!). Such conditions include ingestion of drugs like oral contraceptives and steroids; acromegaly; Cushing's Syndrome; thyrotoxicosis; Conn's Syndrome; pheochromocytoma; and renovascular hypertension. I wonder if it is cost effective to actively rule out these causes in all diabetics with high blood pressure. I usually do not carry out detailed investigations for the presence of these disorders unless there is a clinical evidence for the possible presence of these disorders. It is true that often, the presentations may be subtle, but a good physician should be able to suspect these disorders even when they are present in their subtle forms provided he knows what to look for! Incidently, most secondary and surgically correctable causes of high blood pressure usually occur in the young patient (under 30 years of age) or in those over the age of 60. This additional point should be of help in deciding which patient merits detailed investigation to rule out causes where one would find both, a raised blood glucose and high blood pressure in the same patient, or the surgically correctable forms of high blood pressure which may occur coincidently in a diabetic patient.
Having ruled out the secondary and/or surgically correctable causes of high blood pressure, as also the presence of other medical conditions where one could find both, a raised blood glucose and high blood pressure, the next step would be the specific management of high blood pressure in a patient with diabetes.
In view of the fact that many of the drugs commonly used to treat high blood pressure, have side effects which are detrimental to a diabetic, the best method to control the high blood pressure in such patients would be to try and use non-pharmacological means as far as possible. Inspite of this, if the drugs will still need to be used, it is possible that they will be required in much smaller doses and consequently the side effects also would be that much less.
Obesity leads to an increase in the blood pressure and a reduction in the weight would tend to lower the blood pressure. Thus, one of the first aims in an obese diabetic would be to make him achieve optimal body weight. This would not only help in lowering the blood pressure, but more importantly, is absolutely critical for a proper management of the diabetes! I have discussed the ways and means of judging optimal weight of a patient as well as the modalities for decreasing the weight of such an overweight patient in the chapter dealing with diet in diabetes.
Salt restriction must play an important role in the management of hypertension and this is all the more so in patients with diabetes. The raised blood pressure, at least in the initial stages is associated with an increase in the blood volume, This increase in the blood volume may be due to the osmotic effect exerted by the raised blood glucose but sodium also plays a central role in causing an increase in the blood volume. It has been shown that the sodium levels in the body of a diabetic with high blood pressure are around 10% more than that seen in a diabetic without high blood pressure!
Sodium also has a direct effect on the smooth muscle cells found in the walls of the smaller arteries and arterioles which determine the peripheral vascular resistance and thereby, the diastolic blood pressure. The sodium content of these smooth muscle cells is much more than normal. Water follows along the osmotic gradient and this makes the cells much bulkier with a loss of resilience. This loss of resilience compromises the ability of these smaller vessels to dilate to the extent required. As the peripheral resistance is dependent upon the lumen of these vessels, this inability to dilate as and when required under conditions of normal physiology, leads to these vessels offering an increased resistance to the flow of blood. This increased resistance leads to an increase in the diastolic blood pressure and consequently, the systolic blood pressure also rises.
Incidently, and this is quite important from the point of view of a diabetic, when blood glucose is lowered, (especially with the use of insulin, although this is also seen with the use of oral hypoglycemic agents), sodium is retained in the body and this adds to the increased levels of sodium seen in a diabetic with high blood pressure.
In view of the important role played by sodium in the pathogenesis of high blood pressure, a decrease of the sodium content in the body is central to the management of the raised blood pressure. This can be achieved in two ways, an increase in the excretion of the sodium from the body mostly through the use of diuretic drugs, or by lowering the sodium intake. Diuretics are associated with too many unwanted side effects, especially in large doses. Thus, the best means of decreasing the sodium levels should be a low intake of sodium. Even if this does not bring the levels of sodium to an acceptable level, the dose of the diuretic drug needed would be much smaller and this would also mean significantly less of the side effects and metabolic derangements.
I do not believe that it easy to follow a completely salt free diet for any long period of time. At the same time, I feel that it is essential for a diabetic, to try and curtail his salt intake to the maximum possible. Often, in spite of the salt restriction and weight reduction, the blood pressure still remains higher than acceptable and recourse has to be taken to the use of drugs to further lower the blood pressure.
I do not intend discussing all the drugs available to lower the blood pressure, but would rather focus on the best possible anti-hypertensive drugs to use in a patient with diabetes.
Introduced in 1981, ACE inhibitors have become on of the most popular classes of blood pressure-lowering medications in general and specially in patients with diabetes.
As has been discussed in the Chapter dealing with the prevention of the long term complications, ACE inhibitors are used at the stage of incipient diabetic nephropathy (microalbuminuria) even in the absence of hypertension. There is ample evidence to show that this helps in reversing the early renal damage or at the very least significantly slows down the progression of the diabetic nephropathy. They protect against the development of progressive nephropathy at least in part by lowering intraglomerular pressure. ACEi's are also widely considered as the initial drug of choice to be used to treat hypertension in a patient with diabetes. They have proved beneficial in patients who have had a myocardial infarction or congestive heart failure, or who have diabetic renal disease (early or established). Recent trials showed that ACE inhibitor therapy resulted in a 20 to 30 percent decrease in the risk of stroke, coronary heart disease, and major cardiovascular events. ACE inhibitors may provide additional benefits in patients with diabetes. These patients may have impaired fibrinolysis and endothelial dysfunction, which increase their risk of cardiovascular disease. ACE inhibitors have been shown to improve fibrinolysis and endothelial dysfunction.
ACE inhibitors have also been shown to increase insulin sensitivity. Moreover, unlike many other drugs used to lower the blood pressure, these have no adverse effects on lipid metabolism. ACE inhibitors may slow the progression of retinopathy, although these results are preliminary. They appear to lower the incidence of adverse cardiovascular outcomes among diabetics at increased risk for cardiovascular disease and improve ventricular function, especially in patients with ejection fraction < 45.
Angiotensin converting enzyme (ACE) is a protein that triggers the conversion of angiotensin I, an inert substance, to angiotensin II, which is a highly potent constrictor of arteries. ACE inhibitors inactivate this enzyme and as a result, reduce the amount of angiotensin II in the bloodstream. Angiotensin-II is a potent vasoconstrictor and promotes the production of aldosterone. Aldosterone promotes sodium and water retention. By inhibiting the production of angiotensin-II, ACE-inhibitors cause vasodilation and indirectly inhibit fluid volume increases that result from the actions of aldosterone. This makes the arteries dilate and lowers the blood pressure.
Hypersensitivity to the particular ACE inhibitor agent, pregnancy, hyperkalemia and bilateral renal artery stenosis are contra-indications for use. In fact, if after starting these drugs, one finds a rapid deterioration of the renal functions with a rise in the serum creatinine levels, bilateral renal artery stenosis should be the first condition to be ruled out.
One major irritant with the use of ACE inhibitors is that they may precipitate a dry, non-productive cough due to the accumulation of bradykinin. In the rare patient they may precipitate angioedema but these effects most often disappear when the drug is discontinued.
A rare complication of ACE inhibition, particularly in patients with near-normal glycemic control, is hypoglycemia.
Cardiovascular effects include hypotension, angina, and palpitations. Dizziness, fatigue, headache, and weakness have been reported. GI disturbances include nausea, vomiting, diarrhea, constipation, and abnormal taste. Neutropenia is another very rare side effect, and patients with renal dysfunction or collagen vascular diseases are more likely to experience this side effect than the general population. Dermatologic effects include rash and flushing. Impotence has been reported with ACE inhibitor use.
Hyperkalemia or proteinuria may occur, especially in patients with renal dysfunction. Renal insufficiency is possible, especially in patients with bilateral renal stenosis.
But the drugs are generally well tolerated, and the most troublesome side effect is a dry cough. There is not much difference between the different drugs in this class.
Concomitant use of NSAIDS may result in decreased ACE inhibitor effectiveness secondary to decreased synthesis of renal prostaglandins. Thiazide and loop diuretics may precipitate postural hypotension (first dose) secondary to vasodilation and a relative depletion of intravascular volume. Potassium-sparing diuretics may have an additive effect on potassium retention, resulting in hyperkalemia. Lithium toxicity has been reported when used in combination with ACE inhibitors. Concomitant use of cyclosporine with ACE inhibitors may cause acute renal failure.
Captopril and moexipril experience decreased absorption when taken with food.
Angiotensin-Converting Enzyme Inhibitors
|Benazepril||10 mg QD||20-40 mg QD|
|Captopril||25 mg BID-TID||25-150 mg BID-TID|
|Enalapri||5 mg QD||10-40 mg QD or in divided doses|
|Fosinopril||10 mg QD||20-40 mg QD|
|Lisinopril||10 mg QD||20-40 mg QD|
|Moexipril||7.5 mg QD||7.5-30 mg QD||Should be taken 1 hour before meals|
|Perindopril||4 mg QD||4-16 mg QD|
|Quinapril||10-20 mg||QD 20-80 mg QD or in divided doses|
|Ramipril||2.5 mg QD||2.5-20 mg QD||Capsule may be opened and sprinkled on apple sauce or mixed with apple juice or water|
|Trandolapril||1 mg QD||2-4 mg QD|
Angiotensin II inhibitors are the most recently approved class of drugs for treatment of hypertension and have been shown to be as effective as the ACEi's in managing diabetes patients with hypertension. In fact, recently, two major trials demonstrated a clear benefit in terms of renoprotection with ARBs in patients with nephropathy due to type 2 disease, as compared to other drugs. Interestingly, this renoprotective effect was independent of its blood pressure lowering effect and the ability to lower the raised urinary albumin excretion even at the stage of microalbuminuria in patients of diabetes who do not have hypertension.
These drugs block interaction of angiotensin II with its receptor. By blocking the binding of angiotensin-II to the angiotensin-II receptor, these agents inhibit the vasoconstriction effects of angiotensin-II and prevent the angiotensin-II-mediated release of aldosterone. Aldosterone promotes sodium and water retention. By inhibiting the production of aldosterone, ARBs indirectly inhibit fluid volume increases that result from the actions of aldosterone.
The contraindications to the use of this group of drugs is very similar to that of the ACEi's. They include hypersensitivity to the particular ARB agent, pregnancy, hyperkalemia and bilateral renal artery stenosis are contra-indications for use. In fact, if after starting these drugs, one finds a rapid deterioration of the renal functions with a rise in the serum creatinine levels, bilateral renal artery stenosis should be the first condition to be ruled out.
Cardiovascular side effects include orthostatic hypotension and angioedema. Central nervous system side effects include headache, dizziness, and fatigue. GI disturbances, including dyspepsia and diarrhea, have been reported. Muscle cramping, rash, and decreased renal function have also occurred with ARB use.
Unlike ACE inhibitors, these agents do not cause accumulation of bradykinin, so patients are less likely to have the dry cough that occasionally occurs with use of ACE inhibitors.
Concomitant use of ARBs with lithium may result in increased risk of lithium toxicity secondary to increased renal reabsorption of lithium. Digoxin concentrations should be monitored with candesartan use, as fluctuations in digoxin levels have been reported. Indomethacin may cause decreased effectiveness of losartan. The mechanism of this interaction is unknown.
Food does not appear to interfere with the bioavailability of these agents.
Angiotensin II Receptor Antagonists
|Candesartan||16 mg QD||8-32 mg/day in single or divided doses|
|Eprosartan||600 mg QD||400-800 mg QD|
|Irbesartan||150 mg QD||150-300 mg QD|
|Losartan||50 mg QD||25-100 mg QD|
|Telmisartan||40 mg QD||20-80 mg QD|
|Valsartan||80 mg QD||80-320 mg QD|
Between the Acei's and ARBs, which would be the better drug to use in patients with diabetes.
Presently, the evidence shows that and ACE inhibitor would be more beneficial for use in Type 1 patients in view of its lack of metabolic complications, the renal sparing effect and the net mortality benefit. An ARB should be used in those patients who do not tolerate ACE inhibitors ( mostly because of the cough). At the same time, there many ongoing trials which may show that either ARB's are better or that there is in fact, no real difference between the two.
Again if one goes by evidence based medicine, ARB's seem to be more beneficial in patients with Type 2 diabetes. However, the choice between an ACE inhibitor or ARB is less certain, given the lack of comparative data and the probable (but unproven) similar protective effect for nephropathy and adverse cardiovascular events.
From a practical viewpoint, most of us have been using ACEi's for their renal protective mechanisms in Type 2 diabetes with excellent results and therefore, I personally feel that a change over to ARB's is not justified until the ongoing trials show a definite better results for this group of drugs. One also has to keep in mind the relatively high cost of the ARB's as compared to the older and tried.
Even the wide consensus is that there is not much difference between the two in so far as the renal protective action is concerned. What one does know is that an ARB should be used in type 2 diabetic hypertensive patients with electrocardiographic evidence of LVH and/or nephropathy An ACE inhibitor should be administered to type 2 diabetic hypertensive patients without LVH or nephropathy.
I would not switch such a patient who is already receiving and tolerating an ACE inhibitor to an ARB.
A separate issue is whether an ARB can be given with an ACE inhibitor.
At first glance, one might question the concept of using the combination of an ACE inhibitor and an ARB in the same patient. Both classes of drugs work to inhibit the renin-angiotensin-aldosterone (RAA) system. Combined use would therefore seem redundant.
In actuality, the mechanism of action of ACE inhibitors and ARBs is not exactly the same. Although it is true that the end result of each agent is angiotensin-II inhibition, the site of action of ARBs is more distal than that of ACE inhibitors. ACE inhibitors block the action of the ACE. As a result, angiotensin-I is no longer converted to angiotensin-II. ACE is also responsible for breakdown of bradykinin, which is an inflammatory mediator and vasodilator. ACE inhibition therefore leads to accumulation of bradykinin, which serves to augment the amount of vasodilatation produced by ACE-inhibitor drugs. Just how potent the vasodilatory effect produced by bradykinin will be in any given patient is uncertain. Bradykinin is also important because it may be responsible for the adverse effects of cough and angioedema that occur with ACE inhibitors, but which are rare with ARBs.
In contrast to ACE inhibitors, ARBs do not affect ACE, and therefore do not result in bradykinin accumulation. Instead, ARB drugs produce a more distal (end-receptor blockade) effect that inhibits angiotensin-II. Because enzyme systems other than ACE are involved in angiotensin production, this more distal effect of ARB drugs may actually produce a greater overall angiotensin-II inhibitory effect than ACE inhibitors. However the effect of bradykinin on various vascular beds may counteract the somewhat lesser overall inhibition of angiotensin-II, so that the clinical potency of ACE inhibitors and ARBs for blood pressure reduction is comparable in most studies. Use of ACE inhibitors is usually preferred initially for treatment of heart failure if there are no contraindications, because of the much greater body of supportive literature on the use of this class of drugs compared with the ARBs. However, when bothersome cough or other idiosyncratic reaction prevents use of ACE inhibitors, substitution of an ARB is usually recommended.
The augmented effect even if seen has been shown to be directed towards the treatment of heart failure and should not routinely concern diabetes management. In fact, in the one trial which looked into the augmented effect on heart failure did not show any added benefit of adding and ARB failed to show additional benefit from use of an ARB if both an ACE inhibitor and a beta-blocker were already being used. It is a different matter that a few patients may be benefited if one does not see the full benefit after using both ACE inhibitors and beta blockers, and this is especially relevant if persistent hypertension remains problematic, but that has to be left to the individual doctor rather than making a sweeping statement.
Till a few years back, the diuretics were not favored for use in patients with diabetes. The reason for this was their adverse impact on glucose and lipid levels and a possible increase in cardiovascular risk have been a major concern with high doses of diuretics in diabetic patients. In recent times, they have again come into focus and are the drugs of choice after the ACEi's and the ARB's.
The reason for this are manifold. Dietary salt restriction and diuretics are likely to be effective in hypertensive diabetic patients. Salt restriction reduces the blood pressure in most patients, at least in part by reversing the underlying tendency to volume expansion. Furthermore, mild fluid contraction increases the antihypertensive effect of an ACE inhibitor, since the hypovolemia-induced rise in renin and angiotensin II production that normally limits the diuretic response is diminished.
Just as the diurtics may help the ACE inhibitors and the ARB's, the latter too may minimize or prevent some of the metabolic complications associated with diuretic therapy, such as hypokalemia (by lowering angiotensin II-induced aldosterone release), hyperlipidemia (via an unknown mechanism), and hyperuricemia (perhaps by decreasing proximal sodium and urate reabsorption).
Thus, there seems to be symbiotic relationship between the two groups of antihypertensives that make them ideal for use together. Moreover, the metabolic decompensation is seen to usually occur when heavy doses of the diuretics are used and such problems may be avoided with low-dose therapy, such as 12.5 to 25 mg of hydrochlorothiazide (or its equivalent) per day. Low-dose thiazide therapy can prevent or at least markedly minimize the fall in plasma potassium concentration and the rise in plasma glucose, triglyceride, and uric acid concentrations induced by 50 mg of hydrochlorothiazide (or its equivalent) in hypertensive type 2 diabetic patients.
The fear that the use of the diuretics, particularly the thiazide group of drugs may precipitate diabetes has been shown to be misplaced and finally, lowering the blood pressure with a low dose of a thiazide does not appear to reduce the expected cardiovascular benefit.
Inhibition of sodium and chloride reabsorption in the distal tubule of the kidney, resulting in increased urinary excretion of sodium and water. Direct arteriolar vasodilation is also seen and would reduce the raised blood pressure levels..
Known hypersensitivity to thiazides or other sulfonamides and anuria.
Electrolyte abnormalities, including hypokalemia, hypomagnesemia, hyponatremia, and hypercalemia may occur. Elevated blood glucose levels have also been reported. Hyperuricemia is possible, therefore use with caution in patients who suffer from gout.
Arrhythmias may be precipitated secondary to electrolyte abnormalities. Hyperlipidemia (increase in total cholesterol, triglycerides, and LDL cholesterol) has occurred. Dermatologic side effects include photosensitivity and an SLE-like syndrome. Drug-Drug Interactions.
Hypotension may occur when used in combination with ACE inhibitors. Patients taking carbamazepine may experience symptomatic hyponatremia with thiazide use. Corticosteroids may have a synergistic effect on potassium levels, resulting in hypokalemia. Concomitant use of cholestyramine may result in drug binding. Decreased clearance of lithium may result in an increased risk of lithium toxicity. There is a potential for digitalis toxicity due to a hypokalemia-induced proarrhythmic state. Methotrexate used in combination with thiazides may result in myelosuppression. Concomitant use of NSAIDS may result in decreased diuretic effectiveness and increased potassium levels secondary to decreased synthesis of renal prostaglandins. Propranolol may exacerbate hyperglycemia and hypertriglyceridemia.
Food may result in a small (15%) decrease in hydrochlorothiazide efficacy.
Amiloride and triamterene interfere with the sodium-potassium exchange at the distal convoluted tubule of the kidney. Spironolactone acts as an aldosterone antagonist. Aldosterone promotes sodium and water retention. By blocking the actions of aldosterone, spironolactone prevents increases in fluid volume.
Hypersensitivity to the particular potassium-sparing diuretic. Renal dysfunction, including anuria, elevated serum creatinine, and elevated BUN. Elevated serum potassium levels or potassium supplementation. Triamterene should not be used in patients with severe hepatic disease.
Hyperkalemia is a common side effect of these medications. GI disturbances, including nausea, vomiting, diarrhea, anorexia can occur. Triamterene and spironolactone have been known to cause impotence and sexual dysfunction. Spironolactone may precipitate gynecomastia or an SLE-like syndrome.
May experience synergistic effects on potassium elevation with the use of ACE inhibitors, cyclosporine, tacrolimus, and other potassium-sparing diuretics. Concomitant use of NSAIDS may result in decreased diuretic effectiveness and increased potassium levels secondary to decreased synthesis of renal prostaglandins. Decreased clearance of digoxin, lithium, and metformin may result in elevated serum levels of these drugs. Increased metformin levels may increase the risk of developing lactic acidosis. Use with caution in patients taking dofetilide, as there is an increased risk of cardiotoxicity (QT prolongation, torsades de pointes) secondary to competition for the renal cation transport system. Warfarin may have a decreased anticoagulant effect secondary to diuresis-induced concentration of clotting factors.
Amiloride and triamterene should be taken with food to help decrease GI disturbances. Absorption of spironolactone is enhanced when taken with food.
|Amiloride||5 mg QD||5-20 mg QD|
|Benzthiazide||25-50 mg BID||50-150 mg/day in divided doses|
|Chlorothiazide||500-1,000 mg/day in single or divided doses||500-2,000 mg/day in single or divided doses|
|Chlorthalidone||25 mg QD||25-100 mg QD|
|Furosemide||40 mg BID||40 mg BID|
|Hydrochlorothiazide||12.5 mg QD||25-100 mg QD|
|Hydroflumethiazide||50 mg BID||50-200 mg/day (divide doses >100 mg/day)|
|Indapamide||1.25 mg QD||1.25-5 mgQD|
|Metolazone||2.5-5 mg QD||5-20 mg QD||Different brands are not interchangeable. Doses must be individualized|
|Polythiazide||2-4 mg QD||2-4 mg QD|
|Spironolactone||50-100 mg/day in single or divided doses||50-400 mg/day in single or divided doses|
|Torsemide||5 mg QD||2.5-10 mg QD|
|Trichlormethiazide||2-4 mg QD||2-4 mg QD|
Calcium channel blockers are widely used for the treatment of high blood pressure and angina, but a few years ago, came under fire because of reports that they might cause heart attacks. This, however, applied only to the short-acting form of nifedipine, which was actually never actually approved for the treatment of high blood pressure, and produces a 'yo-yo' effect on blood pressure. It is generally thought that the long-acting forms (all the ones currently recommended for treating hypertension) are quite safe, because they lower the pressure much more gradually and smoothly. In recent times, this group of drugs has again started to be considered as beneficial for use in lowering the blood pressure.
Calcium Channel blockers (CCBs)are basically of two types: the dihydropyridines (e.g., amlodipine, diltiazem,) and the nondihydropyridine CCBs (e.g., verapamil).
There is still some controversy about the precise role of calcium channnel blockers in the management of hypertension in a patient with diabetes. Are they just blood pressure lowering agents or do they have additional intrinsic actions which would be of benefit to a person with diabetes. Whilst some studies have shown that the dihydropyridine CCBs do not have any intrinsic heart protective action they do show cardiac protection due to the lowering of the blood pressure rather than any intrinsic action. The combination of an ACE inhibitor and a dihydropyridine CCB has been shown to reduce proteinuria.
Combining a nondihydropyridine CCB with an ACE inhibitor in hypertensive patients with diabetes is associated with greater reductions in proteinuria than if either agent was used individually.
The contraction of the muscle cells of arteries is triggered by calcium entering the cell, which it does through special channels in the cell membrane known as calcium channels. As their name implies, calcium channel blockers (also known as calcium antagonists) plug the entrance to these channels and weaken the contraction of the muscle cell. This relaxation dilates the artery and lowers the blood pressure. The contraction of heart muscle is also calcium-dependent, but the configuration of the channels is slightly different, so that some of the calcium channel blockers have effects on the heart, while others do not. Their ability to dilate coronary arteries accounts for their effectiveness in angina as well as in hypertension.
Hypersensitivity to the particular calcium channel blocker agent. Second or third degree heart block, Wolfe-Parkinson-White syndrome, or sick sinus syndrome. Symptomatic hypotension. Congestive heart failure or coronary artery disease.
Cardiovascular effects include AV heart block and peripheral edema. Central nervous system effects include headache and dizziness. Gingival hyperplasia has been reported with some agents. GI disturbances include constipation.
Beta blockers, digoxin, and amiodarone may have additive cardiovascular effects when used in combination with calcium channel blockers. Some agents may inhibit the clearance of digoxin, resulting in increased risk of digoxin toxicity. Cimetidine in combination with nifedipine or diltiazem may result in increased cardiovascular toxicity. Carbemazeine, phenytoin, and tacrolimus metabolism may be inhibited by concomitant use with diltiazem. Cyclosporine metabolism may be inhibited by certain calcium channel blockers, resulting in an increased risk of cyclosporine toxicity. Azole antifungal agents may increase the potential for cardiovascular toxicity of dihydropyridine calcium channel blockers due to inhibition of metabolism. Theophylline metabolism is inhibited by diltiazem and alterations in theophylline serum concentrations (increase or decrease) can occur with nifedipine use.
Calcium channel blockers interact with numerous agents, and these interactions vary depending upon the agent selected.
Diltiazem should be taken before meals. Grapefruit juice should be avoided with felpodpine use.
Calcium-Channel Blocking Agents
|Amlodipine||5 mg QD||2.5-10 mg QD||May be taken with or without food. Avoid grapefruit products|
|Diltiazem||30 mg QID or 60-120 mg BID(SR) or 180-240 mg QD (CD and XR)||120-480 mg total daily dose (division of dose depends upon formulation)||Should be taken on an empty stomach. Sustained release dosage forms should not be opened, crushed, or chewed|
|Felodipine||5 mg QD||2.5-10 mg QD||Should not be crushed or chewed.Avoid grapefruit products|
|Isradipine||2.5 mg BIDor 5 mg QD (SR)||2.5-10 mg BID or 5-20 mg QD (SR)||Sustained release dosage forms should not be crushed or chewed|
|Nicardipine||20 mg TID or 30 mg BID(SR)||20-40 mg TID or 30-60 mg BID(SR)||Sustained release dosage forms should not be crushed or chewed|
|Nifedipine||30 mg QD||30-90 mg QD||Sustained release dosage forms should not be crushed or chewed. Avoid grape-fruit products|
|Nisoldipine||20 mg QD||20-60 mg QD||Sustained release dosage forms should not be crushed or chewed. Avoid taking with high fat meal or grapefruit products|
|Verapamil||80 mg TID or 120-240 mg QD (SR)||120-360 mg total daily dose (division of dose depends upon formulation)||Should be taken with food. Sustained release dosage forms should not be crushed or chewed. Avoid grapefruit products|
In the past, beta blockers were used extensively in the management of hypertension in a patient with diabetes. This was especially due to their proven benefit in lowering the risk of adverse cardiovascular outcomes.
Later, concerns about the masking of hypoglycemic symptoms and possible exacerbation of peripheral vascular disease, as well as the fact that the use of beta blockers have and adverse effect on the blood glucose levels and the lipid levels lead to their use to decrease significantly.
Beta blockers can aggravate the diabetes through a direct action of decreasing the secretion of insulin from the islets. This occurs both basally and after a meal challenge. It has been estimated that on an average the use of beta blockers increases the blood glucose levels by about 25-30% mg%. In some patients the rise may be much more severe. This increase in the blood glucose level brought about by a decrease in the insulin secretion is seen usually with non selective beta blockers like propranalol and rarely with the use of selective drugs like metoprolol and atenolol. It is true that a rise in the blood glucose of around 30mg% which is the average seen in most diabetics taking a beta blocker is not too significant and can be brought down through anti diabetic medications. At the same time, it is not possible to forecast which patient will react adversely to these drugs with a very severe rise in the levels of the blood glucose.
There are many other facets which make the routine use of betablockers in diabetics fraught with danger.
The release of glucagon from the islets is also under beta adrenergic control and the use of propranalol may decrease the secretion of glucagon. Glucagon is one of the main defences against hypoglycemia. Secondly, the beta blocade decreases the ability of the liver to form and release "new" glucose if required. Finally, the peripheral utilisation of glucose may be increased with the use of beta blockers. Whilst these actions may seem to be beneficial to a diabetic, they could also precipitate hypoglycemia, especially in any patient receiving exogenous insulin injections. It has been shown that the recovery from hypoglycemia is definitely delayed in the patient who takes beta blockers. Beta blockers also decrease the release of norepinephrine which plays an important role in countering hypoglycemia.
Many authorities have been against the use of beta blockers in a diabetic as they tend to mask many of the signs and symptoms of an impending hypoglycemic attack. However it should be realised that it is only the symptoms of sympathoadrenal discharge like palpitations, anxiety and tremors that are masked or blunted. Sweating may still be seen. I do not believe that patients would be able to recognise other, more subtle signs and symptoms of hypoglycemia. Subtle signs and symptoms are often missed not only by the patient but also by doctors. Sweating really cannot be used as a diagnostic pointer towards hypoglycemia in our country where the ambient temperature makes most patients sweat the year round!
The metabolic derangements brought about by beta blockers in so far as the blood glucose levels are concerned may seem a bit confusing, but can be summed up as causing a rise in the blood glucose levels and also inhibiting a rapid recovery from hypoglycemia, especially insulin induced hypoglycemia, even if they may not directly precipitate hypoglycemia in some patients.
Both the non-selective beta blockers like propranalol and the selective ones like metoprolol and atenolol, cause a 30 to 40% increase in the plasma triglycerides and a 10-15% decrease in the HDL cholesterol. The beta blockers with intrinsic sympathomimetic activity like practolol and pindolol do not seem to have any significant effect on the lipid levels.
As distrurbing was a study that when people without diabetes were given beta blockers to lower the blood pressure there was a 28 percent increased risk of developing type 2 diabetes compared to no antihypertensive therapy; this relationship was not seen with thiazides, calcium channel blockers, or ACE inhibitors This was especially so with the advent of drugs such as calcium channel blockers and the ACE inhibitors as well as the recently introduced ARB's.
It must be said that many of these effects are seen to a significant extent only when the beta blockers are used in large doses and may not be so adverse with the use of smaller doses.
Moreover, recent trials have again shown that despite these adverse findings, the proven benefits with beta blockers in lowering the risk of adverse cardiovascular outcomes in diabetic hypertensive patients suggest that these agents should continue to have a significant role as antihypertensive agents in this population, although not as the agents of initial choice. As can be seen from the flowchart, they are now extensively recommended as additional drugs if the blood pressure is not optimally controlled with the initiating drugs.
Beta blockers derive their name from the fact that they block beta receptors. The sympathetic nervous system, which regulates the actions of the heart and blood vessels, exerts its effects by secreting a chemical, norepinephrine from nerve endings, which interacts with receptors on the surfaces of the cells of the heart and blood vessels and makes them contract or relax. Beta blockers sit on these receptors and prevent the norepinephrine from getting to them.
Blockade of the beta-1 receptors, primarily located in cardiac tissue, results in decreased heart rate, decreased contractility and slowed AV conduction.
Hypersensitivity to the particular beta blocker agent, cardiogenic shock or overt cardiac failure, severe sinus bradycardia, second and third degree heart block, bronchial asthma or chronic obstructive pulmonary disease.
Cardiac side effects include hypotension and bradycardia. CNS side effects include depression, headache, dizziness, and insomnia. Beta blockers may cause cholesterol abnormalities (increase in triglycerides and LDL, decrease in HDL). These agents may induce bronchospasm and antagonize the effects of bronchodilator medications (albuterol) used for the treatment of asthma. Beta blockers have been reported to cause sexual dysfunction, primarily decreased libido and impotence.
The most troublesome side effect is lethargy.
There are substantial differences between the different drugs in this class.
Beta-Adrenergic Blocking Agents
|Acebutolol*||200 mg BID||200-600 mg BID|
|Atenolol*||50 mg QD||50-200 mg QD|
|Betaxolol||10 mg QD||10-20 mg QD|
|Bisoprolol||2.5-5 mg QD||2.5-20 mg QD|
|Carteolol||2.5 mg QD||2.5-10 mg QD|
|Metoprolol*||50 mg BID or 50-100 mg QD (XL)||100-450 mg/day in divided doses or 100-400 mg QD (XL)||Blood pressure after one week of therapy will be reflective of maximum effect of that dose for the particular patient|
|Nadolol*||40 mg QD||40-80 mg QD (doses up to 320 mg QD may be used)|
|Penbutolol||20 mg QD||10-40 mg QD||Full effect may take weeks|
|Pindolol*||5 mg BID||5-30 mg BID|
|Propranolol*||40 mg BID or 80 mg QD(LA)||120-240 mg/day in divided doses or 120-160 mg QD (SR)|
|Timolol*||10 mg BID||10-30 mg BID||Allow at least 7 days between dose changes.|
Concomitant use of beta blockers with alpha-1 antagonists may result in an exaggerated hypotensive response to the first dose of the alpha antagonist. This is due to suppression of the beta-mediated compensatory mechanism of increased heart rate in response to alpha blockade. Calcium channel blockers, digoxin, amiodarone, and quinidine may have additive cardiovascular effects when used in combination with beta blockers. The actions of beta-2 agonist medications (eg, albuterol) may be antagonized, thus lessening their effectiveness.
Beta blockers interact with numerous agents, and these interactions vary depending upon the agent selected.
Beta blockers should be taken in a consistent manner in relation to food consumption, to help prevent fluctuations in bioavailability.
I would not recommend the use of a beta blocker as amongst the initial choices for the management of hypertension in a person with diabetes. But it also well known that monotherapy rarely allows us to bring the raised blood pressure down to the optimal 120/80 levels. Therefore, there may be patients, as can be seen from the Flow chart above that may require the addition of a beta blocker.
If for any other reason, a beta blocker is to be used in a person with diabetes, they should be used in the smallest doses required and it may be better to use a selective beta blocker like metoprolol or atenolol rather than propranalol. At the same time, it should be remembered that in high doses the so called selective beta blockers lose their selectivity and can cause as much of a problem as a non selective beta blocker. Here again, one can appreciate the importance of using only small doses of the drugs.
As can be seen from the flow chart, this group of drugs are usually needed only in the rare patient with diabetes whose hypertension is very difficult to control. They are definitely not to be considered as being amongst the drugs of choice for the management of blood pressure in people with diabetes, but may be rarely combined with other agents to treat poorly controlled blood pressure.
Recently, a large United States study on antihypertension drugs, discontinued the doxazosin treatment arm because of adverse effects (higher incidence of congestive heart failure) and less benefit (unlikely to better prevent coronary heart disease). Given these data, alpha-adrenergic blockers should not be used as primary therapy, but they may prove useful as add-on therapy, particularly in older men with prostatism.
Alpha blockers lower blood pressure by preventing the constriction of arteries produced by the sympathetic nervous system. They block the alpha receptors on the muscle cells of the arteries, which are normally stimulated by norepinephrine to make the muscles contract. There is a decrease in the total peripheral resistance and venous return.
The very first dose of an alpha blocker can sometimes produce a dramatic reduction of blood pressure that is not seen with subsequent doses (sometimes referred to as a first-dose effect). This reduction of blood pressure may be particularly pronounced while standing, and makes one feel faint. The problem can be avoided in two ways: first, by starting off with a very small dose and gradually increasing it, and second, by taking the medication at night, so that the peak effect occurs while the patient is sleeping and are less vulnerable to the effects of a sudden reduction of pressure.
Other cardiac effects include palpitations, bradycardia, and edema. Central nervous system side effects including dizziness, headache, fatigue, and anxiety have been reported. Alpha blockers have been noted to effect cholesterol levels (decrease in total cholesterol, LDL, and triglycerides; increase in HDL). GI effects include nausea, diarrhea, constipation, and vomiting. Genitourinary side effects include nocturia, urinary frequency, impotence, and priapism.
Concomitant use of beta blockers may result in an exaggerated hypotensive response to the first dose of the alpha antagonist. Additive effects on hypotension may occur with concomitant use of verapamil. Cimetidine may exaggerate the hypotensive response.
Food does not appear to interfere with the bioavailability of these agents.
Usual Dosage Range
|Doxazosin||1 mg QD or QHS||1-16 mg QD||First dose may cause significant hypotension|
|Prazosin||1 mg BID-TID||6-15 mg/day in divided doses||First dose may cause significant hypotension|
|Terazosin||1 mg QHS||1-20 mg/day, may use divided doses||First dose may cause significant hypotension|