Posts Tagged ‘ACE inhibitor’

Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)

Reporter: Aviva Lev-Ari, PhD, RN

Risks of Hypoglycemia in Diabetics with CKD

By Mark Abrahams, MD

Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY

Published: 03/13/2012


According to the National Institutes of Health (NIH), approximately 40% of adults with diabetes have some degree of chronic kidney disease (CKD).1 That’s a lot of patients—perhaps more than one might think.

What should we be doing differently for these patients? Sure, they should be getting an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for renoprotection, and blood pressure and lipids should be aggressively managed, but how does (or should) our approach to managing their antidiabetic therapy change?

We might consider taking a more aggressive approach to their glycemic control. In clinical trials, tight glycemic control has been shown to be the primary determinant of decreased microvascular complications.1 However, once we’ve decided how aggressively to manage glycemia, the choice of which antidiabetic to use (and how to dose it) is especially important in these patients.

Unfortunately, when the therapeutic strategy is to maximize glycemic control, the risk of hypoglycemia also increases – in both frequency and severity.2 Patients taking oral antidiabetics that are primarily eliminated by the kidneys are particularly susceptible.1 Furthermore, it should be noted that older patients are also at higher risk.3

Dosing errors are common in CKD patients and can cause poor outcomes.3 Drugs cleared renally should be dose-adjusted based on creatinine clearance or estimated glomerular filtration rate (eGFR). Dose reductions, lengthening of the dosing interval, or both may be required.3

As metformin is nearly 100% renally excreted, it is contraindicated in a number of patients: when serum creatinine is higher than 1.5 mg/dL in men or 1.4 mg/dL in women, in patients older than 80 years, or in patients with chronic heart failure. The primary concern here is that other hypoxic conditions (e.g., acute myocardial infarction, severe infection, respiratory disease, liver disease) may increase the risk of lactic acidosis. Because of this danger, and despite the fact that metformin is usually the recommended first-line treatment for type 2 diabetes, one should use caution when considering metformin in patients with renal impairment.3

Similarly, sulfonylureas should be used with care in diabetics with CKD. The clearance of both sulfonylureas and their metabolites is highly dependent on kidney function. As such, severe and sustained episodes of hypoglycemia due to sulfonylurea use have been described in dialysis patients.2

Regardless of which antidiabetic agent is selected, HbA1c and kidney function should be regularly monitored and the antidiabetic regimen appropriately adjusted. As patients with type 2 diabetes tend to progress over time, most will require a combination of agents to achieve desired glycemic control. These combinations should be chosen carefully in patients with CKD.1

Finally, awareness of and screening for renal impairment in diabetics is a necessary precursor to successful intervention. In these patients, CKD is underdiagnosed and undertreated, and awareness of the disease is low among providers and patients alike.1

Early detection of disease via eGFR or urinary albumin excretion can lead to timely, evidence-based intervention and help prevent or delay progression of CKD. The benefit? Improved kidney and cardiovascular outcomes, and lower associated costs.1


  1. Bakris GL. Recognition, Pathogenesis, and Treatment of Different Stages of Nephropathy in Patients With Type 2 Diabetes MellitusMayo Clin Proc. 2011;86:444-456.
  2. Cavanaugh KL. Diabetes Management Issues for Patients With Chronic Kidney DiseaseClin Diab. 2007;25:90-97.
  3. Munar MY, et al. Drug Dosing Adjustments in Patients With Chronic Kidney Disease. Am Fam Physician. 2007;75:1487-1496.


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Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Curator: Aviva Lev-Ari, PhD, RN


Excellent review of Hypertension Medications is provided in the following two short videos:


Hypertension Explained Clearly! 1 of 2

Hypertension Explained Clearly! 2 of 2



Hypertension Treatment in the Last Decade

 The need for combination drug therapy was recognized in 2000, In Combination Antihypertensive Drugs: Recommendations for Use

NEIL S. SKOLNIK, M.D., JONATHAN D. BECK, M.D., MATHEW CLARK, M.D., Abington Memorial Hospital, Jenkintown, Pennsylvania

Am Fam Physician. 2000 May 15;61(10):3049-3056

Combination Medication: Impact on Compliance

Increased Compliance with fewer pills a favorable outcome of combination medication for Hypertension.

More medications, fewer pills: Combination medications for the treatment of hypertension Richard Lewanczuk, MD PhD1 and Sheldon W Tobe, MD2

Can J Cardiol. 2007 May 15; 23(7): 573–576.

Classification of Blood Pressure

Category SBP mmHg DBP mmHg

Normal <120 and <80

Prehypertension 120–139 or 80–89

Hypertension, Stage 1 140–159 or 90–99

Hypertension, Stage 2 ≥160 or ≥100

Principles of Hypertension Treatment

• Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients

with diabetes or chronic kidney disease.

• Majority of patients will require two medications to reach goal.

Without Compelling Indications

Stage 1


(SBP 140–159 or DBP

90–99 mmHg)

Thiazide-type diuretics

for most. May consider


or combination.

 Stage 2


(SBP ≥160 or DBP

≥100 mmHg)

2-drug combination for

most (usually thiazidetype

diuretic and ACEI,

or ARB, or BB, or CCB).

Causes of Resistant Hypertension

• Improper BP measurement

• Excess sodium intake

• Inadequate diuretic therapy

• Medication

– Inadequate doses

– Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs

(NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)

– Over-the-counter (OTC) drugs and herbal supplements

• Excess alcohol intake

• Identifiable causes of hypertension (see reverse side)

Compelling Indications for Individual Drug Classes

 Compelling Indication  and Initial Therapy Options

• Heart failure THIAZ, BB, ACEI, ARB, ALDO ANT

• Post myocardial infarction BB, ACEI, ALDO ANT

• High CVD risk THIAZ, BB, ACEI, CCB

• Diabetes THIAZ, BB, ACEI, ARB, CCB

• Chronic kidney disease ACEI, ARB

• Recurrent stroke prevention THIAZ, ACEI

Key: THIAZ = thiazide diuretic, ACEI= angiotensin converting enzyme inhibitor, ARB = angiotensin receptor

blocker, BB = beta blocker, CCB = calcium channel blocker, ALDO ANT = aldosterone antagonist


JNC-7 on Treatment for Hypertension

According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, or JNC-7, most people require more than one medication to achieve treatment goals. Some medications are being manufactured in combinations, which reduces the number of pills a patient must take and may reduce costs.


All combination drugs for Hypertension are presented in


JNC-7 lists the following Combinations of Drugs for Hypertension:

ACE Inhibitors and Calcium Channel Blockers

The angiotensin converting enzyme inhibitors, or ACEIs, are a group of drugs that work in the kidneys to block a reaction that leads to tightening of the blood vessels and retention of sodium and water. They lower blood pressure by counteracting these effects.

Calcium channel blockers, or CCBs, work by relaxing smooth muscle in the heart and blood vessels. One common side effect of this group of drugs is leg swelling. This can be lessened when they are used in combination with the ACEIs.
Amlodipine-benazepril, enalapril-felodipine and trandolapril-verapamil are examples of these medicines that have been combined into a single pill. Multiple dosing variations are available.

ACE Inhibitors and Diuretics

Diuretics are commonly known as “water pills” because they work by increasing urine output and lowering blood volume, and therefore blood pressure. Diuretics are generally inexpensive, work well to enhance the effects of other medicines and have a proven track record in preventing cardiovascular complications of hypertension, as discussed in JNC-7.

Many ACE inhibitors are available packaged with hydrochlorothiazide, or HCTZ. Benazepril, enalapril, lisinopril and others are commonly seen in this combination.

ARBs and Diuretics

The angiotensin receptor blockers, or ARBs, are related to the ACEIs, in that they work on the same renal pathway. However, the ARBs work farther down the process and often have fewer side effects. The beneficial effects on blood pressure are similar between the two groups.

Candesartan, losartan, telmesartan, valsartan and others are available as combination drugs with HCTZ.

Beta-blockers and Diuretics

Beta-blocking medications work in the peripheral nervous system to slow the heart rate and decrease adrenalin-type effects on the blood vessels. JNC-7 notes that the beta-blockers are especially useful in those with hypertension and heart disease or angina.

Atenolol is available with the diuretic chlorthalidone, which is similar to HCTZ. Bisoprolol, metroprolol, propranolol LA and timolol come in combination with HCTZ.

Centrally Acting Drugs and Diuretics

Methyldopa and reserpine affect the central nervous system to produce a lowering of blood pressure. They are not used often, but can be effective in the appropriate situation. Each come in a combination drug with HCTZ, while reserpine is also produced with chlorthalidone and chlorothiazide.

Diuretic Combinations

Various diuretics work in different locations of the kidneys to affect their anti-hypertensive properties. HCTZ tends to lower blood potassium, so is available in combination with spironolactone or triamterene, which are known to elevate potassium. The combination tends to be potassium neutral.

ARB and Calcium Channel Blocker and Diuretic

In July 2010, a triple combination drug for hypertension was approved by the US Food and Drug Administration. Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide, according to Monthly Prescribing Reference.

Three Combination Drug Therapy for Antihypertension from Daiichi Sankyo’s Portfolio of Products

Daiichi Sankyo has a
comprehensive portfolio of drugs offering a wide range of treatments for patients in a number of disease
categories including hypertension, heart disease and hyperlipidemia/atherosclerosis.

The discovery of epinephrine (also known as adrenaline) in 1889, to the development of the statin class of lipid-lowering agents and the development of the first glitazone, which revolutionized long-term control of type 2 diabetes.

New ideas and pairing of existing information with novel concepts, led to the  creation of  medicines as well as new methods of drug discovery and delivery.

Daiichi Sankyo products for hypertension, heart disease and hyperlipidemia/atherosclerosis which are currently marketed in the U.S. include several drug combinations for Cardiovascular disease.


TRIBENZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker and Diuretic


Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. TRIBENZOR can help your blood vessels relax and reduce the amount of fluid in your blood. This can make your blood pressure lower. Medicines that lower blood pressure may lower your chance of having a stroke or a heart attack.

Some people may need more than 1—or even more than 2—medicines to help control their blood pressure. TRIBENZOR combines 3 effective medicines in 1 convenient pill. Read the following chart to learn how each medicine works in its own way to help lower blood pressure.

TRIBENZOR: 3 effective medicines in 1 pill

The medicine in TRIBENZOR How it works What it does
Angiotensin II receptor blocker Blocks a natural chemical in your body that causes blood vessels to narrow.





Calcium channel blocker Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.
Diuretic (water pill) Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood.


            Effectively lower blood pressure. People taking the 3 medicines in TRIBENZOR had greater reductions in blood pressure than did people taking any 2 of the medicines combined

            Start to work quickly. People taking TRIBENZOR saw results in as little as 2 weeks

AZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker

How AZOR work

AZOR relaxes and widens blood vessels to help lower blood pressure.

You may have already tried another blood pressure medicine that works a certain way to lower blood pressure. But 1 blood pressure medicine may not be enough for you. You may find the help you need with the 2 effective medicines in AZOR.

AZOR combines 2 effective medicines in 1 convenient pill.

Learn how each medicine in AZOR works in its own way to help lower blood pressure.

The medicine in AZOR How it works What it does
Angiotensin II receptor blocker (ARB) Blocks a natural chemical in your body that causes blood vessels to narrow. This helps your blood vessels relax and widen.





Calcium channel blocker Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.



Benicar and Benicar HCT are Daiichi Sankyo’s products an ARBs and Diuretics

How Benicar and Benicar HCT work

Benicar and Benicar HCT are prescription medicines used to lower high blood pressure (hypertension). They may be used alone or with other medicines used to treat high blood pressure. Benicar HCT is not for use as the first medicine to treat your high blood pressure.

 Lowering blood pressure with Benicar or Benicar HCT

There are many different choices to treat high blood pressure. You may have started with some lifestyle changes or different medicines to find what works for you. You and your doctor can talk about whether Benicar or Benicar HCT is a good choice for you.

The medicine in Benicar How it works

What it does

Angiotensin II receptor blocker (ARB) Blocks a natural chemical in the body that causes blood vessels to narrow. This helps the blood vessels relax and widen.





Some people may need more than 1 medicine to help manage high blood pressure. So doctors may choose to prescribe Benicar HCT. The 2 medicines in Benicar HCT help to lower blood pressure more than taking either medicine alone. You and your doctor can talk about what’s right for you.

The medicines in Benicar HCT How it works

What it does

Angiotensin II receptor blocker (ARB) Blocks a natural chemical in the body that causes blood vessels to narrow. This helps the blood vessels relax and widen.





Diuretic(a water pill) Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood.

Benicar and Benicar HCT are medicines that both

Block calcium

Block a chemical called angiotensin II

Block water and salt

There are no generic forms of Benicar or Benicar HCT


Risk of Antihypertensive drugs

Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study

BMJ 2012;344:d8190

Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.


Affordability of the Combination Medication for Hypertension from the Daiichi Sankyo’s product portfolio is supported by a Manufacturer Program to 2016.

There are no generic drugs for the Combination Medication for Hypertension from the Daiichi Sankyo’s product portfolio. Daiichi Sankyo, Inc., will cover up to $140 of the co-pay for BENICAR, BENICAR HCT, AZOR, and TRIBENZOR after the patient pays the first $25. Offer applies to patients with commercial insurance; $25 initial savings available for patients without insurance; offer expires 2016. If a retail or mail-order pharmacy does not accept the Savings That Last card, patients may obtain a Direct Member Reimbursement form by calling the number on the back of the card to receive instructions on how to obtain the savings benefit. Offer not valid for patients enrolled in a state or federal healthcare program including but not limited to Medicaid, Medicare, Veterans Administration, or TRICARE/CHAMPUS. Offer valid in the United States and Puerto Rico. Void where taxed, restricted, or prohibited by law. Void in Massachusetts, except for patients without insurance. Daiichi Sankyo, Inc., reserves the right to rescind, revoke, or amend this program, at any time, without notice.

 TRIBENZOR is preferred on some of the largest Medicare Part D plans.


Cost Savings Associated with Filling a 3-Month Supply of Prescription Medicines


 Out-of-pocket and Total Costs of Fixed-dose Combination Antihypertensives and Their Components

Atonu Rabbani1 and G. Caleb Alexander1,2,3,4

American Journal of Hypertension (2008); 21, 5, 509–513. doi:10.1038/ajh.2008.31

Given patient burden and non-adherence from out-of-pocket prescription costs, the clinical benefits of brand-named fixed-dose combination antihypertensive therapy should be balanced with their greater out-of-pocket costs.



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