Bradley Wright, PharmD

TD is a 61-year-old man who presents to your clinic for follow-up. His past medical history includes type 2 diabetes (T2DM), hypertension, and hyperlipidemia. His current medications are: metformin XR 2000 mg once daily, glimepiride 8 mg daily, valsartan 320 mg daily, pravastatin 40 mg daily, amlodipine 10 mg daily, chlorthalidone 25mg daily, and aspirin 81 mg daily.  

He has been able to keep his diabetes well controlled with the combination of lifestyle modifications and medications for the past 5 years. Laboratory results obtained today are: HbA1c, 7.1%; basic metabolic panel WNL (SCr - 0.9 mg/dL, Na+, 138 mEq/L, K+, 4.0 mEq/L); and urine albumin, 228 µg/mg creatinine. Vitals are: weight, 78 kg; BMI, 28; blood pressure (BP) in clinic, 154/92 and 158/96 mm Hg; pulse, 74 beats/min. Allergies/intolerances include a cough with ace inhibitor therapy. TD checks his BP at home and it ranges from 145/90 to 160/102  mm Hg.  

You are most concerned today with his blood pressure.

C. Continue current medications as patient is at goal BP of <150/90 mm Hg for his age

E. Discontinue chlorthalidone and add carvedilol 6.25 mg twice daily

Most appropriate answer: A. Add spironolactone 25mg daily

Nearly two-thirds of patients with T2DM have hypertension.

Lowering blood pressure in these patients  may help prevent cardiovascular morbidity and mortality, but control is often insufficient in clinical practice.

Resistant hypertension is defined as elevated blood pressure not controlled with optimally dosed antihypertensives from at least 3 different classes, one of which is an appropriate and optimally dosed diuretic. Resistant hypertension is difficult to treat and especially so in patient with T2DM.

Many different treatment options can be considered in these patients; however, one that is particularly effective is the use of an aldosterone antagonist such as spironolactone. Spironolactone has been shown to be safe and effective in the treatment of resistant hypertension in patients with and without diabetes.

In one double-blind, placebo-controlled study, the addition of spironolactone as a fourth agent initiated at 25 mg/day resulted in significant reductions in daytime, night-time, 24-hour, and office BP. More patients in the spironolactone group also achieved BP control after 16 weeks as compared to placebo. The drug was considered safe with no change in glycemic control and a low incidence of adverse effects (hyperkalemia). In addition BP reduction, the urinary albumin/creatinine ratio also was significantly reduced in the spironolactone group.

Adding spironolactone to TD’s regimen would require close monitoring of his serum potassium (1 week after initiation and any change in dose) especially since the patient is on concomitant angiotensin receptor blocker (ARB) therapy.

 This combination could be considered given this patient’s urinary albumin excretion; however, results of the ALTITUDE trial

 suggest that the combination of aliskiren and an ARB/angiotensin converting enzyme (ACE) inhibitor can result in negative outcomes in diabetic patients and is therefore not recommended as a treatment option.

 Although the patient is older than 60 years of age, JNC 8 recommends maintaining a target goal BP of 140/90  mm Hg in patients with diabetes.

Option D may be considered but may not be the most appropriate in this patient.

 Beta-blockers may be considered as a fourth-line agent in this patient; however, there is no clear indication for a beta-blocker that would result in decreased morbidity or mortality in this patient.

Beta-blockers and especially those without vasodilatory effects, such as atenolol, may not result in significant BP reductions in these patients. [Brad: “these patients” meaning those with resistant HTN?] Treatment with beta-blockers, especially non-selective agents, may also result in metabolic adverse effects such as decreased glycemic control.

  Lastly, beta-blockers may mask signs and symptoms of hypoglycemia in patients with diabetes who are on therapy such as sulfonylureas or insulin which are more likely to cause hypoglycemia than other agents.

  If a beta-blocker is chosen, an agent such as carvedilol with vasodilatory effects may provide better efficacy and be more appropriate as it may also result in fewer metabolic effects.

 While carvedilol may prove a useful option and a more ideal beta-blocker in this patient with diabetes and hypertension,

 it is not recommended to discontinue the thiazide at this time in the absence of adverse effects (Na+ and K+ are WNL). Diuretic therapy, especially thiazides in those patients without significant chronic kidney disease, is a mainstay in the treatment of resistant hypertension.

Diabetes and hypertension: the bad companions

De Souza F, Muxfeldt E, Fiszman R, Salles G. 

Efficacy of spironolactone therapy in patients with true resistant hypertension. 

Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. 

Low dose spironolactone reduces blood pressure in patient with resistant hypertension and type 2 diabetes mellitus

: a double blind randomized clinical trial. 

Parving HH, Brenner BM, McMurray JJ, et al. 

Cardiorenal end points in a trial of aliskiren for type 2 diabetes.

2014 evidence-based guideline for the management of high blood pressure in adults. report from the panel members appointed to the Eighth Joint National Committee 

Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study

Giugliano D, Acampora R, Marfella R, et al. 

Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension.

Incidence and correlates of hypoglycemia in type 2 diabetes. The Hypos-1 study.

Poll

There are several reasonable options for intensifying this patient's blood pressure treatment. Which one is optimal, though, given his labs and concomitant meds?   

A 61-year-old Man with Diabetes and Resistant Hypertension

At a follow-up appointment your 53-year-old African American patient reported polyruia and polydipsia; his A1C had risen over 3 months from 8.1% to 9.2%. You have discussed with him the need to consider adding insulin to his current treatment with metformin 1000 mg twice daily. He also is treated for hypertension and osteoarthritis and admits to unreliable adherence to his daily regemin of pills. He has an erratic daytime schedule as a retail store manager and is not as careful as he "should be" about eating breakfast and lunch or following his dietary guidelines.

After a discussion of the pros and cons of insulin therapy, the patient agrees to start.

A. Continue metformin; initiate insulin detemir 10 units QHS, and insulin asparte 4 units TID with meals

B. Continue metformin; initiate premixed Novolin 70/30 6 units BID

C. Stop metformin; initiate insulin glargine 10 units daily, follow-up in 1 month

D. Continue metformin; initiate insulin glargine 10 units QHS with self-titration to glucose goals

E. Continue metformin; initiate NPH insulin 10 units twice daily

Answer: D. Continue metformin, initiate insulin glargine 10 units QHS with self-titration to glucose goals

Basal insulin therapy dosed once daily at bedtime is the best choice for this patient. Basal insulin therapies such as glargine, detemir, and NPH insulin supplement remaining endogenous insulin production to help normalize fasting blood glucose levels and can also help preserve beta-cell function. The addition of low-dose basal insulin to oral antidiabetic drugs can result in a majority of patients achieving an A1C goal of <7% with minimal risk of hypoglycemia.

Most patients will require at least some titration of the basal insulin dose to reach target A1c

In willing and able patients, patient driven self-titration protocols have been shown to be more effective than clinic-controlled protocols. Two common self-titration methods are to instruct the patient to increase basal insulin by 1 unit on every day the fasting glucose is >100mg/dL or increase the dose by 2 units every 3 days until fasting levels are within goals.

) can be ideal for some patients, this patient already has admitted poor adherence to multiple daily doses of medications.  Basal-only regimens, titrated appropriately, will allow the majority of patients to achieve glycemic goals with just 1 injection daily. Addition of bolus, or prandial, insulin should be considered when an optimally titrated basal regimen fails to get the patient to goal or if post-prandial goals are not reached once fasting glucose levels are at goal.

 could be considered for this patient based on the ability of these agents to lower A1C and treat symptoms of hyperglycemia; however, it is not the most appropriate choice for him for several reasons. This patient does not have a routine work schedule and often skips a meal.  A premixed insulin regimen is most effective for persons who maintain a fairly regular daily routine, including regular meals taken at regular times.  This patient’s lifestyle could place him at increased risk for hypoglycemia, especially if he skips lunch. If he progresses to the need for bolus therapy, pre-mixed insulin can be considered as this would decrease the total number of injections daily; however, the patient would need counseling on lifestyle habits to prevent hypoglycemia with this insulin regimen.  Importantly, the patient is insured and therefore would likely not benefit from the decreased cost of Novolin 70/30 vs glargine

In all patients without contraindications, metformin should not be discontinued when insulin is initiated

. Continuing metformin can improve glycemic control and outcomes, decrease the insulin dose required, and prevent additional weight gain without increasing the risk for hypoglycemia.

 while an acceptable option is not the best option for this patient.  Basal insulin analogues have proven to be just as effective as NPH while decreasing the occurrence of hypoglycemia, specifically nocturnal hypoglycemia. Also, this patient is insured and may not benefit from the decreased cost of NPH.

To review part 1 of the case, click here. 

The decision to start insulin therapy requires frank dialogue with a patient about lifestyle, psychosocial, and employment matters. Given this patient's particulars, what type of insulin would you prescribe and on what schedule? 

How Would You Initiate Insulin in this 53-Year-Old Man with T2DM?

A 53-year-old African-American man with a history of type 2 diabetes mellitus (T2DM), hypertension, and osteoarthritis is in clinic for follow-up of T2DM. His only complaint at this time is polyuria. Current medications include metformin, 1000 mg twice daily; lisinopril, 20 mg/d; amlodipine 10mg/d; aspirin, 81 mg/d; simvastatin, 20 mg/d; and acetaminophen 1000 mg TID. He is “mostly” adherent to the regimen but says it is still difficult for him to take multiple medications multiple times a day.

Results of his physical examination today and recent laboratory findings are WNL, with the exception of an A1C of 9.2%, up from 8.1% measured 3 months ago. Vitals are: weight, 82 kg (previously 85 kg); blood pressure, 138/88 mm Hg (previously 141/86 mm Hg); and heart rate, 74 beats/min. He does not bring a home blood glucose log to clinic. He is a manager at a retail store, works an erratic daytime schedule, and often skips breakfast or lunch. He also has a hard time following his diabetic diet. He states that he is often very thirsty, but is proud that he has stopped drinking sodas and is drinking lots of water. He also tells you that he is grateful that while his insurance provider was recently changed, you are still in his network.

A. Initiate glimepiride 2 mg daily, titrated to maximum dose of 8 mg daily

C. Initiate liraglutide 0.6 mg daily, titrated to a maximum dose of 1.8 mg daily

D. Increase metformin to 850 mg three times daily and add saxagliptin 5 mg daily

Insulin therapy should be considered as an option in all patients requiring dual therapy. Insulin becomes the most appropriate choice (in addition to metformin) when the patient is unlikely to reach target A1C on oral agents and/or the patient has significant hyperglycemia (>300mg/dL or symptoms of hyperglycemia).

 While no home blood glucose readings are available, the patient is reporting symptoms of hyperglycemia (ie, polydipsia, polyuria) and guidelines support starting insulin therapy sooner rather than later in this patient.

) is an appropriate second-line option, it is not the best option for this patient at this stage of the disease as the drug is not sufficiently potent to lower his A1c to the target goal of <7% and treat the symptoms of hyperglycemia. This also holds true for initiating liraglutide (

, even at the maximum dose of 1.8 mg daily.

The patient is already taking the optimal daily dose of metformin (2000 mg/day) and therefore increasing the dose 

 would not be expected to provide any further significant decrease in A1C. Saxagliptin 

 is associated with only a modest decrease in A1C and so adding the drug at this time is unlikely to help the patient achieve his glycemic goals.

The patient is a 53-year-old African American with type 2 diabetes, in the clinic for regular follow-up. Review the rest of his exam results and select your option for the next step(s). 

Polydipsia, Polyuria, and Elevated A1C--What's Your Next Step for This Patient?

A 63-year-old African American man with a history of type 2 diabetes mellitus, hypertension, and atrial fibrillation is a new patient to the clinic. Current medications include canagliflozin, 300 mg/d; metformin, 1000 mg twice daily; glipizide ER, 20 mg/d; lisinopril, 20 mg/d; metoprolol, 100 mg twice daily; hydrochlorothiazide 25mg/d; aspirin, 81 mg/d; digoxin 0.125 mcg/d; warfarin 5mg/d; and simvastatin, 20 mg/d.

Recent laboratory findings are WNL, including an A1c of 6.7% (American Diabetes Association goal of <7%) and an eGFR of >60 mL/min/1.73m

. Vitals include a blood pressure of 138/88 mm Hg and a heart rate of 64 beats/min. After review, you are concerned about a potential drug interaction with the canagliflozin and speak with the patient about close monitoring.

Coadministration of digoxin (option B) and canagliflozin can result in a 20% increase in AUC of digoxin and an increase in the mean peak drug concentration (C

) of 36%. Current labeling suggests to monitor digoxin closely when given with canagliflozin.

Canagliflozin is metabolized by the UGT enzyme system and therefore does not interfere with the metabolism of either warfarin (option A) or simvastatin (option D),

 both of which depend on the CYP enzymes for metabolism. Canagliflozin does not inhibit or induce CYP enzymes.

Hydrochlorothizide (option C) has been shown to be safe in combination with canagliflozin.

While the patient’s volume status should always be monitored when starting this class of agents, volume related adverse reactions are more common with loop diuretics and unlikely with low-dose hydrochlorothiazide. The patient also does not have other risk factors (age older than 75 years and moderate renal impairment) for volume depleted reactions as discussed in a 

Canagliflozin also has been shown to be safe in combination with metformin and sulfonylureas, eliminating glipizide (option E) as a potential problem. Canagliflozin is unlikely to cause hypoglycemia as a result of its insulin-independent mechanism of action, a finding from a study in which the drug was compared to sitagliptin as add-on therapy in patients uncontrolled on metformin plus a sulfonylurea.

Invokana (canagliflozin ) [package insert]. Gurabo, PR: Janssen Ortho LLC; 2013.

Devineni D, Vaccaro N, Polidori D, Rusch S, Wajs E. Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants. 

Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. 

The patient is new to you, he's got type 2 DM and has a lot of meds on board. There's danger in this mix. Read the history and see if you spot the problem.

Polypharmacy Perils: What’s Wrong With This Rx Plan?

A 76-year-old African American woman with a history of type 2 diabetes mellitus and chronic kidney disease is evaluated for an elevated A1c level of 7.6% (American Diabetes Association goal, <7%). Current medications include metformin, 1000 mg twice daily; glimepiride, 8 mg/d; lisinopril, 20 mg/d; carvedilol, 25 mg twice daily; furosemide, 40 mg twice daily; aspirin, 81 mg/d; and atorvastatin, 80 mg/d. Recent laboratory findings are significant for an estimated glomerular filtration rate (eGFR) of 50 mL/min/1.73 m

. The patient would like to try the “new diabetes drug” she saw advertised on TV, but you inform her that she cannot take canagliflozin at this time.

A. Canagliflozin will not lower her A1c to goal.

B. Canagliflozin is not recommended with an eGFR of less than 60 mL/min

C. Canagliflozin cannot be combined with sulfonylureas (glimepiride).

D. Canagliflozin is not recommended because of the patient’s risk for hypotension.

Answer: D. Canagliflozin is not recommended because of the patient’s risk for hypotension.

In patients uncontrolled with 2 oral medications, the new class of agents-sodium glucose cotransporter 2 (SGLT2) inhibitors, such as canagliflozin-have many advantages. They offer a new mechanism of action and are associated with a modest reduction in A1c level, a low risk of hypoglycemia, and weight loss.

They are not appropriate, however, for this patient who is at significant risk for hypotension. Through their mechanism of action, the SGLT2 inhibitors cause osmotic diuresis and intravascular volume contraction. As a result, symptomatic hypotension can occur; this has been noted particularly in patients receiving the 300-mg dose of canagliflozin. The prescribing information recommends monitoring the volume status in patients who have risk factors for hypotension. The 3 risk factors associated with symptomatic hypotension are the use of loop diuretics, moderate renal impairment (eGFR of 30 to less than 60 mL/min/1.73 m

), and age 75 years or older. This patient has all 3 risk factors and, therefore, an alternative agent is recommended at this time.

Choice A is not correct because in the CANTATA-MSU trial, canagliflozin decreased the A1c level by 0.71% and 0.92%, respectively, for the 100-mg and 300-mg doses when compared with placebo in patients uncontrolled on metformin and a sulfonylurea. Choice B is not correct because this drug can be used in moderate renal disease (eGFR between 45 and 60 mL/min/1.73 m

); however, the dose should be reduced to no higher than 100 mg/d. Choice C is incorrect because this drug has been studied and shown to be safe and effective in combination with metformin, metformin and sulfonylureas, and metformin and pioglitazone.

The sodium glucose cotransporter-2 inhibitors have many advantages eg, modest A1c reduction and low hypoglycemia risk. But careful patient selection is critical. 

Bradley Wright, PharmD

Articles

A 61-year-old Man with Diabetes and Resistant Hypertension

How Would You Initiate Insulin in this 53-Year-Old Man with T2DM?

Polydipsia, Polyuria, and Elevated A1C--What's Your Next Step for This Patient?

Polypharmacy Perils: What’s Wrong With This Rx Plan?

Why Not Prescribe a SGLT2 Inhibitor for This Patient?