Bradley M. Wright, PharmD, BCPS

RM, a 78-year-old woman, presents to the clinic to establish care. Her past medical history is significant for type 2 diabetes (T2DM), hypertension, and atrial fibrillation. Current medications are:



         500 mg/bid                      

      10 mg/day
Pioglitazone         45 mg/day                      Atorvastatin      10 mg/day  


             10 mg/day                     

     20 mg/day   
Metoprolol          100 mg/day
 

She states that she is happy with her current medications as all are “affordable” given her limited income and that it took her a long time to get her diabetes under control. Laboratory values include: HbA1c, 6.6%; basic metabolic panel, WNL (SCr, 1.2; eGFR, 45 mL/min). Vitals signs are: weight, 70kg; blood pressure, 126/72 mm Hg; pulse, 64. RM lives alone and tries to exercise 3 times per week and watches her diet. She notes that at least twice a week she obtains fasting blood glucose (FBG) readings <70 mg/dL but denies feeling poorly.

A. Yes, discontinue pioglitazone due to high likelihood of hypoglycemia

B. No, her A1c is well controlled and she is not experiencing symptomatic hypoglycemia 

C. Yes, discontinue glyburide and switch to an alternative sulfonylurea

D. No, her A1c is well controlled and she is not on therapy likely to cause hypoglycemia

E. Yes, increase glyburide to 20 mg daily to obtain a target A1c of <6.5%

Recommended answer: C. Yes, discontinue glyburide and switch to an alternative sulfonylurea



Sulfonylureas, which lower blood glucose by stimulating insulin release from Î²-cells, are the oldest class of oral agents used to treat T2DM.

 These agents are still in common use because they are effective (lower A1c by 1% to 1.5%) and because they are generally inexpensive.

 Because of the mechanism of action however, hypoglycemia is a major side effect associated with sulfonylurea therapy.

Elderly patients can be especially vulnerable to hypoglycemia and serious complications such as falls are more likely in this population.

of potentially inappropriate medications and classes to avoid in older adults specifically lists the second-generation sulfonylurea glyburide and advises the use of alternative, shorter-acting secretagogues or other agents.

  While the mechanism for the increased risk of hypoglycemia with glyburide compared to other second-generation sulfonylureas is not fully understood, it is likely a result of differences in duration of action, potency, and accumulation of active metabolites.

 Glipizide is generally recommended as the preferred alternative in older adults and in several clinical studies has been noted to have a lower incidence of hypoglycemia, especially in the elderly population.



In this patient, a switch to an equivalent dose of glipizide with further titration based on her home readings may result allow her to retain A1c control with less hypoglycemia.

 While she would also be a candidate for other oral medications or insulin analogues, these medications can be expensive and she has noted cost to be a concern. A significant advantage of the sulfonylureas is their low cost in addition to their efficacy. Given RM’s financial concerns, newer oral medications such as DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors may not be optimal.



 Pioglitazone is associated with a very low incidence of hypoglycemia, although use of this agent with sulfonylureas can increase the risk of hypoglycemia.

 Although RM’s A1c is well controlled, her home blood glucose readings indicate hypoglycemia. While she says that she is not symptomatic despite these readings, this could be a result of beta-blocker therapy for her atrial fibrillation. Beta-blockers may mask most signs of hypoglycemia and can make it very difficult for patients to identify symptoms other than sweating.

  For elderly patients, undetected symptoms of hypoglycemia can lead to serious consequences.



 RM’s A1c is well controlled; however, glyburide is a sulfonylurea agent capable of causing hypoglycemia, especially in the elderly.



. It is likely that the patient’s current dose of glyburide is contributing to her hypoglycemic blood glucose readings at home and so increasing the dose could expose her to further harm. Additionally, current American Diabetes Association goals include an A1c goal for most patients of <7%; at her current reading of 6.6%, she is at goal.







1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.
2. Bryan J, Crane A, Vila-Carriles WH, Babenko AP, Aguilar-Bryan L. Insulin secretagogues, sulfonylurea receptors and K(ATP) channels. Curr Pharm Des. 2005;11:2699–2716
3. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and Diabetes:  A Report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384-95.
4. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60:616–631. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571677/
5. Shorr RI, Ray WA, Daughery JR, Griffin MR. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc. 1996;44:751-755.
6. Van Staa T, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulfonylureas. J Clin Epidemiol. 1997;50:735-741.
7. Gangji AS, Cukierman T, Gerstein HC, et al. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30:389-394.
8. Rosenstock J, Carrao PJ, Goldberg RB, Kilo C. Diabetes control in the elderly: a randomized, comparative study of glyburide versus glipizide in non-insulin-dependent diabetes mellitus. Clin Ther. 1993;15:1031-1040.
9. Vickova V, Cornelius V, Kasliwai R, et al. Hyopglycaemia with pioglitazone: analysis of data from the Prescription-Event monitoring study. J Eval Clin Pract. 2010;16(6):1124-8.
10. Actos Package insert
11. Schwab KO, Menche U, Schmeisl G, Lohse MJ. Hypoglycemia dependent beta2-adrenoceptor downregulation: a contributing factor to hypoglycemia unawareness in patients with Type-1 diabetes? Horm Res. 2004;62:137-141.
12. Giorda CB, Ozzello A, Gentile S, et al. Incidence and correlates of hypoglycemia in type 2 diabetes. The Hypos-1 study. J Diabetes Metab. 2014;5: 344-52.

Poll

RM is an active 78-year-old woman with no complaints about her health or her medications. Then she tells you about her home blood glucose readings. 

An Older Woman at A1c Goal with Asymptomatic Hypoglycemia: What Next?

A 66-year-old African-American woman with an 11-year history of type 2 diabetes mellitus (T2DM) comes to the clinic for follow-up. Current medications include metformin, 1000 mg twice daily, insulin glargine 60 units at bedtime, lisinopril 10mg/d, chlorthalidone 25mg/d, aspirin 81mg/d, and atorvastatin, 80 mg/d. Recent laboratory findings include: A1c, 7.8% (American Diabetes Association [ADA] goal,  <7%); all other laboratory results are within normal range. The patient reports that she has been checking her blood glucose at home for the last month (average fasting reading, 125mg/dL and average post-prandial reading, 195 mg/dL). She realizes the post-meal reading is not ideal and wants to know what she can do to gain better control. She worries about the possibility of hypoglycemia if her insulin is intensified and of gaining more weight; she has gained 10 lbs (current BMI, 32) over the last couple of years).  

Therapy for patients with T2DM can be complex and new guidelines from the American Diabetes Association stress the importance of individualizing therapy, taking into consideration specific patient factors and needs. While therapy is most often initiated with one or more oral agents, the typical decline in beta-cell function that characterizes T2DM results in most patients eventually requiring insulin replacement therapy. Once oral agents and/or non-insulin therapies fail, once-daily basal insulin is typically added, (ie, insulin analogues glargine or detemir). If A1c and/or post-prandial targets are not met in a reasonable period of time, insulin therapy is intensified with a more complex basal-bolus regimen, which usually represents the last line in therapy. 

Basal-bolus regimens, often including a long-acting insulin analogue, taken once or twice daily, in combination with a rapid-acting insulin analogue at meals can be effective at controlling A1c and both fasting and post-prandial blood glucose target levels. Managing the multiple daily injections (MDI) of 2 different insulin formulations is complex and can be overwhelming for some patients and frustrating for both patient and physician. It is also associated with barriers that can prevent its full effectiveness in clinical practice. Reaching glycemic goals typically requires frequent dose titration based on home blood glucose readings. This is a difficult task for both patients and providers. Even when dose titration is frequent, nonadherence can limit continued glycemic control. Concerns about the increased risk of hypoglycemia as well as weight gain with the additional bolus insulin may also prevent achievement of glycemic control. 


Given these limitations it would seem that an ideal regimen for patients uncontrolled on basal insulin would combine drugs that target both basal and PPG levels, without increasing the risk of hypoglycemia and/or weight gain. Simplified dosing and titration may also increase adherence and streamline the process of reaching glycemic targets. This ideal situation is difficult to achieve with any combination of basal and bolus insulins. With many new drug classes available, clinical focus has been shifting toward combining insulin with non-insulin therapies that target PPG excursions.  

One option that has promise is the combination of basal insulin with glucagon-like peptide–1 (GLP-1) agonists. These relatlively novel injectable agents are often used as second- or third-line therapy once one or more oral agents fail; however, newer guidelines also list this option as an alternative to bolus insulin for patients not at goal on basal insulin.

 The combination offers many physiological advantages, including a synergistic effect where limitations of each individual agent used alone may be overcome by the other agent.

Once basal insulin alone, typically targeting fasting blood glucose, fails and PPG levels are uncontrolled, focus shifts to targeting PPG, traditionally by adding bolus insulin at mealtime. GLP-1 agonists primarily target PPG levels as they stimulate glucose-dependent insulin release. Additionally, these agents inhibit gastric emptying and suppress glucagon, further limiting PPG excursions. Thus, GLP-1 agonists are less likely than bolus insulin to cause hypoglycemia, which may ease anxiety for both patients and providers and potentially increase adherence to therapy.

Also unlike insulin, GLP-1 agonists are associated with weight loss, a major benefit for patients with T2DM. Through multiple mechanisms, GLP-1 agonists also may allow a reduction in total insulin dosage, an effect which could further limit hypoglycemia, weight gain, and costs associated with insulin therapy.  Finally, GLP-1 agonists are typically dosed less frequently than bolus insulins and taken independent of mealtime.


These theoretical benefits of combining the two classes have been verified by several clinical trials, including most recently a systematic review and meta-analysis published by Eng and collegues.

A total of fifteen studies, published between 2011 and 2014 comparing GLP-1 agonist and basal insulin to another treatment strategy (placebo or bolus insulin) and with a treatment duration of at least 8 weeks (mean duration 24 weeks) were included in this analysis.

Participants had a mean baseline A1c of 8.13%, a mean body mass index (BMI) of 32.9 kg/m

, and a mean duration of diabetes of 12 years.  Three of these trials compared basal insulin plus a GLP-1 agonist with intensive basal-bolus insulin regimens, which is the primary comparison when considering intensification of therapy in patients uncontrolled on basal insulin alone.

In a pooled analysis, the combination of a GLP-1 agonist and basal insulin led to a mean greater reduction in A1c than any other treatment as well as a greater proportion of patients achieving an A1c of 7% at the end of the study. When compared specifically to basal-bolus insulin, the combination of basal insulin and GLP-1 agonists led to a greater reduction in A1c, although the proportion of patients achieving A1c goals was similar.

The combination of GLP-1 and basal insulin showed no significant differences with regards to the risk of hypoglycemia when compared to other treatments; however, when specifically compared to basal-bolus insulin the GLP-1/insulin combination showed a significantly lower risk of hypoglycemia. The GLP-1/basal insulin combination led to a mean reduction in weight that was greater than other treatments, including basal-bolus insulin.

The data from this analysis show that the combination of GLP-1 agonists and basal insulin can be a safe and effective alternative treatment for patients with T2DM. The combination offers several advantages over intensified, basal-bolus insulin therapy, including less frequent dosing, lower risk of hypoglycemia, and weight loss. 

More long-term data are needed in order to fully determine the long-term safety and place in therapy of this combination. More information is also needed in order to determine the best GLP-1 agonist to use and whether there are differences in safety and efficacy among the various GLP-1 agents (ie, short- vs  long-acting agents). The initial data, however, is promising and this combination can be considered as alternative when patients fail basal insulin alone. This combination may prove most effective for patients with pronounced fear of hypoglycemia and/or weight gain associated with intensified insulin therapy. The simplified regimen may prove useful in patients who have difficulty adhering to a MDI insulin regimen and frequent dose titrations. Further benefit may be seen if combination preparations of basal insulin and GLP-1 agonists become commercially available. 

In the case above, the addition of a GLP-1 agonist could be considered since the patient’s fasting blood glucose has been maintained well but PPG levels continue to be high. Additionally, she is concerned about hypoglycemia and the weight gain associated with her therapy and these concerns may prevent adherence to and achievement of glycemic control with an intensified insulin regimen. 

Inzucchi SE, Bergenstal RM, Buse JB, et al.  Management of hyperglycemia in type 2 diabetes: a patient-centered approach. 

Garger AJ, Abrahamson MJ, Barzilay JI, et al.  AACE comprehensive diabetes management algorithm. 

Nauck MA.  Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. 

Eng C, Kramer CK, Zinman, B, Retnakaran R.  Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. 

Articles

If you could intensify therapy for your type 2 diabetes patients without risking hypoglycemia and/or additional weight gain, the regimen might look like this. 

Insulin Plus GLP-1 Agonists: An Alternative Approach

A 44-year-old Caucasian male with a 1-year history of type 2 diabetes mellitus (DM) comes to the clinic for follow-up. Recent laboratory findings include an A1c level of 6.9% (American Diabetes Association [ADA] goal, lower than 7%); all other laboratory results are within normal range. Current medications include metformin, 1000 mg twice daily, and atorvastatin, 80 mg/d. Vitals today include a blood pressure of 146/84 mm Hg (average of 2 readings). Blood pressure at the most recent visit was 158/94 mm Hg (average of 2 readings). The patient states that he has been checking his blood pressure at home for the last month (average reading, 154/96 mm Hg) and wants to know his blood pressure goal.

Hypertension is a common comorbidity of DM, and both DM and hypertension are considered major risk factors for the development of cardiovascular (CV) and microvascular complications. Patients with both DM and hypertension are at about twice the risk for CV disease and are at increased risk for DM complications, such as nephropathy.

Lowering blood pressure in patients with DM clearly has a benefit in reducing renal complications, CV events, and death.

 Because hypertension occurs in the majority of patients with DM, lowering patients’ blood pressure is vital to their care and should remain a priority in the overall prevention and treatment of CV and microvascular complications.

Understanding the goals for the management of hypertension in patients with DM is an important first step. Although this may sound simple, the release of multiple guidelines in recent years has somewhat complicated the picture. The Eighth Joint National Committee (JNC 8) and the American Society of Hypertension (ASH) guidelines, both released late in 2013, agree on a goal blood pressure. However, a difference is noted with the European Society of Hypertension/European Society of Cardiology (ESH/ESC) guideline from 2013 and with the 2014 American Diabetes Association’s Standards of Care.

 These blood pressure goals are summarized as follows:

Previous guidelines, such as JNC 7, identified a lower blood pressure goal of 130/80 mm Hg in patients with DM, supporting the “lower is better” notion in these patients with diagnoses of both DM and hypertension.

 In 2009, the ESH guidelines suggested that this goal was unsupported by prospective clinical trial data and adjusted the systolic goal to lower than 140 mm Hg.

 More recent guidelines have followed with further analysis of the data and further adjustments in blood pressure goals.

Current guidelines agree on the systolic blood pressure goal and recommend that the systolic blood pressure be managed to a goal of lower than 140 mm Hg.

 As noted above, previous systolic blood pressure goals were lower than 130 mm Hg; however, it has been determined that evidence for these lower goals is limited.

The most notable trial used in considering systolic blood pressure goals is the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

 This study examined the cardioprotective benefits of intensive blood pressure lowering (lower than 120 mm Hg SBP) as compared with standard therapy (SBP goal, 130 to 139 mm Hg) in high-risk patients with type 2 DM.

Although a small yet statistically significant benefit was seen with the secondary end point of stroke reduction in the intensive group, no difference was seen for the primary end point of nonfatal myocardial infarction, nonfatal stroke, and CVD death. Serious adverse events were significantly higher in the intensive group, and no changes were seen with regard to renal function or other microvascular complications, although albuminuria was reduced significantly.

Because there was a lack of evidence of benefit of a lower systolic blood pressure goal, the guidelines consistently recommend a systolic blood pressure goal of lower than 140 mm Hg, although it is unclear whether a somewhat lower goal (lower than 135 mm Hg) may be more beneficial, especially in younger patients or those with renal disease, or whether intensive therapy should be a target for those at high risk for stroke.

The goal for diastolic blood pressure is less clear according to those guidelines referenced above; both ESH/ESC and the ADA recommend a lower diastolic blood pressure goal than JNC 8 and ASH.

The most frequently cited studies used in considering diastolic blood pressure goals in patients with DM are the Hypertension Optimal Treatment (HOT) and UK Prospective Diabetes Study (UKPDS) trials. The HOT trial targeted diastolic blood pressure goals of lower than 90 mm Hg, lower than 85 mm Hg, and lower than 80 mm Hg. Investigators found a benefit with more intensive therapy, specifically a diastolic blood pressure of lower than 85 mm Hg. The treatment effects were small and the event rates were low, probably because of the profound decrease in blood pressure in all patients from baseline and the very effective blood pressure control achieved with only 8.5% of patients having a diastolic blood pressure of higher than 90 mm Hg. JNC 8 specifically graded the evidence from this trial as low quality because the information in patients with DM came from a post hoc analysis of a small subgroup.

The UKPDS study compared tight blood pressure control (lower than 150/85 mm Hg) to less tight blood pressure control (lower than 180/105 mm Hg) in patients with DM. The tight blood pressure control group achieved a mean blood pressure of 144/82 mm Hg, decreased from 159/94 mm Hg at baseline. The rates of stroke, heart failure, DM-related end points, and deaths related to DM were significantly lower in this group; however, because the diastolic blood pressure of lower than 85 mm Hg was compared with the goal of lower than 105 mm Hg and because the study targeted both systolic and diastolic blood pressure goals, JNC 8 did not conclude this to support the lower diastolic blood pressure goal.

Regardless of the diastolic blood pressure goal chosen, evidence clearly shows that lowering blood pressure in patients with DM can decrease both CV and microvascular outcomes. Therefore, clinicians should place a priority on identifying patients with elevated blood pressure and treating these patients. They often require 2 or more antihypertensives to control their blood pressure, and clinicians should initiate treatment and frequently titrate medications.

The multidisciplinary team can assist with closely monitoring and adjusting therapy to achieve a goal of at least lower than 140/90 mm Hg while also educating patients and making sure they understand the need for and benefits obtained from adherence to life-long treatment. Once treatment has been initiated, the team can focus on identification of selected patients who may be more likely to benefit from a more intensive blood pressure goal, such as those with a long life expectancy, chronic kidney disease, and albuminuria as well as those at high-risk for stroke.

In the case above, a 1- or 2-drug regimen should be initiated and the patient should be monitored closely to titrate medications to the blood pressure goal. Because of this patient’s young age, he may be less susceptible to adverse effects associated with more intensive therapy and may benefit from a tighter blood pressure goal. However, the priority should be placed on initiating therapy, educating the patient, and treating to a blood pressure goal of at least lower than 140/90 mm Hg.

1. Lopez-Jaramillo P, Lopez-Lopez J, Lopez-Lopez C, Rodriguez-Alvarez MI. The goal of blood pressure in the hypertensive patient with diabetes is defined: now the challenge is go from recommendations to practice. 

2. James PA, Oparil S, Cater BL, et al. 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 (JNC 8). [Erratum in 

3. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: A statement by the American Society of Hypertension and the International Society of Hypertension. 

4. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society ofHypertension (ESH) and of the European Society of Cardiology (ESC). 

5. American Diabetes Association. Standards of medical care in diabetes-2014. 

6. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. 

7. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. 

8. Cushman WC, Evans GW, Byington RP, et al; the ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. 

9. Hansson L, Zanchetti A, Carruthers SG, et al; the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. 

10. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. [Erratum in 

Lowering blood pressure is vital to care and should remain a priority in preventing and managing cardiovascular and microvascular complications.

Hypertension and Diabetes: Understanding the Goals

A 76-year-old female with a history of type 2 diabetes mellitus (DM), hypertension, peripheral neuropathy, macular degeneration, osteoarthritis, and heart failure with reduced ejection fraction presents to the clinic for follow-up of her DM and insulin adjustments. Recent laboratory findings include an A1c level of 7.6% (American Diabetes Association goal, lower than 7.5% in older patients); all others are within normal range. Current medications include insulin glargine, 40 units QHS; lisinopril, 20 mg/d; carvedilol, 25 mg twice daily; spironolactone, 25 mg/d; furosemide, 40 mg/d; aspirin, 81 mg/d; gabapentin, 600 mg 3 times daily; and atorvastatin, 20 mg/d. The patient’s home blood glucose log reveals several episodes of either hypoglycemia (home blood glucose level lower than 70 mg/dL) or hyperglycemia (home blood glucose level higher than 250 mg/dL). Her daughter states that the patient has had increasing difficulty self-administering insulin and occasionally has skipped doses.

DM affects almost 30 million persons older than age 20 years, or about 12% of the population.

 In addition to a large percentage of the overall population, DM affects a large number of older patients: Among adults aged 65 years or older, more than 11 million (almost 26% of the older population) have DM.

 The number almost certainly will rise as the percentage of the population older than 65 years continues to rise.

Treatment of patients with DM can be difficult, often requiring a multidrug regimen that may contain insulin to attain and maintain glycemic control. Clinicians’ treatment decisions may be influenced by various comorbidities, such as 

The American Diabetes Association (ADA) recommends insulin as a second or third add-on agent to metformin in uncontrolled patients or as initial therapy in patients with significant hyperglycemia.

 In a national survey, 14% of adults with DM used insulin alone and almost 15% used insulin in combination with an oral medication

; the rate may be even higher in the older population. Insulin use can present unique problems for safe and effective treatment of these patients because it requires that they have good visual and motor skills and cognitive function.

Although many patients of all ages are treated with insulin therapy, specific concerns arise in the older population regarding the safety and efficacy of this high-alert medication. Insulin therapy can be complicated by multiple comorbidities-such as dementia, neuropathies, poor mobility and dexterity, and vision loss-because these factors can affect the patient’s ability to self-administer the insulin. In addition, safety becomes especially concerning because hypoglycemia can be particularly troublesome in the older population.

The above factors also can affect identification and management of hypoglycemia. Many older patients may make significant errors in drawing up and administering the correct dose of insulin, further contributing to safety and efficacy concerns. As a result, insulin dosing and regimens should be simplified in the older population to maintain efficacy while ensuring safety.

Insulin therapy in older patients with type 2 DM often can be initiated with basal insulin alone or in combination with oral therapies. Options include intermediate-acting neutral protamine Hagedorn and long-acting glargine or detemir. Although the latter 2 analogues (glargine and detemir) are more expensive, they are associated with lower rates of hypoglycemia, making them better options in older patients.

As noted above, insulin administration in the older population is associated with a greater possibility of dosing errors.

 Not only is insulin administration complex, but visual and physical disabilities in older patients (eg, visual impairment, joint immobility, and peripheral neuropathy) contribute to inaccurate dosing. Studies have demonstrated that patients who use the traditional vial and syringe method of insulin delivery experience a relative error rate of about 19% with regard to accuracy of dosing

; this rate can be even higher in the older population.

Insulin pen devices, such as the SoloStar (glargine) and the FlexPen (detemir), can help improve the safety and efficacy of insulin administration, and they offer unique advantages for the older population. Large digits and single-unit dosing increments inside the dose window and the use of audible clicking are advantageous for patients who have visual impairment. The larger device size, easy-to-push dose release button, and large dose selector can assist patients who have joint immobility, neuropathy, and other dexterity problems.

These features can make the pen devices easier to use and preferable, especially among older patients. Studies have shown that use of the insulin pens can significantly improve rates of hypoglycemia and improve dosing accuracy.

 Although it may take longer to teach older patients to use these devices, patients prefer pen devices and identify them as easier to use than the vial/syringe method.

 Older patients are more likely to self-administer their insulin doses, reducing the burden on caregivers and potentially decreasing costs associated with daily nursing assistance.

 Insulin pens also have been noted to improve adherence rates with injections and to make significant improvements in glycemic control.

In the case above, the older patient’s insulin therapy may be complicated by polypharmacy and multiple comorbidities, such as neuropathy and arthritis limiting dexterity and age-related macular degeneration leading to visual impairments. These factors may lead to problems drawing up the correct dose using the vial/syringe method as well as difficulty with self-administration. Those problems may lead to an increased risk of hypoglycemia, decreased adherence and resulting hyperglycemia, or both, as this patient is experiencing. Switching to an insulin pen device may help the patient draw up the correct dose by making the dose easier to see and improve administration with easier use.

In addition to the choice of insulin and the use of pen devices, proper patient education is imperative in the older population to ensure that all insulin is administered appropriately and adverse effects are avoided or managed. An interprofessional effort that involves physicians, DM educators, dieticians, nurses, and pharmacists can help provide patients with information regarding all aspects of insulin use, including dosing, injection technique, storage, glucose monitoring, diet, and hypoglycemia recognition and management.

Insulin therapy in older patients can be difficult to manage. The risks of this high-alert medication include hypoglycemia, and therapy often is complicated by multiple comorbidities, polypharmacy, vision impairment, poor mobility and dexterity, neuropathies, and cognitive impairment.

Clinicians must ensure that the most appropriate insulin is chosen and that the method of delivery is safe and efficacious, improving patient ease of use, adherence, and acceptability while decreasing the risk of hypoglycemia. Insulin pens offer greater simplicity, flexibility, and convenience than traditional vial and syringe administration, and features such as audible clicks and large dosing windows help patients who have visual impairments; the greater size and overall ease of use can help patients who have impairments of dexterity. In addition, the interprofessional team should counsel patients on hypoglycemia recognition and management as well how to properly store, dose, and administer insulin.

1. National Diabetes Statistics Report, 2014. CDC. 

http://templatelab.com/national-diabetes-report-2014/

2. Standards of medical care in diabetes-2014. 

3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). [Erratum in: 

4. Wright BM, Bellone JM, McCoy EK. A review of insulin pen devices and use in the elderly diabetic population. 

Clinical Medicine insights: Endocrinology and Diabetes.

5. Coscelli C, Lostia S, Lunetta M, et al. Safety, efficacy, acceptability of a pre-filled insulin pen in diabetes patients over 60 years old. 

6. Kesson CM, Bailie GR. Do patients with diabetes inject inaccurate doses of insulin? 

7. Albano S; for the ORBITER Study Group. Assessment of quality of treatment in insulin-treated patients with diabetes using a pre-filled insulin pen. 

8. Lee WC, Balu S, Cobden D, et al. Medication adherence and the associated health economic impact among patients with type 2 diabetes mellitus converting to insulin therapy: an analysis of third-party managed care claims data. 

9. Miao R, Wei W, Lin J, et al. Does device make any difference? A real-world retrospective study of insulin treatment among elderly patients with type 2 diabetes. 

10. Korytkowski M, Bell D, Jacobsen C, Suwannasari R; for the FlexPen Study Team. A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or type 2 diabetes mellitus. 

11. Shelmet J, Schwartz S, Cappleman J, et al; for the Innolet Study Group. Preference and resource utilization in elderly patients: Innolet versus vial/syringe. 

Treatment of patients with diabetes can be difficult, and specific concerns arise in the older population regarding the safety and efficacy of this high-alert medication.

Special Problems Sour Insulin Use in Elderly

A 68-year-old female with a history of type 2 diabetes mellitus (DM), hypertension, and chronic kidney disease presents to the clinic complaining of increasing hypoglycemic events. Recent laboratory findings include an A1c level of 6.8% (American Diabetes Association goal, lower than 7%) and worsening renal function, with a serum creatinine (SCr) level of 2.1 mg/dL (previously, 1.6 mg/dL; normal range: 0.6 to 1.1 mg/dL) and an estimated glomerular filtration rate (eGFR) of 28 mL/min (previously, 40 mL/min). Current medications include glyburide, 5 mg/d; lisinopril, 20 mg/d; amlodipine, 10 mg/d; aspirin, 81 mg/d; and atorvastatin, 20 mg/d.

The prevalence of type 2 DM is increasing worldwide, making it imperative that safe and efficacious medications are available to manage this disorder. However, DM management often is complicated by the presence of comorbid conditions and increasing age.

Moderate to severe renal impairment (defined as eGFR lower than 60mL/min) occurs in about 20% to 30% of patients with DM, and it presents specific difficulties for the clinician and the patient.

 Changes in renal function affect most DM medications; therefore, the clinician must be aware of the doses and contraindications associated with reduced clearance as well as adverse effects associated with their use, especially in renal impairment.

Patients with DM and renal impairment are at increased risk for hypoglycemia and even death.

 This increased risk is in large part caused by the reduced clearance of insulin as well as most medications that are available to manage DM. As seen in the case above, this risk is a serious concern in patients with chronic kidney disease, one that can complicate treatment.

Metformin, most often the first-line agent in the treatment of patients with DM, has particular concerns in renal impairment. The drug is renally eliminated, and although lactic acidosis is rare, the risk is increased in patients with decreased renal function. Current prescribing guidelines list an SCr level of 1.5 mg/dL or higher in men or 1.4 mg/dL or higher in women as a contraindication to its use,

 although this is controversial. Other data suggest that the use of metformin may be continued until the eGFR falls below 30 mL/min, with a dose reduction occurring when the eGFR falls below 45 mL/min.

Sulfonylureas, a common second-line option, are associated with a higher risk of hypoglycemia than metformin and other oral therapies. These agents also exhibit decreased elimination in the setting of renal impairment and therefore place the patient at greater risk for hypoglycemia with decreased clearance of the drug. This risk is of particular concern with glyburide, as seen in the case above, because of a prolonged duration of action and active metabolites; therefore, the use of this drug should be avoided, especially in older patients and those with renal impairment. Other sulfonylureas (glimepiride and glipizide) require dosage adjustment for patients with severe renal impairment and should be used with caution in patients with kidney disease because they can increase the risk of hypoglycemia.

Because the thiazolidinedione pioglitazone is not eliminated renally, there are no dosing restrictions in this population. However, fluid retention and edema are common adverse effects of this medication.

 They may be of concern and limit its use, especially in patients with kidney disease.

The incretin agents are one of the newest classes of medications for the management of DM. They include the dipeptidyl peptidase-4 (DPP-4) inhibitors as well as the glucagon-like peptide-1 (GLP-1) agonists exenatide and liraglutide.

GLP-1 increases the glucose-dependent stimulation of insulin and suppression of glucagon secretion, and it has other beneficial effects, such as delaying gastric emptying and increasing satiety. The GLP-1 agonist exenatide is contraindicated in severe renal impairment (creatinine clearance [CrCl] less than 30 mL/min), and because this drug can cause nausea and vomiting, caution is advised in patients with moderate renal impairment-worsening renal function has been noted with hypovolemia.

 Although no dosage adjustment is needed with liraglutide, there are limited data regarding its use in severe renal impairment. In addition, warnings similar to those with exenatide regarding the potential for worsening renal function require the drug be used with caution, especially in patients with kidney disease.

DPP-4 inhibitors meanwhile have garnered increased interest, especially for use in older patients and in patients with kidney disease. The agents in this class, which include sitagliptin, saxagliptin, alogliptin, and linagliptin, inhibit the breakdown of endogenous GLP-1 and can be used for initial monotherapy for patients with DM; they have been studied in combination with metformin, sulfonylureas, and pioglitazone. Although they lower the A1c level only modestly, they generally are well tolerated by most patients who have little or no hypoglycemia.

 This minimal risk of hypoglycemia is especially intriguing in the setting of kidney disease because decreased clearance of the drug, resulting in higher drug levels, should not result in an increased risk of hypoglycemia.

Although the risks with DPP-4 inhibitors are minimal, 3 of the available drugs do need dose reduction in moderate-severe renal insufficiency. Sitagliptin is available in 100-mg tablets taken once daily with a dose reduction to 50 mg/d, with a CrCl of 30 to 49 mL/min, and a dose of 25 mg/d, with a CrCl lower than 30 mL/min.

 Saxagliptin, typically dosed at 5 mg/d, also requires a dosage reduction to 2.5 mg/d in patients with a CrCl lower than 50mL/min.

 Alogliptin, the newest agent, requires adjustment when the CrCl falls below 60mL/min and then again when less than 30 mL/min.

 Linagliptin, also dosed at 5 mg/d, requires no dosage adjustment with renal impairment and has been shown to be safe and effective even in severe renal impairment (eGFR less than 30 mL/min).

 The patient in the case above may benefit from a switch to a DPP-4 inhibitor, such as linagliptin, to maintain glycemic control while reducing the risk of hypoglycemia.

Chronic kidney disease is common in patients with type 2 DM and can complicate the treatment of these patients, especially when available noninsulin therapies are considered. Clinicians should be aware of the concerns and consequences associated with current type 2 DM therapies when they are used in patients with renal impairment and, when appropriate, consider discontinuation or dose reduction. The DPP-4 inhibitors may be a safe and effective alternative in these patients, especially linagliptin, which requires no dosage adjustment in patients with kidney disease.

1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). [Erratum in: 

2. Moen MF, Zhan M, Hsu VD, et al. Frequency of hypoglycemia and its significance in chronic kidney disease. 

4. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. 

11. McGill JB, Sloan L, Newman J, et al. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. 