Case Studies of Patients with Type 2 Diabetes Mellitus: Exercises in Problem Solving

ABSTRACT: Primary care clinicians are often at the front line in the management of type 2 diabetes mellitus (T2DM), and they regularly face the challenge of making the best choices in an increasingly complex field. This article presents a series of hypothetical case studies that represent some of the more common therapeutic dilemmas that primary care clinicians face in their daily management of patients with T2DM.

Diabetes mellitus currently affects 6.4% or 285 million adults worldwide, and that number is expected to increase to 7.7% or 439 million by 2030.¹ In the United States, the prevalence of diabetes in adults increased from 11.3% in 2010 to 12.3% in 2012.² The current type 2 diabetes mellitus (T2DM) epidemic is closely associated with a parallel obesity epidemic, with more than 85% of patients with diabetes being overweight or obese.³ Furthermore, many glucose-lowering treatments only complicate weight management by causing patients to gain even more weight.⁴ The increase in the prevalence of diabetes, along with its comorbidities and complications, places a substantial burden on society and primary care providers. In the United States, diabetes now represents 1 in 10 visits to primary care physicians⁵ and was reported as the seventh leading cause of death during 2010, with some suggesting that the true figure may be even higher.²  

The American Diabetes Association (ADA) provides recommendations on targets for glycemic control in T2DM. A glycated hemoglobin (HbA1c) treatment goal of <7.0% is suggested for most patients, with less (<8.0%) or more (<6.5%) stringent goals applied in special situations such as when patients have particularly short or long projected lifespans, respectively.^6,7 Despite evidence linking good disease control with improved outcomes, glycemic control in patients with T2DM remains suboptimal.^8-13 One important reason for this is the adverse events associated with glucose-lowering therapies, particularly weight gain and hypoglycemia,¹⁴ which may have an impact on medication adherence.^9,11 Other patient-related reasons for suboptimal glycemic control include limited disease knowledge,^9,10,14 high emotional burden of T2DM,⁹ lack of acceptance of the disease,⁹ reluctance to intensify medications,^10,14 and confusion related to complex treatment regimens.^8,10 Clinician behaviors can also present barriers to good glycemic control—including failure to intensify treatment in a timely fashion (commonly termed clinical inertia),¹¹ insufficient time with patients to fully explore and/or explain treatment advancement options,⁹ and emphasis on comorbidities (eg, hypertension, dyslipidemia, and obesity). 

Recognizing that diabetes management is often suboptimal, and understanding the diversity of potential reasons behind this, the ADA and the European Association for the Study of Diabetes issued a joint position statement in 2012, which was updated in 2015.^4,6 Central to this communication was the principle that therapy should be individualized, taking into account each patient’s characteristics and preferences as much as possible. In particular, age, weight, risk of hypoglycemia, costs, problematic medication side effects, comorbid conditions, and existing medications should all be considered. 

If lifestyle intervention is insufficient to maintain adequate glycemic control, monotherapy with metformin is generally the recommended initial pharmacotherapy (in the absence of contraindications or tolerability issues). However, since diabetes is generally a progressive disorder, combination therapy is likely to be required at some point for the vast majority of patients. There are now many glucose-lowering treatment options available, targeting a wide range of pathologies underlying T2DM. When choosing combination therapy, the use of agents with complementary mechanisms of action (Table and Figure) maximizes the potential for good glycemic control.^6,15,16 

Primary care clinicians are often at the front line of T2DM management and face the day-to-day challenge of making the best choices for patients. This article presents a series of representative hypothetical case studies describing some of the more common challenges faced in the management of  T2DM.

Case 1: Failure of Metformin Monotherapy

A 68-year-old male patient with T2DM has received optimal metformin monotherapy for the last 2 years (current dose of 2000 mg/day) and tolerates the treatment well. Hypoglycemia has not been an issue to date. His body mass index (BMI) is 28 kg/m², which he has worked hard to reduce from 35 kg/m² over the last 2 years. He has mild hypertension, which is well- controlled on a thiazide plus an angiotensin-converting enzyme inhibitor. His blood lipids are well-controlled on atorvastatin 10 mg daily. 

He now presents at the clinic with an HbA1c of 7.6%. During consultation, the patient mentions that he has seen advertisements for canagliflozin (Invokana) and questioned its efficacy. 

After reviewing the available therapeutic choices and using a shared decision-making model, a dipeptidyl peptidase-4 (DPP-4) inhibitor is selected as add-on therapy based upon simplicity of use, tolerability, and the patient’s wish to avoid anything that might cause weight gain. Because he is an uncircumcised male, he decided against canagliflozin once informed of the potential side effect of balanitis.

Discussion

A common challenge faced in primary care is how to manage patients whose glycemic control has declined on monotherapy, but not to a gross extent. Before stepping up pharmacotherapy with add-on medication, it is imperative to ensure that current treatments are being used in an optimal way. The clinician should assess whether improvements could be achieved through increased adherence or as a result of more intensive lifestyle changes (eg, diet and exercise). 

In this case, the patient has already done very well in terms of weight reduction and maintenance. At this point, add-on therapy may be needed to improve glycemic control. Where the patient was only modestly above his ADA-recommended HbA1c goal of 7.0%, aggressive therapy—which may be associated with adverse effects—was not warranted. Although not obese, this patient was concerned about body weight; therefore, treatments associated with weight gain—eg, sulfonylureas (SUs) and insulin—may not be suitable.¹⁷ 

Patients in the United States may be exposed to direct-to-consumer advertising of pharmaceuticals, and it is common for patients to express opinions about named drugs. In these situations, it is important to listen carefully to the patient’s thoughts. Allowing the patient a role in the decision-making process may help obviate some of the patient-related barriers to optimal glycemic control, and it improves the chances of good adherence and disease understanding.⁴ In situations where the treatment requested by the patient is not ideal, time spent on patient education is critical. The reasons why the suggested therapy is not preferred should be outlined and the patient should be involved as much as possible in the choice of an alternative therapy. 

In this case, the patient and doctor opted for a DPP-4 inhibitor as add-on treatment. Other reasonable options might include a 3-month trial of lifestyle modification, a glucagon-like peptide-1 receptor agonist (GLP-1RA), a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or an alpha-glucosidase inhibitor. Because the patient was disinclined to use an injectable agent, GLP-1RAs were not the best choice. Although SGLT-2 inhibitors would be a consideration and the patient specifically mentioned that class, because he is uncircumcised, he may be at increased risk to incur one of the genital mycotic infections seen with this class of agents. Such infections are less common in men than in women, but the risk in men may be increased in uncircumcised individuals. Tolerability of alpha-glucosidase inhibitors is substantially less than DPP-4 inhibitors, hence the shared decision to use this class of agents.

Case 2: Failure of Metformin and a DPP-4 Inhibitor

A 65-year-old female patient with a 10-year history of T2DM presents with an HbA1c of 9.0% despite receiving metformin (2000 mg/d) plus a DPP-4 inhibitor for the last 12 months. Her BMI is 29 kg/m². Renal function is near normal (estimated glomerular filtration rate [eGFR] of 64 mL/min/1.73 m²). She has mild dyslipidemia controlled with a statin and hypertension controlled with an angiotensin II receptor blocker (blood pressure ≤140/90 mm Hg).

Because of concerns of hypoglycemia, the patient elects to avoid insulin. 

Appropriate therapies in this case could include an add-on GLP-1RA or SGLT-2 inhibitor. The patient chooses to add an SGLT-2 inhibitor. 

Discussion

This case features a patient with a marked loss of glycemic control, suggesting a need for treatment intensification. When deciding on triple therapy, agents with complementary mechanisms of action should be considered.⁴ Most oral agents lower HbA1c, on average, by approximately 1.0%, which means that achieving a goal of <7.0% may be difficult without significant lifestyle modification in this case. Triple therapy is an intensive approach, with an increased potential for adverse events and drug interactions. Furthermore, decreased patient adherence to therapy is an issue associated with multidrug regimens.⁴ For these reasons, the patient in this case should be closely monitored. 

In the case presented, the patient opted for an add-on SGLT-2 inhibitor. Combining a DPP-4 inhibitor with a GLP-1RA might seem counterintuitive, since both agents work through modulation of GLP-1, but a single trial has indicated that the combination does provide a further 0.68% reduction of HbA1c,¹⁸ which may be useful in some cases. In the presented case, this degree of glucose lowering would be insufficient to attain HbA1c goals.

Case 3: Recurrent Hypoglycemic Episodes

A 62-year-old patient with T2DM had been uncontrolled with metformin plus SU (HbA1c of 8.6%). Add-on basal neutral Protamine hagedorn (NPH) insulin/regular insulin 70/30 (a schedule of two-thirds in the morning/one-third in the afternoon) was initiated and titrated to goal. This choice was driven by the need for a low cost, high-efficacy agent, but this resulted in a few mild hypoglycemia episodes (fasting blood glucose or overnight glucose of >56 mg/dL to <70 mg/dL not requiring assistance). As insulin titration progressed, hypoglycemic episodes were more frequent but not severe.

In an effort to reduce hypoglycemia and simplify the regimen, the SU was discontinued. After re-titration of insulin and implementation of very careful meal management, glycemic control was achieved without hypoglycemic episodes.

Discussion

In such case, an important goal is to eliminate the hypoglycemic episodes. The severity of hypoglycemia should be assessed, as well as the conditions under which the episodes occurred. Hypoglycemia is often seen when patients take their medications as prescribed without eating. An irregular eating pattern and volume could be implicated in this scenario. In the presented case, the patient was receiving 2 agents that have a propensity to cause hypoglycemia (SU and insulin). The SU was withdrawn and the insulin re-titrated. As control becomes tighter during re-titration, the potential for hypoglycemia between meals and at night could increase. For between-meal hypoglycemia, small snacks can help but have an additional caloric burden. Nighttime hypoglycemia can be managed by decreasing the evening dose and moving away from the fixed two-thirds in the morning/one-third in the afternoon dosing. 

Cost considerations drove this patient to use NPH basal insulin. While basal insulins (NPH, detemir, glargine, and degludec) all offer similar levels of fasting blood glucose control, “second-generation” (more expensive) basal insulins (detemir, glargine, and degludec) offer a flatter insulin profile, with less nocturnal hypoglycemia. 

An alternative approach in this case could be to start the patient on a basal insulin alone until fasting blood glucose goals are attained, followed by the addition of a rapid-acting insulin at appropriate meals.

Case 4: Deteriorating Kidney Function

A 70-year-old obese female presents with stage 3 chronic kidney disease (CKD) and treatment-naïve T2DM (HbA1c of 7.6%). Her current eGFR is 45 mL/min/1.73 m² (ie, “moderate” renal impairment). She is normotensive.

Insulin and GLP-1RAs are considered; she elects to try a GLP-1RA.

Discussion

CKD is a common condition in patients with T2DM that complicates the management of these patients. Drug clearance is often impaired, leading to prolonged exposure to increased drug levels.¹⁹ As such, kidney function should be assessed before starting glucose-lowering therapy, and the patient should be carefully monitored for hypoglycemia (which may indicate increased drug levels) during treatment.²⁰ Many available glucose-lowering drugs are contraindicated, or should be used with caution, in patients with T2DM and CKD.^19,20 For example, the standard first-line glucose-lowering therapy (metformin) is contraindicated in patients with an eGFR <60 mL/min/1.73 m². GLP-1RAs can be used with caution in patients with CKD as long as the eGFR is >30 mL/min/1.73 m², and DPP-4 inhibitors can be used at reduced doses.²⁰ SGLT-2 inhibitors act by inhibiting reabsorption of glucose from the renal tubules into the bloodstream, thereby increasing urinary glucose excretion. Thus, as eGFR decreases, the ability of SGLT-2 inhibitors to lower blood glucose by this mechanism will also decrease. SGLT-2 inhibitors are not indicated in patients with an eGFR <45 mL/min/1.73 m².^21,22 All forms of insulin are safe to use in mild to severe renal failure including dialysis, although healthcare providers and patients should be aware that dosage adjustments may be needed as renal function changes.

Case 5: Fear of Injections

A female patient presents with an HbA1c of 9.5% and has received metformin plus SU for the last 2 years. During a discussion of therapeutic options, the patient expresses anxiety about using injectable therapy, but her target HbA1c goal has not been attained with any of the multiple oral regimens she has tried.

Once the patient actually experiences an injection in the office, she is much less apprehensive. The idea of a once-weekly GLP-1RA appeals to her more than daily basal insulin.

Discussion

In this case, it was important to help the patient overcome her fear of injections because adding a third oral agent had not been successful. Although it can sometimes be a challenge, there is value in determining the reasons why patients are anxious about injectable therapy and if there are any potential trade-offs that would make it more attractive (eg, weight loss or the need for only once-weekly administration). An injection trial, even with saline, in the office can sometimes help patients overcome their fear and become more willing to try injectable therapies. Where insulin is required, a strategy to assist patients in overcoming their fear of injections is to start with very low-dose basal insulin. Many patients can accept basal insulin but fear multiple mealtime injections. In such cases, taking a stepwise approach may be helpful, such as starting with just evening mealtime insulin.

Simplifying Treatment Decision-Making

Choosing the right therapy for the right patient is important to create a positive cycle of change for patients, enabling them to improve their glycemic control while increasing exercise, eating healthier, and losing weight. The requirement for additional medication is an unwanted burden for patients, and the way in which the clinician presents further treatment to the patient is of utmost importance. It is critical that patients are aware that diabetes is typically a progressive disorder and that the requirement to augment treatment is an anticipated part of the process, despite a patient’s best efforts. Factors that should be considered when deciding on therapy options include efficacy, side effect profile, cost, contraindications, previous therapy/adverse events, therapy delivery route/regimen, and patient preferences and perceptions. A positive patient–clinician relationship, which incorporates shared decision-making, can increase the likelihood of successful treatment. Clinician awareness of these factors should lead to better treatment choice, improved adherence, and improved outcomes for patients.

References:

1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;
2. 87(1):4-14.
3. American Diabetes Association. Statistics about diabetes. www.diabetes.org/diabetes-basics/statistics/. Published June 10, 2014. Accessed March 5, 2015.
4. Centers for Disease Control and Prevention. Prevalence of overweight and obesity among adults with diagnosed diabetes–United States, 1988-1994 and 1999-2002. MMWR. 2004;53(45):1066-1068.
5. 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(6):1364-1379.
6. Diabetic Connect. CDC: 1 in 10 primary-care visits involve diabetes. www.diabeticconnect.com/diabetes-information-articles/general/1070-cdc-1-in-10-primary-care-visits-involve-diabetes. Accessed March 5, 2015.
7. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
8. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014;37(Suppl 1):S14-S80.
9. Fonseca V. Diabetes mellitus in the next decade: novel pipeline medications to treat hyperglycemia. Clin Ther. 2013;35(5):714-723.
10. Graffigna G, Barello S, Libreri C, Bosio CA. How to engage type-2 diabetic patients in their own health management: implications for clinical practice. BMC Public Health. 2014;14:648.
11. Munshi MN, Segal AR, Suhl E, et al. Assessment of barriers to improve diabetes management in older adults: a randomized controlled study. Diabetes Care. 2013;36(3):543-549.
12. Schmittdiel JA, Uratsu CS, Karter AJ, et al. Why don't diabetes patients achieve recommended risk factor targets? Poor adherence versus lack of treatment intensification. J Gen Intern Med. 2008;23(5):588-594.
13. Shah ND, Mullan RJ, Breslin M, et al. Translating comparative effectiveness into practice: the case of diabetes medications. Med Care. 2010;
14. 48(Suppl 6):S153-S158.
15. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580-591.
16. Lee YK, Ng CJ, Lee PY, et al. What are the barriers faced by patients using insulin? A qualitative study of Malaysian health care professionals' views. Patient Prefer Adherence. 2013;7:103-109.
17. Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005;172(2):213-226.
18. Defronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.
19. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009. 32(1):193-203.
20. Violante R, Oliveira JH, Yoon KH, et al. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. Diabet Med. 2012;29(11):e417-e424.
21. Cavanaugh KL. Diabetes management issues for patients with chronic kidney disease. Clinical Diabetes. 2007;25(3):90-97.
22. Abe M, Okada K, Soma M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr Drug Metab. 2011;12(1):57-69.
23. European Medicines Agency. Forxiga: Summary of product characteristics.  www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002322/WC500136026.pdf. Accessed March 10, 2015
24. Europeans Medicines Agency. Summary of product characteristics: Invokana (canagliflozin). www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002649/WC500156456.pdf. Accessed March 10, 2015.