Use of oral combination therapy for type 2 diabetes in primary care: Meeting individualized patient goals

Abstract

The management of type 2 diabetes mellitus (T2DM) by primary care physicians (PCPs) has become increasingly complex due to limitations on consultation time, an increasing array of drug treatment options, and issues of comorbidities and polypharmacy. Diabetes is a progressive condition and treatment with a single glucose-lowering agent can only address limited pathophysiologic targets and does not provide adequate glycemic control in many cases. Consequently, most patients with T2DM will eventually require treatment with multiple glucose-lowering medications. Oral combination therapy in T2DM may be given as multiple-pills, or as single-pill, fixed-dose combinations (FDCs), the latter of which offer convenience, ease of administration, and a reduction in the medication burden. Therefore, FDCs can potentially improve patients’ treatment adherence and optimize achievement and maintenance of glycemic targets. However, cost factors also need to be considered. An understanding of the issues associated with the use of combination therapy in T2DM will help PCPs to guide patient-centered decision making and promote the effective management of T2DM.

Keywords:

• Combination drug therapy
• fixed-dose combination
• single-pill combination
• primary care
• type 2 diabetes mellitus

Introduction

The incidence of type 2 diabetes mellitus (T2DM) has reached pandemic levels, affecting an estimated 382 million (8.3%) of adults worldwide in 2013. This figure will likely exceed 590 million in less than a quarter of a century [1]. Despite advances in both our understanding of the pathophysiology of T2DM and the development of new treatment strategies, current management of patients with T2DM remains sub-optimal. In 2012, an estimated 28.4 million (11.8%) US adults had diabetes, of whom 20.5 million (72.2%) were aware of their diagnosis. Individualized glycated hemoglobin (HbA1_c) goals were achieved by about two-thirds (63.7%) of these diagnosed individuals [2]. During the same year, the American Diabetes Association estimated that medical care for diabetes (i.e. type 1 diabetes mellitus [T1DM] and T2DM) in the United States cost US$245 billion, and this number is expected to rise in coming decades as the impact of diabetes increases with age [3]. If healthcare professionals are to have any chance of controlling the burden of T2DM, then interventions to limit or reduce its associated pathophysiologic defects (DeFronzo’s “ominous octet” [4]) are vital [5]. However, treatment with a single glucose-lowering agent can only address limited targets [6] and does not provide adequate glycemic control in many cases [7,8]. Combination drug therapy in T2DM should use the lowest number of agents to combat the highest number of pathophysiologic mechanisms causing hyperglycemia; therefore, agents should have an additive effect, correct established pathophysiologic defects, and preserve or improve pancreatic β-cell function to ensure durable glycemic control [5].

Challenges for the management of T2DM in primary care

Current guidelines for the management of individuals with newly diagnosed T2DM recommend initial treatment with metformin monotherapy, unless there are intolerances or contraindications, in conjunction with lifestyle modifications [9,10]. However, this strategy does not achieve glycemic control in a significant proportion of patients [7-9,11]. In fact, due to the progressive nature of T2DM, even at the time of diagnosis, most patients with T2DM will require multiple glucose-lowering medications to achieve adequate glycemic control [7,8,12]. Monotherapy underestimates the complexity and progressive nature of the disorder and can provide temporary benefits at best. However, the choice of subsequent drug therapy is not straightforward, and a diverse range of pharmacological agents (consisting of at least 12 drug classes [10]) is now available for the treatment of T2DM. Paradoxically, although this expanding armamentarium of drugs can be beneficial in terms of providing the physician with more options for individualized care, the sheer number of treatments available has also made T2DM more challenging to manage than it was a decade ago. Several factors must be considered when tailoring individualized care for patients with T2DM. These include pathophysiology (e.g. remaining pancreatic β-cell function and mass), modifiers of treatment response (e.g. age, body mass index, and baseline HbA1_c), and the risk of non-adherence to treatment [13]. Non-adherence is affected by factors such as out-of-pocket costs, tolerability/side effects, and the complexity of daily treatment regimens [13].

In addition, many patients with T2DM present to their primary care physician (PCP) with comorbid conditions, such as hypertension, dyslipidemia, and/or obesity [14]. Management of these multiple morbidities further adds to the complexity of treating patients to goals and, in particular, increases the pill burden. This may then lead to an increased risk of medication-related problems, including drug–drug interactions and adverse events. Factors such as increasing the numbers of tablets, multiple daily dosing schedules, and the concurrent use of several types of glucose-lowering medications are associated with poor treatment adherence [15-17].

Another factor that may influence the ability of patients to achieve and maintain their HbA1_c treatment targets are time limitations for PCPs. Analysis of primary care patient population data showed that practice guidelines for 10 chronic illnesses, including diabetes, required more time than PCPs have available for total patient care overall [18]. Patients with diabetes attended for up to four visits to their PCP per year, with an average of 10 min per visit: this was insufficient for patients to gain the required knowledge to self-manage their diabetes [18]. To help address this issue, health-system-wide approaches are being used, such as pharmacist-led diabetes medication-therapy management programs [19,20]. Patient attendance at diabetes self-management education classes is also an integral part of effective diabetes care [10,21], even though achieving and maintaining patient attendance at such classes may be challenging.

Combination therapies for T2DM

Current guidelines from the American Association of Clinical Endocrinologists and American College of Endocrinology recommend initiating dual therapy (usually with metformin, unless contraindicated or not tolerated, plus a second agent) in patients with entry HbA1_c levels >7.5%, and initiating dual or triple therapy with oral glucose-lowering agents in patients with entry HbA1_c levels >9.0% but without symptoms of hyperglycemia (symptomatic hyperglycemia requires insulin therapy ± oral agents) [9,11]. Whereas the American Diabetes Association and European Association for the Study of Diabetes guidelines recommend proceeding to a two-drug combination if the target HbA1_c is not achieved within 3 months of monotherapy, or initiating dual combination therapy when HbA1_c is >9.0% [22].

Given the increasing complexities in managing T2DM, interest in the development, use, and potential benefits of combination therapies has grown steadily. A meta-analysis of 15 randomized controlled trials demonstrated that therapy with metformin combined with other oral agents (thiazolidinediones [TZDs], insulin secretagogues, dipeptidyl peptidase-4 [DPP-4] inhibitors, or sodium–glucose co-transporter 2 [SGLT2] inhibitors) resulted in significant improvements in HbA1_c and attainment of glycemic goals compared with metformin alone [23]. Initiation of combination therapy at diagnosis is considered the optimal approach for many patients [5,9,11,24-28]. A similar strategy is used in the treatment of hypertension and hyperlipidemia, in which initial therapy with a combination of drugs is common. Treatment combinations in T2DM should be individualized based on efficacy, risk–benefit profile, patient preference, and cost [11,22,25] The pharmacologic rationale for combination therapy is to address the pathophysiologic defects present in T2DM [5] by selecting therapies that offer complementary mechanisms of action. Initiating therapy with a combination of agents provides potential advantages over a stepwise treatment approach (e.g. earlier achievement of glycemic goals) [23].

Approaches to combination therapy: advantages and disadvantages

The traditional stepwise approach to T2DM management is conservative and involves lifestyle modification, then treatment with a single oral glucose-lowering agent. A disadvantage of many monotherapy options is lack of glycemic durability. When monotherapy begins to fail, the dosage is subsequently up-titrated to the maximal recommended dose before the addition of a second glucose-lowering agent [24]. Unfortunately, there is often a delay in titrating monotherapy or in initiating combination therapy, caused by “clinical inertia” [29,30], which results in prolonged hyperglycemia before treatment is stepped up [31], with the associated risk of micro- and macrovascular complications [24]. In contrast, initial combination therapy with metformin and another agent offers the advantage of earlier achievement of glycemic goals than use of monotherapy [23].

Another disadvantage of up-titration of monotherapy is the potential for dosages that reach, or exceed, the maximum effective dose [32]. This high dosage may lead to increased adverse effects [24], whereas early use of combination therapy may permit use of a lower (submaximal) dose of each agent to minimize dose-related side effects (e.g. gastrointestinal distress with metformin) [24,33]. On the other hand, a stepwise approach may allow an evaluation of a drug’s efficacy and of any possible adverse effects before further glucose-lowering agents are added, to which the patient may or may not respond [34].

Oral combination therapy in T2DM may be given as separately dispensed, individual medications, or as fixed-dose combinations (FDCs; i.e. a single-pill formulation), which are available for many glucose-lowering agents. Products that are single-pill FDCs offer several advantages over multiple-pill combinations [12,35]. They reduce the complexity of a dosing regimen, which is associated with improved patient adherence with treatment [35-37]. The lower doses of the two agents in an FDC product may offer greater efficacy in combination than that provided by higher or maximal doses of monotherapy [38-40], or of coadministered dual therapy [37]. Importantly, single-pill FDCs may offer cost advantages over multiple-pill combinations (see following sections) [6,12,35].

Metformin-based combination therapies

Metformin forms the basis of most oral combination therapies in T2DM (Table 1). Options for dual therapy (i.e. add-on) with metformin include oral agents (DPP-4 inhibitors, SGLT2 inhibitors, sulfonylureas, TZDs), injectable glucagon-like peptide 1 (GLP-1) agonists, or basal insulin [10]. Many drug classes are available in the United States as FDC products containing metformin immediate release or metformin extended release [6], including combinations with DPP-4 inhibitors (sitagliptin [41,42], linagliptin [43], saxagliptin [44], and alogliptin [45]), sulfonylureas (glipizide [46] and glyburide [47]), SGLT2 inhibitors (dapagliflozin [48], canagliflozin [49], empagliflozin [50]), a meglitinide (repaglinide [51]), and a TZD (pioglitazone [52,53]).

Table 1. Oral glucose-lowering medications available in a fixed-dose, single-pill combination approved in the USA for the treatment of type 2 diabetes mellitus.

Primary mechanism of action	Drug class	Formulation	Tablet size, mg/mg	Cost for 30-day supply (US$/tablet quantity) (based on normal dosing)
Glucose-mediated insulin stimulation + insulin sensitizer	DPP-4 inhibitor + biguanide	Kombiglyze™ XR (saxagliptin/metformin XR)	2.5/1000	354.76/60
			5/500	354.76/30
			5/1000	354.76/30
		Janumet® XR (sitagliptin/metformin XR)	50/500	361.01/60
			50/1000	361.01/60
			100/1000	722.03/60
		Janumet® (sitagliptin/metformin)	50/500	361.01/60
			50/1000	361.01/60
		Jentadueto® (linagliptin/metformin IR)	2.5/500	361.06/60
			2.5/850
			2.5/1000
		Kazano® (alogliptin/metformin)	12.5/500	340.64/60
			12.5/1000
Insulin sensitizers (two independent mechanisms)	TZD + biguanide	Actoplus Met® XR (pioglitazone/metformin ER)	15/1000	280.56/30
			30/1000	556.13/30
		Actoplus Met® (pioglitazone/metformin IR)	15/500	518.22/60
			15/850
		Pioglitazone/metformin IR	15/500	319.71/60
			15/850
		Avandamet® (rosiglitazone/metformin IR)	2/1000	165.31/60
Insulin sensitizer + stimulation	SU + biguanide	Glucovance® (glyburide/metformin IR)	1.25/250	147.86/120
			2.5/500	93.49/60
			5/500	93.49/60
		Glyburide/metformin	1.25/250	105.83/120
			2.5/500	61.70/60
			5/500	62.90/60
		Glipizide/metformin	2.5/250	99.48/120
			2.5/500	59.33/60
			5/500	59.33/60
	Meglitinide analog + biguanide	PrandiMet® (repaglinide/metformin IR)	1/500	308.52/60
			2/500
Increased renal glucose excretion + insulin sensitizer	SGLT2 inhibitor + biguanide	Xigduo™ XR (dapagliflozin/metformin XR)	5/500	823.20/60
			10/500	823.20/60
			5/1000	411.84/60
			10/1000	823.20/60
		Invokamet® (canagliflozin/metformin IR)	50/500	411.41/60
			50/1000
			150/500
			150/1000
Glucose-mediated insulin stimulation + insulin sensitizer	DPP-4 inhibitor + TZD	Oseni® (alogliptin/pioglitazone)	12.5/15	340.64/30
			12.5/30
			12.5/45
			25/15
			25/30
			25/45
		Duetact® (pioglitazone/glimepiride)	30/2	521.18/30
			30/4
		Pioglitazone/glimepiride	30/2	368.67/30
			30/4
Increased renal glucose excretion + glucose-mediated insulin sensitizer	Dual inhibitor (SGLT2 inhibitor + DPP-4 inhibitor)	Glyxambi® (empagliflozin/linagliptin)	10/5 25/5	576.00/30

Pricing and product availability data from Lexicomp, 2015 February © Copyright 1978-2015. All Rights Reserved. February 2015. Hudson, OH, USA. Disclaimer: The pricing data provide a representative Average Wholesale Price from a single manufacturer of the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for reimbursement or purchasing functions. Pricing data are updated monthly.

Abbreviations: DPP-4 = Dipeptidyl peptidase 4; ER = Extended release; IR = Immediate release; SGLT2 = Sodium–glucose cotransporter 2; SU = Sulfonylurea; TZD = Thiazolidinedione; XR = Extended release.

One historically popular combination is that of metformin plus a sulfonylurea [54]. In 2012, 22.1% of metformin use in the United States was concomitant with that of a sulfonylurea [55]. The appeal of using sulfonylureas may be limited by the associated increased risk of hypoglycemia [10,56], weight gain, and increased risk of cardiovascular mortality [57,58]. TZDs are another option for combining with metformin, but this class is associated with a risk of congestive heart failure and bone fractures [10]. Use of TZDs declined steeply in the United States following concerns regarding the cardiovascular safety of rosiglitazone, although subsequent US prescribing restrictions have since been lifted [55]. Pioglitazone was not associated with similar risks [59]; however, prescription use still declined [55]. Evidence suggests that pioglitazone improves β-cell function in patients with T2DM, which is associated with improvements in glycemic control [60]. This agent is an insulin sensitizer with good glycemic durability and a low risk of hypoglycemia but use of this agent has not rebounded [5]. Nonetheless, concerns with sulfonylureas and TZDs may result in the need to consider alternate combinations.

Prescription data show that 22.0% of metformin use in 2012 was concomitant with that of a DPP-4 inhibitor [55]. When used as an FDC, added separately to metformin, or initiated soon after diagnosis, this combination has produced greater HbA1_c efficacy than use of monotherapy, with a good safety profile, low risk of hypoglycemia, and weight neutrality [61]. Moreover, a meta-analysis of initial therapy in treatment-naive patients with T2DM demonstrated that significantly more patients achieved an HbA1c goal of <7% with initial metformin and DPP-4 combination therapy versus metformin monotherapy [23].

The SGLT2 inhibitors have also been studied in combination with metformin and provide improvements in glycemic control and the additional benefits of reducing body weight and blood pressure [62-64]. They have a good safety profile, although they are associated with increased risk of genital mycotic infections, particularly in women [10]. The US FDA released a warning in May 2015 advising individuals receiving SGLT2 inhibitor therapy to be on alert for potential signs of diabetic ketoacidosis (DKA), particularly nausea, vomiting, or fatigue [65]. This warning is based on 20 reports in the FDA Adverse Events Reporting System of individuals with either T1DM or T2DM; however, the SGLT2 inhibitors available in the United States are not approved for the treatment of T1DM. Subsequently, the first case series of DKA has described 13 episodes in nine individuals: seven with T1DM and two with T2DM [66]. Mild infection, increased physical activity, reduced food intake, reduced insulin dose, or a combination of these were contributing factors in some, but not all, cases. All patients experienced the euglycemic form of DKA, which is rare. The absence of significant hyperglycemia delayed diagnosis. Increased awareness of this atypical presentation will help PCPs identify this condition moving forward as the etiology and physiologic pathways are further elucidated. The precise cause of DKA in patients receiving SGLT2 inhibitors is not yet known, but several mechanisms may be involved [67]; for example, a reduction in insulin dose to reduce the risk of hypoglycemia when given in combination therapy with SGLT2 inhibitors may be insufficient to suppress lipolysis and ketogenesis; SGLT2 inhibitors are known to promote glucagon secretion [68,69], which may be expected to cause hepatic ketogenesis; animal studies have shown that inhibition of SGLTs may decrease urinary excretion of ketone bodies; and a decrease in renal clearance of ketone bodies could increase plasma ketone body levels [67]. Furthermore, the mechanism of SGLT2 inhibitor action predisposes to volume contraction, which may exacerbate the hypovolemic state in DKA, particularly in a patient with nausea/vomiting and/or diarrhea [66]. Patients should be advised not to stop their medications without consulting a physician [65].

Non–metformin-based combination therapies

Non-metformin oral combinations are also available [6], although fewer in number, and may be used in patients who are unable to tolerate metformin, or added for patients who do not achieve glycemic control with metformin. Combinations of TZDs plus sulfonylureas demonstrate efficacy in lowering HbA1_c [70,71], and an FDC containing both classes is available for clinical use [72]. The combination of TZDs plus DPP-4 inhibitors is well studied, demonstrating improved glycemic control without an increased risk of hypoglycemia [73-78]; alogliptin and pioglitazone are available as a single-pill FDC tablet [79]. More recent clinical trials have shown the glycemic efficacy of SGLT2 inhibitors in combination therapy, with or without background metformin. Examples include SGLT2 inhibitors plus DPP-4 inhibitors (e.g. dapagliflozin + saxagliptin [80], empagliflozin + linagliptin [81,82]), SGLT2 inhibitors plus sulfonylurea (e.g. dapagliflozin + glimepiride [83], canagliflozin + sulfonylurea [84], empagliflozin + sulfonylurea [85]), and SGLT2 inhibitors plus TZD (e.g. dapagliflozin + pioglitazone [86], canagliflozin + pioglitazone [87], empagliflozin + pioglitazone [88]).

The combination of saxagliptin plus dapagliflozin as an FDC has been submitted for US FDA regulatory approval. A 24-week, Phase III study has compared the efficacy and safety of dual add-on of saxagliptin (5 mg/day) plus dapagliflozin (10 mg/day), versus both agents added on alone, in patients with T2DM inadequately controlled on metformin [80]. Patients were randomized to saxagliptin plus dapagliflozin (n = 179), or saxagliptin plus placebo (n = 176), or dapagliflozin plus placebo (n = 179) with continuing background metformin extended release >1,500 mg/day. At week 24, adjusted mean change from baseline (8.9%) in HbA1c was –1.5% with the triple combination versus –0.9% with saxagliptin plus metformin (difference –0.59%, p < 0.0001) and –1.2% with dapagliflozin plus metformin (difference –0.27% p < 0.02) [80]. The rate of hypoglycemic events was low and similar across groups, with no episodes of major hypoglycemia [80].

In 2015, the US FDA approved a combination of empagliflozin plus linagliptin, available in two strengths: 10 mg empagliflozin/5 mg linagliptin and 25 mg empagliflozin/5 mg linagliptin [89]. The US FDA approval is based on data from two 52-week, Phase III studies that investigated the efficacy and safety of the single-pill combinations of empagliflozin 25 mg/linagliptin 5 mg and empagliflozin 10 mg/linagliptin 5 mg in patients with T2DM. In treatment-naive patients (n = 677), the mean treatment difference in HbA1_c changes from baseline (∼8.0%) at week 24 with the empagliflozin 25 mg/linagliptin 5 mg single-pill combination was statistically significant versus linagliptin 5 mg (–1.08 vs –0.67%; difference −0.41%; p < 0.001), but not versus empagliflozin 25 mg (–1.08 vs –0.95%; difference −0.14%; p = 0.179). The empagliflozin 10 mg/linagliptin 5 mg single-pill combination, however, resulted in statistically significant mean treatment differences in HbA1_c versus both individual components (10 mg/5 mg vs linagliptin 5 mg: –1.24 vs –0.67% [difference −0.57%; p < 0.001]; 10 mg/5 mg vs empagliflozin 10 mg, –1.24 vs –0.83% [difference −0.41%; p < 0.001]) [82]. In patients inadequately controlled on metformin (n = 686), combinations of empagliflozin/linagliptin provided greater reductions in HbA1_c from baseline (∼8.0%) compared with empagliflozin or linagliptin alone as an add-on to metformin. At week 24, adjusted mean changes from baseline in HbA1c were –1.19% and –1.08% for empagliflozin 25 mg/linagliptin 5 mg and empagliflozin 10 mg/linagliptin 5 mg, respectively, compared with –0.62% for empagliflozin 25 mg, –0.66% for empagliflozin 10 mg, and –0.70% for linagliptin 5 mg (treatment differences p < 0.001 for both combinations vs monotherapy components). In both the treatment-naive and background metformin studies, improvements in HbA1c were maintained at week 52. Furthermore, benefits were also shown in terms of weight loss and blood pressure reduction: in both studies the empagliflozin/linagliptin single-pill combinations produced significantly greater reductions in body weight from baseline, compared with linagliptin alone, at weeks 24 and 52. In addition, in the background metformin study, the single-pill combinations also resulted in significantly greater reductions in systolic blood pressure from baseline, versus linagliptin alone, at week 52. The proportion of adverse events was similar across all groups over 52 weeks in both trials [81,82].

Advancement to a triple combination of oral therapies, which are not yet available in an FDC product, may benefit some patients who do not achieve glycemic control with dual oral therapy. However, the addition of basal insulin is often the next step in an attempt to achieve the glycemic target [10]. After basal insulin is added, usually in combination with metformin (± another agent), either a GLP-1 receptor agonist or mealtime insulin may be added. GLP-1 receptor agonists have an acceptable safety profile [90-92] and may be less complicated for patients than a multi-dose insulin regimen [10]. An FDC injectable containing ultra–long-acting basal insulin (degludec) and a GLP-1 receptor agonist (liraglutide) demonstrated good efficacy and safety [93-95], and was recently given marketing approval in the European Union [96].

Cost considerations

Cost factors should be examined when considering FDCs versus coadministered dual therapies; however, data describing the direct effects of glucose-lowering agents on healthcare costs are limited [6]. A systematic review of 17 studies of patients with T2DM, including six describing economic data, reported reduced direct medical costs, better healthcare utilization, and improved satisfaction with FDCs versus multiple-pill regimens [35]. However, other systematic literature reviews found a disparity between treatment adherence and overall treatment costs in T2DM [6,97,98]. The acquisition costs of FDCs are shown in Table 1 and example cost comparisons versus multiple-pill regimens are illustrated in Table 2. Patients with insurance may have only a single co-pay for an FDC prescription (as a single-pill or premixed injectable), compared with two co-pays for the corresponding free combination of agents [12]. However, costs will vary according to preferred formulary status, and it should also be noted that some insurers may not cover FDC prescriptions [12]. In addition, the cost of any potential long-term complications must be considered during drug selection. For example, for metformin plus sulfonylurea, both drugs are available as generic medications and, as such, have low co-pays; however, sulfonylureas are associated with an increased risk of hypoglycemia, particularly in the elderly [56], and the management of hospitalization-related hypoglycemic episodes can be costly [99]. Thus, consideration of combination therapies with a low risk of hypoglycemia could be a potential cost-effective long-term approach.

Table 2. Cost comparison examples of oral glucose-lowering medications as single-drug formulations and their fixed-dose, single-pill combinations approved in the US for the treatment of type 2 diabetes mellitus.

Fixed-dose, single-pill combination	Formulation	Cost per tablet, US$	Cost for 30-day supply (US$/tablet quantity) (based on normal dosing)
Sitagliptin + metformin	Januvia® (sitagliptin 50 mg) once daily	12.03	360.90/30
	Metformin (generic) 1000 mg twice daily	1.45	86.97/60
	Combined cost	12.73	447.87
	Janumet® (sitagliptin 50 mg/metformin 1000 mg) twice daily	6.02	361.01/60
Rosiglitazone + glimepiride	Avandia® (rosiglitazone) 4 mg once daily	4.68	140.45/30
	Glimepiride 1 mg once daily	0.40	12.05/30
	Combined cost	5.08	153.50
	Avandaryl® (rosiglitazone 4 mg/glimepiride 1 mg) once daily	5.22	156.64/30
Empagliflozin + linagliptin	Jardiance® (empagliflozin 10 mg) once daily	13.71	411.38/30
	Tradjenta® (linagliptin 5 mg) once daily	12.03	361.03/30
	Combined cost	25.74	772.41
	Glyxambi® (empagliflozin 10 mg/linagliptin 5 mg) once daily	19.20	576.00/30

For illustration purposes only, based on data from Table 1, and using cost of individual components to calculate combined cost. Pricing data from Lexicomp, © Copyright 1978-2015. All Rights Reserved. February 2015. Hudson, OH, USA. Disclaimer: The pricing data provide a representative Average Wholesale Price from a single manufacturer of the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for reimbursement or purchasing functions. Pricing data are updated monthly.

Managing the patient with T2DM: practical guidance for the PCP

As discussed above, single-pill FDC therapies may help patients with T2DM to achieve and maintain their HbA1_c targets and provide potentially greater adherence to therapy via a reduced pill burden, simplification of the treatment regimen, and favorable cost factors. Treatment guidelines recommend combination therapy when HbA1c goals are not achieved [9,10]. Yet, US prescription data for 2012 showed that approximately one-third to one-half of sulfonylurea, DPP-4 inhibitor, TZD, and GLP-1 agonist use was not accompanied by metformin (the SGLT-2 inhibitors were not marketed at that time) [55]. What else can PCPs do to help optimize the management of T2DM at patient visits, especially given the time constraints for office visits?

Optimizing patient visits for T2DM care

1. Develop a detailed patient care plan soon after diagnosis and identify treatment goals (current and future).

2. Explain that T2DM and its management is an ongoing process and that treatment will be modified as the condition progresses.

3. Stress that not all treatment goals can be achieved at the first follow-up visit: goals should be reviewed at each 3-month visit and dosing/medication(s) should be adjusted accordingly.

4. Focus on one treatment goal at each subsequent visit. If consultation time is limited, create a checklist of topics to cover with the patient at each visit (Table 3) – this may help to formulate an individualized treatment plan/HbA1_c target, encourage the patient to proactively monitor their glycemic control between visits, and help both parties to determine whether the patient is achieving that target.

5. Consider motivational interviewing to gauge the patient’s current/past experiences of their medical condition and readiness to make changes [100]. Avoid taking a paternalistic approach in instructing or trying to convince the patient to change their behavior. Instead, foster a mutual understanding of the perspectives and priorities of both patient and PCP, in order to educate and empower the patient to take an active role in their treatment [101]. Understanding how the patient perceives their medical condition may help to improve treatment adherence and the effectiveness of the physician [102]. Motivational interviewing may enable treatments to be selected more appropriately; thereafter the care plan can be tailored to an individual’s circumstances.

Table 3. Sample checklist of topics to cover/goals to set with the patient.

Diabetes history	When was the patient diagnosed with T2DM?
	How was T2DM diagnosed?
	Does the patient use self-monitoring of blood glucose?
	If so, how often does s/he test?
	What is the patient’s history of hypoglycemic events (plasma glucose <70 mg/dL)?
	What is their response to hypoglycemic events?
	(e.g. skip medication, eat extra carbohydrates/meal, alter their activities)
	What prior adverse reactions has the patient experienced to T2DM therapies?
Medical and drug history	Are there any pre-existing cardiovascular complications that would influence the HbA1c goal?
	What types of medication does the patient currently use?
	What types of medication has the patient used previously?
	(e.g. medications for chronic disorders, such as cardiovascular, pulmonary, rheumatic; alternative therapies; vitamins, etc.)
	What are the reasons for continuation or discontinuation?
	What is the patient’s health literacy and numeracy?
	What prior adverse reactions has the patient experienced to T2DM therapies?
Lifestyle	Does the patient have any specific dietary challenges and/or cultural food preferences that may impact on management of their T2DM?
	How active is the patient?
	What type of activity does s/he do?
	(e.g. gardening, housework, structured exercise, aerobic exercise, weightlifting, etc.)
Diabetes education	Has the patient ever received diabetes education?
	If so, what type of program did s/he attend?
Realistic goals	What realistic goals should be set for the patient for the following parameters?
	• Fasting plasma glucose
	• 2-h postprandial glucose
	• Blood lipids
	• Blood pressure
	• Weight reduction

Abbreviations: HbA1_c = Glycated hemoglobin; T2DM = Type 2 diabetes mellitus.

Conclusion

The time available to PCPs for treating patients with T2DM is limited, and the number of available treatment options is becoming increasingly complex. This is compounded by the challenges of polypharmacy due to comorbidities with T2DM, especially among elderly patients, and the often detrimental effect this can have on treatment adherence. Combination therapies in T2DM can reduce the medication burden for oral and injectable agents alike, thereby potentially encouraging an improved adherence to treatment that, in turn, helps patients to achieve and maintain glycemic targets, and may reduce the risks of microvascular complications. Among oral combination therapies, an increasing number of FDC single-pill formulations are available, and these offer further convenience and ease of administration. In addition, preparation of patient care plans that take into consideration the individual patient’s treatment preferences, knowledge of diabetes, and motivation to be proactive in their own healthcare will help the PCP to facilitate patient-centered decision-making, and promote more effective management of T2DM.

Declaration of interest

This review was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). The authors received no direct compensation related to the development of the manuscript. Writing assistance and editorial support was provided by Debra Brocksmith and Charlie Bellinger of Envision Scientific Solutions, which was contracted and funded by BIPI. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. F Lavernia reports receiving compensation for serving on advisory boards for Lilly Global, Janssen, and Sanofi, and on the speaker’s bureau for Janssen. J Shubrook reports receiving research grants from Sanofi, and receiving compensation for serving on advisory boards for Eli Lilly, NovoNordisk, and AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.