Management of Type 2 Diabetes Mellitus: A Patient-centered Approach

Sharon Wu Lahiri

Management of Type 2 Diabetes Mellitus: A Patient-centered ApproachCHAPTER 1

Sharon Wu Lahiri

INTRODUCTION

Diabetes and its associated health and economic consequences are on the rise with no signs of abatement. The prevalence of diabetes worldwide has nearly doubled from 4.7% in 1980 to 8.5% or 422 million people in 2014.¹ In the United States, 10.5% or 34.2 million people had diabetes in 2018, 21.4% of whom were unaware of their diagnosis.² The global direct annual cost of diabetes is estimated to be over 827 billion dollars.^3,4 This costly, growing health problem requires that health professionals become well-versed in treating diabetes and its long-term consequences.

Over the last decade and a half, several new glucose-lowering agents have been developed. Physicians now have a large armamentarium of medications targeting the underlying pathophysiologic abnormalities in type 2 diabetes mellitus (T2DM). The choice of agent(s) to use must be based on patient-specific needs, comorbidities [specifically atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD)], body mass index and risk of weight gain, risk of adverse effects from treatment including hypoglycemia, ability of the patient to administer and tolerate medications, the efficacy and potency of medications, and cost of treatment.

Excellent comprehensive algorithms on a patient-centered approach to diabetes management have been published by the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) as well as the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) and other groups.^5–13 These algorithms and strategies will be reviewed in this chapter along with a discussion of currently available medications and how to choose among these medications based on patient-specific needs.2

PATHOGENESIS OF DIABETES

The “ominous octet” described by Dr Ralph DeFronzo in his 2009 Banting Lecture provides a valuable framework for understanding the underlying pathogenesis of T2DM and the treatment of this chronic disease.¹⁴ “Ominous octet” refers to defects in eight organ systems in T2DM including the liver and muscle (insulin resistance), pancreatic β-cell (insulin deficiency), fat cell (accelerated lipolysis), intestines (incretin deficiency), pancreatic α-cell (excess glucagon production), kidney (increased glucose reabsorption), and brain (impaired appetite regulation and insulin resistance).¹⁴ Therapies targeting the well-known defects of insulin resistance in the muscle and liver [metformin and thiazolidinediones (TZDs)] and β-cell insufficiency (sulfonylureas and insulin) were the primary therapies used until the last decade and a half when newer therapies targeting the other organ system abnormalities became available. These newer agents, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, are now considered early in the treatment algorithm in the presence of ASCVD, HF, or CKD due to evidence of their cardiovascular and renal benefits. Furthermore, since these newer medications do not directly stimulate insulin secretion, they do not cause hypoglycemia or weight gain on their own. This is especially important since many glucose-lowering medications are associated with increase in weight, leading to worsening insulin resistance and the need for intensification of treatment, especially with higher doses of insulin, leading to further weight gain. These newer agents can help halt or at least limit the vicious cycle of weight gain from insulin leading to further increase in insulin and weight.

PATIENT-CENTERED CARE

The idea of patient-centered care is not a new concept in primary care. The patient-centered medical home as a model for delivery of primary care was described in 1967 by the American Academy of Pediatrics and developed and endorsed by the major primary care associations in 2007 in the Joint Principles of a patient-centered medical home.¹⁵ Patient-centered care or personalized care in diabetes means taking an individual's unique characteristics, lifestyle, comorbidities, preferences, and abilities into consideration when devising a treatment plan for diabetes and determining how that plan will benefit or adversely affect the individual. An important part of patient-centered care is promoting adherence to the diabetes medication regimen by working to better understand the patient experience with taking the medications, improving the patient–provider relationship to gain patient trust, and obtaining healthcare system support of providers.¹⁶3

Evidence supporting the use of patient-centered care is provided by the DCGP (Diabetes Care in General Practice) study. DCGP looked at the effects of 6 years of intervention with structured personal care versus routine care of T2DM over a 19-year follow-up period.¹⁷ At 19 years, DCGP found that intervention resulted in a lower risk of myocardial infarction and any diabetes-related endpoint.¹⁷ Furthermore, an analysis of a subset of patients with concurrent psychiatric illness from the DCGP study demonstrated that structured personal care resulted in lower risk for all-cause mortality, diabetes-related death, any diabetes-related endpoint, and myocardial infarction.¹⁸

Several approaches have been published on this topic, all involving the evaluation of the unique characteristics of each patient to determine glycemic goal and careful assessment of the benefits and risks of specific glucose-lowering agents to prescribe a personalized regimen of medications.^5–13

Glycemic Target

Glycemic targets are determined by weighing the benefits of lower glycated hemoglobin (HbA1c) (reduction in risk of microvascular complications) against the risks of tight control (hypoglycemia, adverse effects from medications, and cost). HbA1c and self-monitored blood glucose levels have been used as parameters of glycemic control, with the former measure being used in most algorithms.

The optimal glycemic target is generally felt to be a HbA1c of 7% or below based on long-term prospective clinical trials demonstrating that tight glycemic control will prevent microvascular complications.^19–22 The UKPDS (United Kingdom Prospective Diabetes Study) evaluated individuals with newly diagnosed T2DM randomized to standard treatment of lifestyle with or without pharmacological therapy to achieve target fasting plasma glucose (FPG) below 15 mmol/L versus intensive treatment with insulin or a sulfonylurea to achieve target FPG below 6 mmol/L over a 10-year period.¹⁹ This landmark study found that the lower HbA1c of 7% achieved in the intensive group (vs. 7.9% in the standard group) was associated with a significant reduction in the risk of microvascular complications.¹⁹ The Kumamoto study also found intensive glycemic control, aiming for a HbA1c below 6.5%, to be beneficial in delaying the onset and progression of microvascular complications in T2DM over a 6-year period.²⁰

The impact of intensive glycemic control on macrovascular complications is less certain. A small reduction in risk of myocardial infarction was found with intensive treatment with sulfonylureas and insulin in UKPDS over the 10-year time period, but this was not significant (p = 0.052).¹⁹ A significant risk reduction in myocardial infarction, diabetes-related death, 4and all-cause mortality was found only in a subset of overweight patients in UKPDS randomized to metformin.²¹ Interestingly, however, risk reductions for myocardial infarction and death from any cause did become apparent in the intensive group after an additional 10-year follow-up of the UKPDS trial from 1997 to 2007 as more events occurred.²²

The effects of intensive HbA1c lowering specifically on cardiovascular endpoints were studied in three trials published in 2008: ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, and VADT (Veterans Affairs Diabetes Trial).^23–25 The ACCORD trial and VADT targeted a normal HbA1c below 6%, while the ADVANCE trial had a target HbA1c of 6.5% or less.^23–25 The duration of the trials was 5 years for ADVANCE and VADT. ACCORD trial was terminated early at 3.5 years due to increased mortality in the intensive treatment group. The ADVANCE trial and VADT did not find any significant effect of intensive treatment on the rate of major cardiovascular events or death but did find benefit of tight glycemic control on the development and progression of nephropathy.^24,25 The ACCORD trial also did not find a significant reduction in major cardiovascular events, but had an unexpected finding of a 22% relative increase in total mortality, mainly due to increase in death from cardiovascular causes, in the intensive group emerging 1–2 years after randomization.²³ Based on the results of these trials, the general consensus from guidelines and expert opinion is to continue to recommend a HbA1c target of 7% for most patients, although a lower or higher target may be appropriate depending on patient characteristics and comorbidities.^8,9,26,27

ALGORITHMS AND GUIDELINES

Personalizing diabetes care based on patient characteristics has been recommended by many major organizations. The most comprehensive and widely used algorithms are the position statements by the ADA/EASD, the ADA Standards of Medical Care in Diabetes, and the consensus statement by the AACE/ACE.^7–9

The ADA Standards of Medical Care recommend determining stringency of glycemic control based on patient preference, risks from hypoglycemia, disease duration, life expectancy, comorbidities and vascular complications, and resources.^9,27 HbA1c goal of <7% is recommended for most nonpregnant adult patients.²⁷ A more stringent target below 6.5% is felt to be reasonable in healthy patients without cardiovascular disease (CVD) if it can be achieved without significant hypoglycemia or adverse effects of treatment.²⁷ A less stringent target of 8% 5should be used in patients with increased risk for severe hypoglycemia, extensive complications and comorbidities, and limited life expectancy.²⁷

The ADA/EASD are less specific about HbA1c goals with the algorithm recommending dual therapy be considered when HbA1c is ≥1.5% above the glycemic target based on the aforementioned factors.^7,9,27 Injectable combination therapy with a GLP-1 receptor agonist and/or insulin is recommended by the ADA/EASD when HbA1c is ≥10% or 2% above glycemic target or blood glucose ≥300 mg/dL.^7,9 New in 2019 and 2020 are specific recommendations to use GLP-1 receptor agonists or SGLT-2 inhibitors based on the presence or absence of ASCVD, HF, or CKD.^7,9 In the absence of these three comorbidities, medication choice is based on cost, risk of hypoglycemia, and risk of weight gain.^7,9

The AACE/ACE algorithm similarly recommends taking patient and medication characteristics into account when determining the glycemic target, but has more stringent goals and is more aggressive with starting and adding glucose-lowering agents. This organization supports a generally lower HbA1c goal of ≤6.5% for most patients to reduce the lifetime risk of microvascular and macrovascular complications, if it can be achieved without hypoglycemia or other adverse effects.⁸ Similar to the ADA/EASD algorithm, less stringent control with a HbA1c above 6.5% is recommended if hypoglycemia, comorbidities, macrovascular disease, advanced renal disease, or limited life expectancy are present.⁸ Their glycemic control algorithm is stratified based on the initial specific HbA1c level. Pharmacologic therapy with one agent is recommended if the patient presents with HbA1c below 7.5%, while two or three agents are advised if entry HbA1c is above 7.5%; insulin is recommended if HbA1c is above 9% with symptoms of hyperglycemia.⁸ This algorithm similarly recommends metformin as first-line therapy and ranks the second- and third-line agents based on the strength of the expert consensus recommendation; those with fewer adverse events, especially weight gain and hypoglycemia, and greater possible benefits, especially cardiovascular or renal, are listed higher, resulting in GLP-1 receptor agonists and SGLT-2 inhibitors having the strongest recommendations.⁸

Other patient-centered algorithms have focused on similar factors for determining treatment. A simple algorithm published in 2010 proposed using four variables (age, body weight, complications, and duration of disease) known as “ABCD” to determine glycemic target and choice of pharmacologic therapy.¹⁰ The Global Partnership for Effective Diabetes Management proposed recommendations in 2010 and 2013 based on similar variables including duration of diabetes, presence of complications, and body weight plus additional 6factors such as glycemic control over time, history of CVD, and risk of hypoglycemia.^11,12 These algorithms generally recommended targeting a HbA1c close to normal (6.5–7%), if individuals had newly diagnosed diabetes, were of younger age, and had no complications while less stringent targets, closer to 7.5–8%, were recommended for those with complications, CVD, and at risk of hypoglycemia.^10–12 Similarly, Subramanian and Hirsch devised a scale called “Elements of Diabetes Care Scoring Scale” to calculate a score to ascertain the intensity of glycemic control with the goal HbA1c ranging between ≤6.5 and 8.5%.¹³ Factors used in this scale include life expectancy based on age, duration of diabetes, glycemic control history, comorbidities, vascular complications, hypoglycemia risk, attitude and diabetes knowledge, and psychosocioeconomic issues.¹³

From these publications and consensus statements, healthcare providers can conclude that stringency of glycemic control and choice of pharmacologic medications should be based on the predicted efficacy, patient ability to tolerate and adhere to a regimen, impact on comorbidities, side effects, and cost.

LIFESTYLE INTERVENTION

Lifestyle therapy is an integral part of diabetes management. If a patient is overweight or obese, weight reduction through dietary means and physical activity is recommended, with consideration of medical or surgical intervention, if indicated. The Diabetes Prevention Program (DPP) and Look Ahead studies have shown that a 7% weight loss is effective in reducing incidence (DPP)²⁸ or achieving a partial remission of T2DM (Look AHEAD).^29,30 Guidelines recommend weight loss for those with a body mass index of ≥25–30 kg/m² through in-person, high-intensity sessions focusing on moderate reduction in caloric intake, increase in physical activity, and use of behavioral strategies to improve adherence to lifestyle changes.^31–33

GLUCOSE-LOWERING AGENTS

Despite the importance of lifestyle measures, diet and physical activity are often insufficient to reverse or stop the progression of T2DM and the addition of pharmacological therapy is usually necessary. The choice of glucose-lowering agents is based on a patient-centered approach, taking into account: (1) Comorbidities of ASCVD, HF, or CKD, (2) Risk of hypoglycemia, (3) Effect on body weight, (4) Side effects, (5) Cost, and (6) Patient preference.^7,9 Prior to the 2019 guidelines, the decision to start pharmacologic therapy was based on factors such as patient motivation and ability to change lifestyle, predicted efficacy 7of diet and exercise, and severity of hyperglycemia; Lifestyle intervention could be tried for 3–6 months if HbA1c was near target (7.5% or below).^5,6 New in the 2019 and 2020 guidelines are general recommendations to avoid treatment inertia and aim for more aggressive and rapid titration of treatment to bring HbA1c to goal. A new change in these guidelines is the recommendation to start metformin at diagnosis of diabetes unless contraindications are present, along with lifestyle intervention.^7,9 Evaluation of glycemic status should occur every 3 months with intensification of treatment until HbA1c goal is reached, with choice of treatment being based on the above patient-centered approach.^7,27 The available treatment options, both oral and injectable, target insulin resistance, insulin deficiency, accelerated lipolysis, incretin deficiency, excess glucagon production, increased glucose reabsorption in the kidneys, and increased appetite. This section will provide an overview of the available noninsulin agents for treatment of T2DM and their individual benefits and drawbacks.

Metformin is recommended as initial pharmacologic treatment in T2DM unless contraindications exist. In addition to its ability to lower HbA1c by 1–2% and FPG by 60–70 mg/dL, metformin has the advantages of no hypoglycemia when used as monotherapy, no weight gain and possible modest weight loss, and availability as a generic agent, providing a cost advantage. Metformin reduces the risk of diabetes-related endpoints in overweight patients with T2DM and should always be considered for use in these patients if not contraindicated.²¹ The main adverse effect is dose-related gastrointestinal symptoms leading to discontinuation of the medication in 5–10% of patients.³⁴ Contraindications to its use include conditions that predispose to hypoxemia and lactic acidosis.³⁴ Renal impairment is also a contraindication, although the Food and Drug Administration (FDA) recently revised warnings to allow continued use of metformin in mild-to-moderate renal impairment estimated glomerular filtration rate (eGFR) 30–45 mL/min/1.73 m² if the benefits outweigh the risks.³⁵

The insulin secretagogues include sulfonylureas and meglitinides. Sulfonylureas, the oldest class of oral agents, were considered second-line after metformin until the introduction of new agents with alternate mechanisms of action. Their advantages include affordability as generics, efficacy (HbA1c lowering of 1–2%), and proven ability to reduce microvascular complications in T2DM.¹⁹ The cardiovascular effects of the sulfonylurea agents are uncertain. The follow-up study of UKPDS provided evidence of cardiovascular risk reduction,²² but increased cardiovascular mortality was found to be associated with tolbutamide in the University Group Diabetes Program study.³⁶ The major disadvantages of the sulfonylureas are the well-known side effects of hypoglycemia 8and weight gain. Meglitinides are shorter-acting insulin secretagogues administered three times daily before meals. Risk of hypoglycemia is lower due to their short half-life and HbA1c lowering varies from 0.1 to 2%.³⁷ Due to weight gain and hypoglycemia, the insulin secretagogues are generally not recommended as a second-line or third-line agent unless cost is an issue.⁹

Thiazolidinediones are insulin sensitizers that act as selective agonists for peroxisome proliferator-activated receptor-γ, a superfamily of nuclear receptors that function as ligand-activated transcription factors.³⁸ Rosiglitazone and pioglitazone are the two TZDs currently approved for use. Benefits include lowering of HbA1c by 1–1.5% and no hypoglycemia as monotherapy. Pioglitazone has been associated with reduction in cardiovascular events, beneficial effects on lipid parameters, and improvements in metabolic and histologic parameters in nonalcoholic steatohepatitis.^39,40 Despite these benefits, TZDs have fallen out of favor for multiple reasons: (1) Side effects of weight gain, (2) Edema, (3) Concerns about HF,⁴¹ (4) Association of rosiglitazone with cardiac events⁴² leading to a temporary restriction on its use, (5) Association with bone fractures,^43,44 and (6) Concerns about increased bladder cancer risk with pioglitazone^45–48 leading to an FDA drug safety communication.⁴⁹ TZDs can be a second- or third-line agent if cost or minimizing hypoglycemia is an issue.⁹

Incretin-based agents are an important part of our current armamentarium for the management of T2DM. GLP-1 is a gut-derived hormone released from the L cells of the ileum and colon when nutrients, namely carbohydrates, enter the gut. GLP-1 stimulates glucose-dependent pancreatic insulin secretion, suppresses postprandial glucagon secretion, slows gastric emptying, increases satiety, and potentially stimulates insulin gene transcription and β cell growth.⁵⁰ In T2DM or impaired glucose tolerance, levels of meal-stimulated GLP-1 are significantly reduced⁵¹ with the extent of change in GLP-1 secretion being inversely correlated with the degree of insulin resistance.⁵² Most are given as injections and include exenatide twice daily, two drugs that are given once daily (liraglutide and lixisenatide), and several once weekly formulations (long-acting exenatide, dulaglutide, and semaglutide). An oral version of semaglutide taken once daily was just approved in 2019. Benefits include HbA1c lowering of 1–2% without significant hypoglycemia and weight loss of 1.5–4 kg over 24–52 weeks.⁵³ The most important and exciting news regarding this group of medications are the recent trial data demonstrating reduction in cardiovascular risk and nephropathy with liraglutide,^54,55 injectable semaglutide,⁵⁶ and dulaglutide.^57,58 Albiglutide was also shown to decrease major adverse cardiovascular events but has been off the market since 2017.⁵⁹ Due to the impressive 9and significant findings of 13% decrease in major adverse cardiovascular events (MACE), 22% decrease in death from cardiovascular causes, 12% decrease in nonfatal myocardial infarction, and 15% decrease in death from any cause in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial, liraglutide was FDA approved in 2017 for use to reduce risk of MACE in adults with T2DM and established CVD.⁵⁴ Injectable semaglutide and dulaglutide were approved by the FDA in 2020 for reduction in the risk of MACE in adults with T2DM and established CVD based on the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) trials, respectively.^56,57 The main drawbacks are the concerns about potential risk of pancreatitis and pancreatic cancer,^60,61 C cell hyperplasia and tumors,⁶² and gastrointestinal side effects of nausea and vomiting. Semaglutide was also found to be associated with a higher rate of retinopathy complications (HR 1.76), but this does not seem to be a class effect.⁵⁶

An alternate method of increasing GLP-1 is inhibition of dipeptidyl peptidase-4 (DPP-4), the enzyme that breaks GLP-1 down. Four DPP-4 inhibitors are approved for use in the United States: Sitagliptin, saxagliptin, linagliptin, and alogliptin. Compared to GLP-1 receptor agonists, this class of medications has modest glycemic efficacy with ability to lower HbA1c by 0.5–1%, is weight neutral, and does not produce nausea.⁶³ Pancreatitis has also been reported with use of DPP-4 inhibitors.⁶⁴ In 2015, the FDA also issued a warning regarding severe joint pain with this class of drugs.⁶⁵ In terms of cardiovascular risk, this class does not have the impressive findings of the GLP-1 receptors agents, but trials showed no increased risk of cardiovascular events or HF with any of these drugs,^66–69 except saxagliptin which was associated with a higher rate of hospitalization for HF compared to placebo.⁶⁶

Sodium-glucose cotransporter type-2 inhibitors, the newest class of glucose-lowering drugs, have a unique mechanism of action that is completely independent of insulin secretion or action. They block renal reabsorption of glucose via SGLT-2 in the proximal convoluted tubule of the kidney.⁷⁰ Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are the four available drugs in this class. Their benefits include low risk of hypoglycemia, weight loss of 2–3 kg, and blood pressure lowering effects.⁷¹ This class has also been found to have impressive cardiovascular and renal benefits in major trials [EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose), CANVAS (Canagliflozin Cardiovascular Assessment Study), CREDENCE (Canagliflozin and Renal Events in Diabetes with Established 10Nephropathy Clinical Evaluation), and DECLARE-TIMI (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction)].^72–79 Empagliflozin lowered risk of the primary composite cardiovascular outcome driven by a significant reduction in death from cardiovascular causes, hospitalization for HF, and all-cause mortality leading to a 2016 FDA approval for empagliflozin's use for reduction in risk of cardiovascular death in adults with T2DM with established CVD.⁷² Canagliflozin similarly reduced the rate of the primary composite cardiovascular outcome⁷⁴ and demonstrated beneficial renal outcomes⁷⁵ resulting in a 2018 and 2019 label revision indicating FDA approval for: (1) Reduction in risk of MACE in adults with T2DM and established CVD and (2) Reduction in risk of adverse renal outcomes and hospitalization for HF in adults with T2DM and diabetic nephropathy. Dapagliflozin's beneficial effects on HF led to a label update in 2019 to include use for reduction in the risk of hospitalization from HF in those with T2DM.⁷⁶ Based on the results of a new study, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), in 2020, dapagliflozin became the first diabetes medicine approved as a new treatment for HF in those with reduced ejection fraction (with or without diabetes).⁷⁹ The main adverse effect is an increase in genital mycotic infections.⁸⁰ Volume depletion and hypotension due to the diuretic effect of the drug can occur but is uncommon, as is acute renal failure.⁸⁰ Occurrence of euglycemic diabetic ketoacidosis,⁸¹ an increase in bone fractures⁸² and leg/foot amputations with canagliflozin,⁷⁴ and Fournier's gangrene⁸³ have been reported.

Alpha-glucosidase inhibitors are oral agents that slow intestinal carbohydrate absorption through inhibition of intestinal alpha-glucosidase and therefore the conversion into monosaccharides.⁸⁴ Available agents in the United States include acarbose and miglitol; voglibose is available in Japan. These agents are especially popular in Asian countries, likely due to consumption of a diet high in carbohydrates, and found to be particularly effective for reducing postprandial glucose levels.⁸⁵ A landmark study, STOP-NIDDM, also found that acarbose resulted in a significant reversal of impaired glucose tolerance back to normal glucose tolerance and reduction in cardiovascular events (HR 0.51, p = 0.03) compared to placebo.⁸⁶ Their lack of popularity in the United States is likely related to the common adverse effects of flatulence and diarrhea.⁸⁵

Two medications used for other conditions, colesevelam and bromocriptine, became approved for use for treatment of T2DM in 2008 and 2009, respectively, but are rarely prescribed for this purpose. Colesevelam, a bile acid sequestrant used for low-density lipoprotein cholesterol (LDL-C) lowering, has a poorly understood mechanism of action with regards to glucose lowering.⁸⁷ It is rarely prescribed for diabetes and 11also infrequently used for cholesterol lowering due to its gastrointestinal side effects and the existence of more efficacious and better tolerated alternative medications. Bromocriptine is a dopamine agonist that is available as a time-release formulation for treatment of T2DM. Its mechanism of action is felt to be reduction in sympathetic nervous system activity, hepatic glucose production, and lipolysis resulting in improved glucose tolerance and insulin sensitivity.⁸⁸

A discussion of the different types of insulin is beyond the scope of this chapter, but differences among insulins with regards to cost, risk of hypoglycemia, and weight gain are discussed below in conjunction with Table 1.1.

TABLE 1.1 Recommendations for specific clinical scenarios.

Clinical scenario	Recommendations
Overweight/obesity	Preferred noninsulin medications: Metformin GLP-1 receptor agonist SGLT-2 inhibitor DPP-4 inhibitor Avoid: Insulin secretagogues Thiazolidinediones Insulin: Detemir has lower weight gain than glargine or NPH⁹⁰
Increased risk of hypoglycemia	Preferred noninsulin medications: Metformin GLP-1 Receptor Agonist SGLT-2 inhibitor DPP-4 inhibitor Thiazolidinediones Avoid: Insulin secretagogues Insulin: Detemir⁹² and degludec⁹³ have lower incidence of hypoglycemia
Renal insufficiency	Preferred noninsulin medications: SGLT-2 inhibitors if eGFR >45 mL/min/1.73 m² GLP-1 receptor agonists if eGFR >30 mL/min/1.73 m² DPP-4 inhibitors: safe at any eGFR; dose adjustment required except for linagliptin Avoid: Insulin secretagogues Metformin if eGFR <30 mL/min; dose reduction if eGFR <45 mL/min Insulin: Careful titration due to slower elimination
Coronary artery disease	Preferred noninsulin medications: GLP-1 receptor agonist SGLT-2 inhibitor Avoid: Insulin secretagogues Insulin: Careful titration to avoid hypoglycemia-HbA1c goal <7%12
Heart failure	Preferred noninsulin medications: SGLT-2 inhibitor GLP-1 receptor agonist Avoid: Thiazolidinediones Saxagliptin Insulin: Careful titration to avoid hypoglycemia-HbA1c goal <7%
Difficulty complying with injections	If injections needed: Once weekly GLP-1 receptor agonist If insulin needed: Once daily basal insulin with oral agents or GLP-1 receptor agonist or Twice daily premixed insulin or U500 insulin (if severe insulin resistance)
Lack of insurance or financial limitations	Preferred noninsulin medications: Generic medications: Metformin or sulfonylureas or pioglitazone Avoid: Brand name medications unless copay card available and patient has commercial insurance If insulin needed: Vials less expensive than pens NPH insulin Regular insulin
(DPP-4: dipeptidyl peptidase-4; eGFR: estimated glomerular filtration rate; GLP-1: glucagon-like peptide-1; HbA1c: glycated hemoglobin; NPH: neutral protamine Hagedorn; SGLT-2: sodium-glucose cotransporter-2)

INDIVIDUALIZING DRUG CHOICES

A patient-centered approach considers: (1) Patient behavioral and psychological variables, (2) Patient health status and comorbidities, and (3) Characteristics of the pharmacotherapy (see Box 1.1).

Specific medications are recommended for certain clinical scenarios as detailed in Table 1.1.

The overweight or obese patient with T2DM is commonly encountered in practice. Excess body weight is an established risk factor for T2DM and is often present at diagnosis. Unfortunately, however, these patients are often prescribed glucose-lowering medications associated with weight gain, leading to further increase in weight, worsening insulin resistance, and need for intensification of treatment. Sulfonylureas and TZDs are associated with a 3–5 kg increase in weight. Insulin has an even greater negative effect on weight, causing an average 7 kg gain in weight over 10 years in UKPDS.¹⁹ With regards to type of insulin regimen, a meta-analysis and systematic review showed that increase in body weight was lower with basal insulin than with a twice-daily insulin regimen or a prandial insulin regimen, although higher insulin doses in the latter two regimens may explain the differences.⁸⁹ Weight gain was also found to be lower with use of detemir versus neutral protamine Hagedorn (NPH) or glargine as basal insulin; no difference was found in weight gain with NPH compared to glargine.^89,9013

BOX 1.1 : Patient behavioral/psychological variables, patient health status and comorbidities, and pharmacotherapy characteristics affecting choice of glucose-lowering therapy.

Patient behavioral and psychological variables:

Motivation
Level of treatment intensity that is acceptable to the patient
Acceptance of and ability to use injections
Treatment history, response, and tolerance to past medications
Support system
Food preferences
Cultural preferences
Level of physical activity
Socioeconomic status
Memory and cognition

Patient health status and comorbidities:

Age
Life expectancy
Disease duration
Severity of hyperglycemia
Presence of overweight/obesity
Tendency toward hypoglycemia/hypoglycemia unawareness
Macrovascular disease:
- ASCVD
- HF
- Stroke
- Peripheral vascular disease
Renal impairment
Liver dysfunction
Microvascular complications

Pharmacotherapy characteristics:

Efficacy
Risk of hypoglycemia
Effect on weight
Side effects/tolerability
Contraindications
Effect on cardiac outcomes (ASCVD, HF)
Effect on renal outcomes
Drug elimination and clearance
Cost/insurance coverage
Oral vs. injectable
Frequency of dosing

(ASCVD: atherosclerotic cardiovascular disease; HF: heart failure)

14Ultra-long acting basal insulin degludec also does not appear to have any advantage over insulin glargine with regards to limiting weight gain.⁹¹ Choosing medications that are weight neutral or associated with weight loss as initial and subsequent treatment for T2DM in overweight and obese individuals is essential and in accordance with the ADA standards of medical care,³³ the ADA/EASD position statement on hyperglycemia management in T2DM,⁷ and the Endocrine Society guidelines on pharmacological management of obesity.³² The recommended glucose-lowering agents in individuals with T2DM and obesity are metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors for the dual benefit of weight loss and improved glycemic control. Most available evidence points to GLP-1 receptor agonists as being associated with the greatest degree of weight loss.⁹

For patients prone to hypoglycemia, with hypoglycemia unawareness, and at increased risk of adverse outcomes from hypoglycemia, medications with a noninsulin-dependent mechanism of action should be chosen. These medications include SGLT-2 inhibitors, GLP-1 receptor agonists, metformin, or DPP-4 inhibitors.⁹ If insulin is needed, insulin detemir and degludec have lower incidence of hypoglycemia compared to glargine or NPH.^92,93

For patients with CKD or nephropathy, GLP-1 receptor agonists and SGLT-2 inhibitors are recommended and can be used in mild-to-moderate renal impairment. GLP-1 receptor agonists (liraglutide, semaglutide, and dulaglutide) were found to decrease new or worsening diabetic nephropathy.^55,56,58 SGLT-2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) demonstrated benefit in reducing a renal composite outcome (worsening eGFR, doubling serum creatinine, initiation of renal replacement, and death from renal cause); canagliflozin is approved by the FDA for this indication based on the CREDENCE trial.^73,75,77 Dose adjustment of the GLP-1 receptor agonists, liraglutide, dulaglutide, and semaglutide, is not recommended in renal impairment, but experience of these agents in end-stage renal disease is limited.^94–96 The GLP-1 receptor agonist, liraglutide, has been studied in a small number of patients with severe renal impairment at baseline and not found to have any differences in safety or efficacy compared to patients with normal renal function.⁵⁵ Exenatide is not recommended for eGFR below 45 mL/min/1.73 m² or end-stage renal disease.⁹⁷ No dose adjustment of lixisenatide is required for mild-to-moderate renal impairment, but its use is not recommended with eGFR below 15 mL/min/1.73 m².⁹⁸ SGLT-2 inhibitors have been found to be effective with eGFR 30–45 mL/min/1.73 m²,⁷⁵ but currently are recommended for use in patients with eGFR >45–60 mL/min/1.73 m². Reports of acute kidney injury with SGLT-2 inhibitor use requiring 15hospitalization or dialysis have also been reported to the FDA, so caution should be exercised and renal function monitored when using in renal insufficiency.⁹⁹ The only noninsulin glucose-lowering agents that can be used at any eGFR including end-stage renal disease are the DPP-4 inhibitors. Dose is adjusted based on the eGFR, except for linagliptin which does not require dose adjustment.⁶³ Metformin can now be used in CKD; It is approved for initiation if eGFR is above 45 mL/min/1.73 m², can be continued with assessment of the risks if eGFR falls below 45 mL/min/1.73 m², and should be stopped if eGFR falls below 30 mL/min/1.73 m².³⁵

For patients with CVD, the GLP-1 receptor agonists (liraglutide, semaglutide, and dulaglutide) and SGLT-2 inhibitors (empagliflozin and canagliflozin) decreased risk of MACE and are recommended based on available evidence.^{54,56,57,72,74} Empagliflozin and dapagliflozin also significantly reduced risk of hospitalization for HF and should be considered in patients with this condition; dapagliflozin is specifically FDA approved for this indication.^72,79 Sulfonylureas have long been felt to have an uncertain impact and potential negative effect on cardiovascular outcomes based on the UGDP study with tolbutamide and therefore avoided in patients with cardiac disease;³⁶ however, second- and third-generation sulfonylureas have not been found to be associated with increased risk for death, myocardial infarction, or stroke.^100,101 Thiazolidinediones⁴¹ and the DPP-4 inhibitor saxagliptin⁶⁶ should be avoided in HF.

For patients with problems with compliance with multiple daily injections or fear of injections, if injectable agents are indicated, several options with fewer injections are available. Once weekly GLP-1 receptor agonists can be used. If insulin is needed, once daily basal insulin can be combined with a GLP-1 receptor agonist or twice daily insulin regimens can be considered using premixed insulin or U500 insulin for those who are very insulin resistant.

Physicians are often limited in their prescribing by lack of insurance coverage or high copays for brand name medications. In these cases, the oral agents available as generics are metformin, the sulfonylureas, or pioglitazone. The least expensive insulins are NPH insulin and regular insulin.

CONCLUSION

With regards to diabetes management, one size does not fit all. A patient-centered approach is the optimal way to best determine glycemic targets and the appropriate glucose-lowering regimen. The unique characteristics of each patient and each medication need to be taken into consideration when devising the ideal treatment regimen.16

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Chapter Notes

Management of Type 2 Diabetes Mellitus: A Patient-centered ApproachCHAPTER 1

BOX 1.1 : Patient behavioral/psychological variables, patient health status and comorbidities, and pharmacotherapy characteristics affecting choice of glucose-lowering therapy.