Comanagement of Obesity-Related Comorbidities: Assessment, Treatment, and Monitoring

Sharon J. Herring

Keerthana Kesavarapu

Jessica Briscoe

CASE STUDY 1

Janice is a 54-year-old woman with a history of class 2 obesity (body mass index [BMI] 37 kg/m²), prediabetes, and nonalcoholic fatty liver disease (NAFLD) who presents to her primary care office for annual follow-up. She is concerned about developing type 2 diabetes (T2D) and cirrhosis and wants to learn more about how she can prevent complications from her higher body weight. She reports a diet high in simple carbohydrates and saturated fat. Her physical examination is unremarkable except for an elevated blood pressure reading of 165/95 mm Hg and darkening of the skin around her neck and in her axillae. HBA1C is 6.0%.

OVERVIEW

Nearly every organ system is affected by obesity. Cardiovascular disease (CVD) and its risk factors (diabetes, hypertension [HTN], and lipids) are the most commonly treated by primary care providers. Other complications, such as reproductive abnormalities in both men and women, also have huge impacts on health-related quality of life. Obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) are common complications of obesity and are underdiagnosed. NAFLD is increasingly recognized as a common complication of obesity. Additionally, some mental health disorders such as depression and binge eating disorder (BED) have a complex, bidirectional relationship with obesity and need evaluation and treatment. Thus, comprehensive obesity care should include evaluation for these weight-related conditions along with weight management using a combination of lifestyle/behavioral, pharmacologic, and surgical therapies. The degree of weight loss needed to ameliorate these conditions varies. This chapter covers the evaluation, management, and monitoring for each of the major complications of excess weight.

CLINICAL SIGNIFICANCE

Healthcare professionals (HCPs) play a critical role in the assessment and treatment of weight-related comorbidities in patients with obesity. Obesity is a leading risk factor for many of the chronic conditions that remain the leading causes of death among US adults.¹ Over 230 comorbidities and complications of obesity have been identified, with nearly every body system affected (Figure 4.1).² The net impact of the increased burden of disease associated with obesity is increased mortality.³ Successful medical management of obesity will result in significant improvements in health outcomes,⁴ and reductions in mortality occur with substantial weight losses from bariatric surgery.⁵

CARDIOVASCULAR COMPLICATIONS OF OBESITY

Hypertension

Assessment

Prevalence

The strong association between obesity and the risk of developing HTN is well documented in both men
and women.⁶ The Framingham Study demonstrated that persons in the highest BMI quintile had a 16 to 17 mm Hg higher systolic blood pressure and an 11 mm Hg higher diastolic blood pressure than persons in the lowest BMI quintile. In this study, a 10-pound weight gain was associated with a 4 mm Hg increase in systolic blood pressure.⁷ Additionally, just over one-quarter of HTN cases were attributable to excess body weight.⁸ Numerous mechanisms for the link between obesity and elevations in blood pressure exist and likely operate simultaneously, including low vascular reactivity, renal injury, hyperinsulinemia and insulin resistance, sleep-disordered breathing, the melanocortin pathway, and genetic susceptibility.⁹

FIGURE 4.1 Obesity and its multiple comorbidities affecting many systems, organs, and tissues.

Screening

According to the 2015 US Preventive Services Task Force Guidelines (USPSTF), annual blood pressure screening for HTN is recommended in adults aged 18 years or older who are overweight or obesity, first using office blood pressure measurements followed by confirmation with ambulatory blood pressure measurements.¹⁰ For accurate in-office measurements, the American College of Cardiology (ACC) and American Heart Association (AHA) stress the use of the correct blood pressure cuff size (cuff bladder should encircle 80% or more of the patient’s arm circumference), particularly in patients with excess adiposity, and no measurements over clothes. HCPs are advised to measure blood pressure in both arms and to use the higher
reading; an average of two to three measurements taken on two to three separate occasions will minimize error and provide a more accurate estimate.¹¹

Definition

In November 2017, the ACC and AHA released clinical practice guidelines for HTN in adults.¹¹ Although the definition of normal blood pressure remained the same as in JNC 7, the 2017 guideline replaced the term “prehypertension” with “elevated” and “stage 1 HTN” (Table 4.1). The upper end of prehypertension was reclassified as stage 1 HTN because adults with blood pressure in this range have an approximately twofold increase in CVD risk compared with adults having normal blood pressure. Randomized clinical trials demonstrated a reduction in CVD events with a systolic blood pressure below 130 mm Hg.¹²

Management

A variety of lifestyle modifications are beneficial in the treatment of HTN, including reduction of sodium intake, moderation of alcohol consumption, weight loss, increased physical activity, smoking cessation, and a diet rich in fruits, vegetables, legumes, and low-fat dairy products and low in snacks, sweets, meat, and saturated fat (Table 4.2).¹¹ Stage 1 HTN is particularly responsive to weight loss, sodium and alcohol restriction, and increased physical activity.¹³ The Dietary Approaches to Stop Hypertension (DASH) trial demonstrated the benefit of this eating plan for HTN (see Chapter 5, Dietary Treatment of Obesity, for additional details of the trial).¹⁴

TABLE 4.1 Criteria for the Diagnosis of HTN^a

NORMAL	LESS THAN 120/80 MM HG
Elevated	Systolic between 120-129 and diastolic less than 80 mm Hg
Stage 1	Systolic between 130-139 or diastolic between 80-89 mm Hg
Stage 2	Systolic at least 140 or diastolic at least 90 mm Hg
Hypertensive Crisis	Systolic over 180 and/or diastolic over 120 mm Hg, with patients needing prompt changes in medication if there are no other indications of problems, or immediate hospitalization if there are signs of acute end organ damage
HTN, hypertension.
^aBased on accurate measurements and average of at least 2 readings on at least 2 occasions.
Adapted from Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248.

Weight loss through caloric reduction is more important than selecting a diet with a specific macronutrient composition for blood pressure lowering. In general, the reduction in blood pressure with weight loss follows a dose-response effect (e.g., greater weight loss produces a greater reduction in blood pressure).¹⁵ Antihypertensive agents are necessary if patients cannot achieve normal blood pressures with lifestyle modification. In general, beta blockers are thought to make weight reduction more difficult and should be considered as second-line agents for blood pressure control.

Coronary Artery Disease/Cerebrovascular Disease

Assessment

Prevalence

Obesity is associated with a number of physiologic and metabolic changes that contribute to increased cardiovascular morbidity and mortality, including insulin resistance and glucose intolerance, systolic and diastolic HTN, hypertriglyceridemia, reduced high-density lipoprotein-cholesterol (HDL-C), and increased systemic inflammation (e.g., C-reactive protein, interleukin-6 and tumor necrosis factor-alpha). There is consistent epidemiologic evidence for an association between obesity and coronary artery disease (CAD), particularly in individuals with increased abdominal adiposity, and significant CAD risk associated with obesity beginning as early as childhood.¹⁶,¹⁷ A publication from the Framingham Heart Study suggested that obesity in middle-aged adults could account for as much as 23% of cases of CAD in men and 15% in women.⁸ Obesity is additionally associated with an increased risk of stroke, and stroke risk is mitigated by weight loss.¹⁸

Screening

Most asymptomatic adults do not need routine screening for CAD/CVD. However, as described in the 2013 American Heart Association/American College of Cardiology/The Obesity Society (AHA/ACC/TOS) Guideline for the Management of Overweight and Obesity in Adults, patients with obesity should undergo risk assessment for cardiovascular risk factors, including lipids, blood pressure measurement, and fasting blood glucose. A waist circumference measurement is recommended for individuals with BMI 25 to 34.9 kg/m² to provide additional information on risk. It is unnecessary to measure waist circumference in patients with BMI ≥35 kg/m² because the waist circumference will likely be elevated and will add no additional risk information. Cut points of (≥88 cm [≥35 inches] for women and ≥102 cm [≥ 40 inches] for men) are indicative of

increased cardiometabolic risk.¹⁹ While there is little evidence to support routine exercise testing in asymptomatic adults, ACC/AHA guidelines suggest that exercise electrocardiogram (ECG) testing may be of benefit in patients with multiple risk factors for CAD in the following situations: as a guide to risk reduction therapy; men ≥45 years of age and women ≥55 years of age who are sedentary and planning to begin a vigorous exercise program; or patients who are involved in occupations linked to public safety.²⁰ If stress testing reveals an abnormal result, referral to a cardiologist and aggressive treatment is needed with secondary prevention measures (e.g., statin therapy, aspirin, tight blood pressure control). The use of computed tomography (CT) to obtain a coronary artery calcium (CAC) score may be useful to further risk stratify and to guide a discussion regarding statin therapy in adults at borderline (5% to < 7.5%) or intermediate (7.5% to < 20%) 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Chapter 3 contains an in-depth discussion of how cardiovascular risk factors can be used to risk stratify patients with obesity.

TABLE 4.2 Lifestyle Modification and Its Effect on Blood Pressure and Treatment of Hypertension

	NONPHARMACOLOGIC INTERVENTION	DOSE	APPROXIMATE IMPACT ON SBP
	NONPHARMACOLOGIC INTERVENTION	DOSE	HYPERTENSIVE	NORMOTENSIVE
Weight loss	Weight/body fat	Ideal body weight is best goal but at least 1 kg reduction in body weight for most adults who are overweight. Expect about 1 mm Hg for every 1 kg reduction in body weight	−5 mm Hg	−2/3 mm Hg
Healthy diet	DASH dietary pattern	Diet rich in fruits, vegetables, whole grains, and low-fat dairy products with reduced content of saturated and trans fat	−11 mm Hg	−3 mm Hg
Reduced intake of dietary sodium	Dietary sodium	<1,500 mg/d is optimal goal but at least 1,000 mg/d reduction in most adults	−5/6 mm Hg	−2/3 mm Hg
Enhanced intake of dietary potassium	Dietary potassium	3,500-5,000 mg/d, preferably by consumption of a diet rich in potassium	−4/5 mm Hg	−2 mm Hg
Physical activity	Aerobic	90-150 minutes/week 65%-75% heart rate reserve	−5/8 mm Hg	−2/4 mm Hg
	Dynamic resistance	90-150 minutes/week 50%-80% 1 rep maximum Six exercises, three sets/exercise, 10 repetitions/set	−4 mm Hg	−2 mm Hg
	Isometric resistance	4 × 2 minutes (hand grip), 1 minute rest between exercises, 30%-40% maximum voluntary contraction, three sessions/week 8-10 weeks	−5 mm Hg	−4 mm Hg
Moderation in alcohol intake	Alcohol consumption	In individuals who drink alcohol, reduce alcohol to Men: ≤2 drinks daily Women: ≤1 drink daily	−4 mm Hg	−3 mm Hg
DASH, Dietary Approaches to Stop Hypertension; SBP, systolic blood pressure.
Modified from Whelton PK, Carey RM, Aronowthe WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248.

Management

In adults who are overweight or have obesity with cardiovascular risk factors (HTN, hyperlipidemia, and hyperglycemia), lifestyle changes that produce even modest, sustained weight losses of 3% to 5% result in clinically meaningful reductions in triglycerides, blood glucose, HBA1C, and the risk of developing T2D. Greater amounts of weight loss will reduce blood pressure, improve low-density lipoprotein-cholesterol (LDL-C) and HDL-C, and reduce the need for medications to control blood pressure, blood glucose, and lipids as well as further reduce triglycerides and blood glucose.¹⁹

Observational studies suggest significant benefits of a Mediterranean diet on reduction in cardiovascular mortality—this diet is typically high in fruits, vegetables, whole grains, beans, nuts, and seeds, includes extra-virgin olive oil as an important source of monounsaturated fat, and allows low to moderate wine consumption. It generally includes low to moderate amounts of fish, poultry, and dairy products, but little red meat. In a meta-analysis of randomized trials, a Mediterranean diet reduced the risk of stroke compared with a low-fat diet (HR 0.60, 95% CI 0.45-0.80) but did not reduce the incidence of cardiovascular or overall mortality.²¹ Data additionally support high-quality plant-based diets that include whole grains as the main form of carbohydrate, unsaturated fats as the predominate form of dietary fat, an abundance of fruit and vegetables, and adequate n−3 fatty acids as important components in preventing CVD.²² Randomized trials support the use of vegetarian diets for weight loss.

Statin therapy may be necessary if 10-year ASCVD risk is ≥7.5%. Lipid-lowering therapy with statins reduces relative cardiovascular risk by approximately 20% to 30% regardless of baseline LDL-C.²³ HCPs can quickly calculate ASCVD risk and need for medication management beyond lifestyle changes using the ASCVD Risk Estimator Plus from the ACC/AHA: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/.

METABOLIC DISORDERS OF OBESITY

Prediabetes/Diabetes Mellitus Type 2

Assessment

Prevalence of Prediabetes and T2D in Populations With Obesity

The prevalence of both diabetes and obesity have continued to rise from 1999/2000 to 2013/2014 using the most recent NHANES data.²⁴ More than 88% of people with T2D have overweight or obesity with 26% of adults being overweight, 44% having obesity, and 18% having severe obesity.²⁵ The risk of T2D rises with increasing body weight, with the prevalence of T2D being three to seven times higher in those with obesity than normal weight adults. Obesity-associated insulin resistance, particularly in patients with visceral adiposity, is the primary mechanism of T2D in populations with obesity.

Symptoms and Physical Examination Findings Associated With Insulin Resistance

Patients may complain of symptoms from hyperglycemia, which include polydipsia, polyuria, polyphagia, fatigue, nausea/vomiting, and abdominal pain, or symptoms from microvascular complications, such as sensory loss (peripheral neuropathy) and vision changes (retinopathy). Physical examination should include a comprehensive foot examination observing for skin integrity, foot deformities, ulcerations, pedal pulses for peripheral arterial disease, and a 10 g monofilament examination for sensation. Skin changes seen in T2D include acanthosis nigricans, which is defined as dark, coarse, and thickened skin commonly located at the back of the neck, and acrochordons (skin tags), defined as small, soft, pedunculated, and benign skin tumors found on the neck, axilla, or groin. These lesions are a sign of insulin resistance and impaired carbohydrate metabolism.²⁶

Screening

Testing for prediabetes and T2D in asymptomatic individuals should be considered in adults of any age who have overweight or obesity (BMI ≥25 kg/m² or ≥23 kg/m² in Asian Americans) and who have one or more additional risk factors for diabetes (Table 4.3). As per the USPSTF, all adults aged 40 to 70 years should be screened at least once for prediabetes and T2D.

TABLE 4.3 Risk factors for Testing for Diabetes or Prediabetes in Asymptomatic Adults

1. First-degree relative with diabetes

2. High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, and Pacific Islander)

3. History of cardiovascular disease

4. Hypertension

5. Dyslipidemia (HDL cholesterol level < 35 mg/dL and/or a triglyceride level >250 mg/dL)

6. Polycystic ovary syndrome

7. Other clinical conditions associated with insulin resistance

Modified from American Diabetes Association. Standards of Medical Care in Diabetes-2019 Abridged for Primary Care Providers. Clin Diabetes. 2019;37(1):11-34.

Definition of Prediabetes and Diabetes

Diabetes and prediabetes may be diagnosed based on plasma glucose, with either fasting plasma glucose (FPG) or 2-hour plasma glucose (2-h PG) value during a 75-g oral glucose tolerance test (OGTT), or using the HBA1C criteria (Table 4.4). Unless there is a clear clinical diagnosis of diabetes in the case of hyperglycemic crisis, classic symptoms of hyperglycemia, or random plasma blood glucose >200 mg/dL, diagnosis requires two abnormal test results.

Management

Prediabetes

The goal of management of prediabetes is prevention or delay in progression to diabetes. The Diabetes Prevention Program (DPP) demonstrated that weight loss achieved through intensive lifestyle modifications can prevent or delay the onset of T2D. In the DPP, the relative incidence of diabetes was reduced by 58% over 3 years in participants randomized to intensive lifestyle intervention.²⁷ The lifestyle intervention arm ran over 1 year. During the first 6 months, patients met weekly for 1 hour to learn about eating healthy, adding physical activity, dealing with stress, coping with challenges, and getting back on track. During the subsequent 6 months, patients focused on sticking to new habits. Follow-up in the Diabetes Prevention Program Outcomes Study has shown a sustained reduction in the rate of developing T2D, by 34% at 10 years and 27% at 15 years.¹⁶

Given these findings, the American Diabetes Association (ADA) recommends referral of patients with prediabetes to an intensive lifestyle intervention program modeled on the DPP, with goals to achieve and maintain 7% loss of body weight and to increase moderate intensity physical activity to at least 150 minutes/week. The Center for Medicare and Medicaid Services (CMS) covers the DPP with no patient out-of-pocket cost, if patients meet the criteria and if the HCP uses ICD-10 diagnosis codes for prediabetes or abnormal blood glucose without diabetes. These programs are readily available in the community (e.g., YMCA).

TABLE 4.4 Criteria for Diagnosing Prediabetes and Diabetes

	PREDIABETES	DIABETES
HBA1C^c	5.7%-6.4%^a	≥6.5%
FPGc	100-125 mg/dL (5.6-6.9 mmol/L)^a	≥126 mg/dL (7.0 mmol/L)
OGTT^c	150-199 mg/dL (7.8-11.0 mmol/L)^a	≥200 mg/dL (11.1 mmol/L)
RPG^b		≥200 mg/dL (11.1 mmol/L)
Modified from American Diabetes Association. Standards of Medical Care in Diabetes-2019 Abridged for Primary Care Providers. Clin Diabetes. 2019;37(1):11-34.FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; RPG, random plasma glucose.
^aFor all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater that the higher end of the range. ^bOnly diagnostic in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. ^cTest requires two abnormal test results prior to establishing diagnosis of diabetes.

Based on intervention trials, eating patterns that may be helpful for prediabetes include a Mediterranean eating plan and/or a low-calorie, low-fat eating plan, as was employed in the DPP.²⁸ For diabetes prevention, the emphasis should be on whole grains, legumes, nuts, fruits, and vegetables and minimal refined and processed foods.²⁹ Red meats and sugar-sweetened beverages are associated with an increased risk of T2D.²⁹

Physical activity, as modeled in the DPP, should be encouraged with at least 150 minutes/week of moderate-intensity activities, such as brisk walking and resistance training.²⁷,³⁰ This allows for improvement in insulin sensitivity.³⁰ These findings also extend to prevention of gestational diabetes mellitus.³¹

Lifestyle intervention may be supplemented with pharmacotherapy. Metformin for prevention of diabetes mellitus type 2 (DM2) should be considered in those with prediabetes who are at high risk for progression, especially those with BMI ≥35 kg/m², those aged <60 years, and women with prior gestational diabetes (ADA recommendations). In the DPP, participants randomized to metformin had a 31% relative reduction in incidence of T2D vs. control. Long-term use of metformin may be associated with vitamin B12 deficiency, and annual measurement should be performed.

Diabetes

The goal of managing diabetes is to achieve glycemic control and prevent and/or reduce progression of microvascular and macrovascular complications. The Look AHEAD trial, a 12-year multicenter randomized trial of patients with T2D, found that meaningful weight loss (≥5%) achieved with lifestyle intervention led to improved glycemic control and a decrease in antihyperglycemic medications use.³²

Nutrition therapy plays an integral role in the treatment of T2D and should be done in collaboration with a registered dietitian nutritionist (RDN). Dietary plans created and delivered by an RDN are associated with improvements in glycemic control with HBA1C decreases of 0.3% to 2% in those with DM2.³³

There is no ideal percentage of macronutrient distribution (fat, carbohydrate, and protein) that is suited for all people with obesity and T2D. Meal plans should be individualized, keeping total calorie count low. Studies of reduced calorie interventions show reductions in HBA1C of 0.3% to 2.0% in adults with T2D, as well as reductions in medication doses and improvement in quality of life.³⁴

Carbohydrate Restriction

Data examining the ideal amount of carbohydrate intake is inconclusive. Monitoring carbohydrate intake and the resulting blood glucose response is key to improving postprandial glucose control, regardless of weight loss. The quality of carbohydrates consumed also is important. Specifically, carbohydrate foods with a high glycemic index (rate of breakdown and absorption) lead to higher postprandial blood glucose, compared to carbohydrate foods with lower glycemic index.

The role of low-carbohydrate diets (<130 g/day, compared to 150 to 175 g for a macronutrient balanced but calorie-restricted eating plan) in T2D remains unclear. Some studies show that lowering glycemic load (i.e., reducing both the glycemic index of carbohydrates consumed, as well as overall carbohydrate intake) lowers HBA1C by 0.2% to 0.5%.³⁵ Studies longer than 12 weeks report no significant influence of glycemic index on HBA1C independent of weight loss. Very-low-carbohydrate or ketogenic diets (<50 g/day) have shown similar weight loss after 1 year, as compared with more balanced eating plans.

Fat Restriction

The ideal total dietary fat content for people with obesity and T2D is inconclusive. The types of fat as well as the quantity of fats appear to play an important role in achieving metabolic goals. As described above, eating a Mediterranean-style diet rich in monounsaturated and polyunsaturated fats and avoiding saturated fats can improve glucose metabolism and lower CVD risk.

Physical Activity

Similar to prediabetes, 150 minutes or more of moderate- to vigorous-intensity aerobic activity, spread over at least 3 days/week, with two sessions per week of resistance training on nonconsecutive days, is recommended by the ADA. Shorter durations of vigorous intensity or interval training may be sufficient for younger and more physically fit individuals. Data suggest that the additive benefit of aerobic and resistance exercise improves insulin sensitivity and lowers HBA1C by 0.66% even without a change in BMI.³⁶ More recent research has focused on improving glucose control by interrupting prolonged sitting (sedentary time) with short bouts of physical activity.

Because of the progressive nature of T2D, lifestyle changes may not be enough over time to maintain euglycemia. Many patients with T2D will require pharmacotherapy. Currently there are 10 approved classes of agents for diabetes management (Table 4.5). A patient-centered approach should be taken to guide use of pharmacologic agents considering comorbidities, risk of hypoglycemia, cost/health plan formularies, and side effects.

When considering glucose-lowering agents for patients with obesity and with T2D, medications promoting weight loss or that are weight neutral should ideally be chosen immediately after metformin (Table 4.5). Agents with weight loss effects include biguanides, SGLT2 inhibitors, and GLP-1 agonists. Metformin is the preferred initial pharmacologic agent.³⁷ Once initiated at 500 mg once daily, metformin should be titrated to maximum tolerated dose (assuming normal renal function). Patients with T2D and coexisting chronic kidney disease (CKD) or CAD should be initiated on SGLT2 inhibitors or GLP-1 receptor agonists, as these classes of medications have been shown to decrease the risk of progression of CKD and/or CVD. Insulin should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when HBA1C (≥10%) or blood glucose levels (>300) are very high. Combination drug therapy should be considered in those newly diagnosed with diabetes who have an HBA1C >1.5% above target.

Monitoring

If results of diabetes screening tests are normal, repeat testing is recommended at a minimum of 3-year intervals. If patients have results near the margins of diagnostic threshold, the HCP should follow the patient closely and repeat the assay in 3 to 6 months. Patients with diabetes on medications should be reevaluated at regular intervals (3 to 6 months), with dose adjustments based on HBA1C findings. Patients with prediabetes should be tested yearly for development of diabetes. Women who are diagnosed with gestational diabetes mellitus (GDM) should have lifelong testing at least every 3 years.

TABLE 4.5 Drug-specific and Patient Factors to Consider When Selecting Antihyperglycemic Treatment in Adults With DM2

	HYPOGLYCEMIA	EFFECT ON WEIGHT	CARDIOVASCULAR EFFECTS		ORAL/SQ	RENAL EFFECTS	OTHER
			ASCVD	CHF		PROGRESSION OF CKD
Biguanide: Metformin	No	Modest weight loss	Potential benefit	Neutral	Oral	Neutral	Gastrointestinal side effects B12 deficiency
SGLT-2 inhibitors: Canagliflozin Empagliflozin Dapagliflozin Ertugliflozin	No	Loss	Benefit	Benefit	Oral	Benefit	FDA black box: Risk of amputation (canagliflozin)
GLP-1 agonists: Liraglutide Semaglutide Exenatide ER Dulaglutide	No	Loss	based on agent	Neutral	SQ	Benefit	FDA black box: thyroid C-cell tumors. GI side effects
DPP-4 inhibitors: Saxagliptin Alogliptin Sitagliptin Linagliptin	No	Neutral	Neutral	Risk	Oral	Neutral	Risk of acute pancreatitis
Thiazolidinediones: Pioglitazone	No	Gain	Benefit	Risk	Oral	Neutral	FDA black box: CHF
Sulfonylureas: Glyburide Glipizide Glimepiride	Yes	Gain	Neutral	Neutral	SQ	Neutral	Injection site reactions
Insulin	Yes	Gain	Neutral	Neutral	SQ	Neutral	Higher risk of hypoglycemia with human insulin vs. analogs
ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; CKD, chronic kidney disease; DM2, diabetes mellitus type 2; ER, extended release; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; SQ, subcutaneous.Modified from American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(suppl 1):S90-S102.