Glycemic Targets and Prevention of Complications

CKM staging (Source: American Heart Association, Inc (45))

Stages	Definition
Stage 0 No risk factors	Normal BMI, waist circumference, normoglycemia, normotension, normal lipids profile, and no evidence of CKD or subclinical or clinical CVD
Stage 1 Excess and/or dysfunctional adiposity	Overweight/obesity, abdominal obesity, or dysfunctional adipose tissue WITHOUT metabolic risk factors or CKD BMI ≥25 kg/m² (≥23 kg/m² if Asian ancestry) Waist circumference ≥88/102 cm in women/men (80/90 cm in women/men of if Asian ancestry) Fasting glucose ≥100-124 mg/dL or HbA1c between 5.7% and 6.4%
Stage 2 Metabolic risk factors and CKD	Metabolic risk factors Hypertriglyceridemia (≥135 mg/dL) Hypertension Metabolic syndrome^a Type 2 diabetes mellitus CKD
Stage 3 Subclinical CVD in CKM	Subclinical ASCVD or subclinical HF among individuals with excess/dysfunctional adiposity, other metabolic risk factors, or CKD Subclinical ASCVD: primarily diagnosed by coronary artery calcification (subclinical atherosclerosis by coronary catheterization/CT angiography also meets criteria) Subclinical HF: diagnosed by elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL, hs-troponin ≥14 ng/L for women and ≥22 ng/L for men) or by echocardiographic parameters, with a combination of the 2 indicating highest HF risk Risk equivalents of subclinical CVD Very high-risk CKD (stage G4 or G5 CKD or very high risk per KDIGO classification) High predicted 10-year CVD risk
Stage 4 Clinical CVD in CKM Stage 4a: no kidney failure Stage 4b: kidney failure present	Clinical CVD (coronary heart disease, HF, stroke, peripheral artery disease, atrial fibrillation) among individuals with excess/dysfunctional adiposity, other CKM risk factors, or CKD

Stages	Definition
Stage 0 No risk factors	Normal BMI, waist circumference, normoglycemia, normotension, normal lipids profile, and no evidence of CKD or subclinical or clinical CVD
Stage 1 Excess and/or dysfunctional adiposity	Overweight/obesity, abdominal obesity, or dysfunctional adipose tissue WITHOUT metabolic risk factors or CKD BMI ≥25 kg/m² (≥23 kg/m² if Asian ancestry) Waist circumference ≥88/102 cm in women/men (80/90 cm in women/men of if Asian ancestry) Fasting glucose ≥100-124 mg/dL or HbA1c between 5.7% and 6.4%
Stage 2 Metabolic risk factors and CKD	Metabolic risk factors Hypertriglyceridemia (≥135 mg/dL) Hypertension Metabolic syndrome^a Type 2 diabetes mellitus CKD
Stage 3 Subclinical CVD in CKM	Subclinical ASCVD or subclinical HF among individuals with excess/dysfunctional adiposity, other metabolic risk factors, or CKD Subclinical ASCVD: primarily diagnosed by coronary artery calcification (subclinical atherosclerosis by coronary catheterization/CT angiography also meets criteria) Subclinical HF: diagnosed by elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL, hs-troponin ≥14 ng/L for women and ≥22 ng/L for men) or by echocardiographic parameters, with a combination of the 2 indicating highest HF risk Risk equivalents of subclinical CVD Very high-risk CKD (stage G4 or G5 CKD or very high risk per KDIGO classification) High predicted 10-year CVD risk
Stage 4 Clinical CVD in CKM Stage 4a: no kidney failure Stage 4b: kidney failure present	Clinical CVD (coronary heart disease, HF, stroke, peripheral artery disease, atrial fibrillation) among individuals with excess/dysfunctional adiposity, other CKM risk factors, or CKD

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CKD, chronic kidney disease; CKM, cardiovascular–kidney–metabolic; CT, computed tomography; CVD, cardiovascular disease; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HF, heart failure; hs-troponin, high-sensitivity troponin; KDIGO, Kidney Disease Improving Global Outcomes; MetS, metabolic syndrome.

^aMetabolic syndrome is defined by the presence of 3 of more of the following: waist circumference ≥88/102 cm in women/men (≥80/90 cm in women/men of Asian ancestry), HDL <40 mg/dL for men, <50 mg/dL for women, triglycerides ≥150 mg/dL, elevated blood pressure (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, and/or use of antihypertensive medications), fasting blood glucose ≥100 mg/dL.

Table 1.

CKM staging (Source: American Heart Association, Inc (45))

Stages	Definition
Stage 0 No risk factors	Normal BMI, waist circumference, normoglycemia, normotension, normal lipids profile, and no evidence of CKD or subclinical or clinical CVD
Stage 1 Excess and/or dysfunctional adiposity	Overweight/obesity, abdominal obesity, or dysfunctional adipose tissue WITHOUT metabolic risk factors or CKD BMI ≥25 kg/m² (≥23 kg/m² if Asian ancestry) Waist circumference ≥88/102 cm in women/men (80/90 cm in women/men of if Asian ancestry) Fasting glucose ≥100-124 mg/dL or HbA1c between 5.7% and 6.4%
Stage 2 Metabolic risk factors and CKD	Metabolic risk factors Hypertriglyceridemia (≥135 mg/dL) Hypertension Metabolic syndrome^a Type 2 diabetes mellitus CKD
Stage 3 Subclinical CVD in CKM	Subclinical ASCVD or subclinical HF among individuals with excess/dysfunctional adiposity, other metabolic risk factors, or CKD Subclinical ASCVD: primarily diagnosed by coronary artery calcification (subclinical atherosclerosis by coronary catheterization/CT angiography also meets criteria) Subclinical HF: diagnosed by elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL, hs-troponin ≥14 ng/L for women and ≥22 ng/L for men) or by echocardiographic parameters, with a combination of the 2 indicating highest HF risk Risk equivalents of subclinical CVD Very high-risk CKD (stage G4 or G5 CKD or very high risk per KDIGO classification) High predicted 10-year CVD risk
Stage 4 Clinical CVD in CKM Stage 4a: no kidney failure Stage 4b: kidney failure present	Clinical CVD (coronary heart disease, HF, stroke, peripheral artery disease, atrial fibrillation) among individuals with excess/dysfunctional adiposity, other CKM risk factors, or CKD

Stages	Definition
Stage 0 No risk factors	Normal BMI, waist circumference, normoglycemia, normotension, normal lipids profile, and no evidence of CKD or subclinical or clinical CVD
Stage 1 Excess and/or dysfunctional adiposity	Overweight/obesity, abdominal obesity, or dysfunctional adipose tissue WITHOUT metabolic risk factors or CKD BMI ≥25 kg/m² (≥23 kg/m² if Asian ancestry) Waist circumference ≥88/102 cm in women/men (80/90 cm in women/men of if Asian ancestry) Fasting glucose ≥100-124 mg/dL or HbA1c between 5.7% and 6.4%
Stage 2 Metabolic risk factors and CKD	Metabolic risk factors Hypertriglyceridemia (≥135 mg/dL) Hypertension Metabolic syndrome^a Type 2 diabetes mellitus CKD
Stage 3 Subclinical CVD in CKM	Subclinical ASCVD or subclinical HF among individuals with excess/dysfunctional adiposity, other metabolic risk factors, or CKD Subclinical ASCVD: primarily diagnosed by coronary artery calcification (subclinical atherosclerosis by coronary catheterization/CT angiography also meets criteria) Subclinical HF: diagnosed by elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL, hs-troponin ≥14 ng/L for women and ≥22 ng/L for men) or by echocardiographic parameters, with a combination of the 2 indicating highest HF risk Risk equivalents of subclinical CVD Very high-risk CKD (stage G4 or G5 CKD or very high risk per KDIGO classification) High predicted 10-year CVD risk
Stage 4 Clinical CVD in CKM Stage 4a: no kidney failure Stage 4b: kidney failure present	Clinical CVD (coronary heart disease, HF, stroke, peripheral artery disease, atrial fibrillation) among individuals with excess/dysfunctional adiposity, other CKM risk factors, or CKD

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CKD, chronic kidney disease; CKM, cardiovascular–kidney–metabolic; CT, computed tomography; CVD, cardiovascular disease; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HF, heart failure; hs-troponin, high-sensitivity troponin; KDIGO, Kidney Disease Improving Global Outcomes; MetS, metabolic syndrome.

^aMetabolic syndrome is defined by the presence of 3 of more of the following: waist circumference ≥88/102 cm in women/men (≥80/90 cm in women/men of Asian ancestry), HDL <40 mg/dL for men, <50 mg/dL for women, triglycerides ≥150 mg/dL, elevated blood pressure (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, and/or use of antihypertensive medications), fasting blood glucose ≥100 mg/dL.

Management

The AHA proposes a multidisciplinary approach based on the stage of CKM (45). Stage 0 is primarily preventive measures such as the promotion of healthy life styles to prevent the development of metabolic risk factors. Stage 1 focuses on weight loss with counseling, comprehensive lifestyle interventions, incretin analogues (ie, GLP-1 RAs and GLP-1/GIP dual agonists), and/or bariatric surgery. Management of stages 2 to 4 include goals for treatment for each component of the metabolic risk factors (diabetes, hypertension, hyperlipidemia, CKD), subclinical atherosclerotic cardiovascular disease (ASCVD)/HF, and clinical ASCVD. The AHA emphasizes the need for interdisciplinary care with targeted referrals to subspecialists (45).

Those with type 2 diabetes are at stage 2 CKM or beyond. The main focus of management at stage 2 is to prevent the progression to subclinical and clinical CVD. Achieving glycemic targets (HbA1c < 7% for nonpregnant adults) is a crucial component of optimizing cardiovascular risk reduction along with obesity, hypertension, and hyperlipidemia management. If HbA1c ≥ 7.5%, metformin plus GLP-1 RAs or SGLT2is is advised, but GLP-1 RAs should be prioritized in individuals with HbA1c ≥ 9%, high insulin requirements, or body mass index ≥35 kg/m². An SGLT2i is prioritized in individuals with CKD and subclinical/overt HF (45).

In subclinical CVD, a coronary artery calcification score greater than 0 with intermediate risk for CVD, statin therapy is favored. If coronary artery calcification score is >100, aspirin is recommended if bleeding risk is low along with consideration of other ASCVD risk-reducing agents. In subclinical HF, SGLT2is are recommended for patients with diabetes. In stage 4 CKM, it is recommended that patients with CVD and diabetes are treated with a GLP-1 RAs which can reduce major adverse cardiovascular events (liraglutide, dulaglutide, and semaglutide) (39-41) and/or SGLT2is which can reduce hospitalizations for HF (dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin) (46-49). Specific goals and management of obesity, hypertension, and hyperlipidemia will be addressed separately (in sections “Obesity”, “Hypertension”, and “Hyperlipidemia”) below (CKD has been addressed in a previous section of this article).

Obesity

Obesity is the beginning of the CKM syndrome cycle but also a significant exacerbating factor. In order to halt this vicious cycle, weight loss is crucial. Lifestyle modifications such as dietary changes and exercise are at the core of both prevention and treatment of obesity. Here, we will focus on incretin therapy, which has been shown to be extremely effective in weight loss. Incretins are valuable choices for weight management as they can also provide cardiovascular and renal protection which is often necessary in those with diabetes.

As mentioned in the previous section, liraglutide, dulaglutide, and semaglutide have been demonstrated to reduce the composite risk of death from cardiovascular event, nonfatal myocardial infarction, and nonfatal stroke in the type 2 diabetes population by 23%, 22%, and 36%, respectively (39-41). Renal outcomes have been discussed in the “Pharmacotherapy for Glycemic Management in People with CKD”. Lirgalutide and semaglutide have indications for the treatment of obesity in individuals without diabetes. In the clinical trial comparing liraglutide to orlistat in the population without diabetes, mean weight loss with liraglutide 3.0 mg was 7.2 kg compared with 4.1 kg with orlistat. After 20 weeks of treatment, 76% of individuals on liraglutide 3.0 mg lost more than 5% body weight and almost 30% lost more than 10% body weight. The proportion of patients with metabolic syndrome decreased by more than 60% (50). In the STEP 1 trial, semaglutide 2.4 mg was compared with placebo in individuals without diabetes. Mean percent weight reduction at 68 weeks was 14.85% compared to 2.4% and mean weight loss was 15.3 kg vs 2.6 kg for semaglutide and placebo, respectively. Five percent weight reduction was achieved in 86.4%, 10% reduction in 69.1%, and 15% reduction in 50.5% of participants in the semaglutide group. Furthermore, greater reductions in wait circumference, systolic and diastolic blood pressure, and fasting lipids levels were noted (51). Dulaglutide has not been studied in the population without diabetes, but an exploratory analyses of secondary outcomes for weight reduction in the AWARD-11 trial (compared dulaglutide 1.5 mg vs 3.0 mg vs 4.5 mg in patients with type 2 diabetes) was conducted. At 36 weeks, dulaglutide 4.5 mg demonstrated the highest average weight reduction of 6.0 kg in the class 3 obesity group. The percentage of individuals who achieved more than 5% weight loss was 49% and more than 10% weight loss was 14% in the dulaglutide 4.5 mg group across all weight groups (52). Tirzepatide is the newest incretin therapy on the market. It is a dual GLP-1/GIP agonist and is also approved for use in individuals with and without diabetes. A cardiovascular outcome trial is currently being conducted. In the SURMOUNT-1 trial (53), the efficacy of tirzepatide for weight loss was compared to placebo in the population without diabetes. At 72 weeks, tirzepatide at 5, 10, and 15 mg doses induced weight reductions of 15%, 19.5%, and 20.9%, respectively, compared to 3.1% in the placebo group. The percentage of individuals who lost more than 5%, 10%, and 15% of their body weight in the tirzepatide 15 mg group was 90.9%, 83.5%, and 70.6%, respectively. Greater improvement in waist circumference, blood pressure, and cholesterol were seen in the tirzepatide group.

Head to head comparison trials among the incretins have not been performed, but tirzepatide, semaglutide, dulaglutide, then liraglutide may be the order of highest to lowest efficacy for weight loss. However, when treating individuals with diabetes, it is prudent to keep in mind that cardiovascular and renal benefits should also be considered when choosing these agents to achieve glycemic targets.

Hypertension

The following encompass clinical practice guidelines for hypertension management endorsed by different professional societies (54-56):

Measure blood pressure at every routine outpatient visit
Diagnosis:
- ≥130/80 mmHg on an average of 2 or more measures obtained on 2 or more separate occasions
- ≥180/110 mmHg plus known cardiovascular disease: diagnosis made on a single measurement
- Pregnant women: ≥140/90 mmHg
Targets:
- <130/80 mmHg if this can be safely attained (consistent with guidelines from the ADA, AHA, International Society of Hypertension, and European Society of Cardiology) (55-57)
- Target should be based on individual risk factors for ASCVD, patient preference, and potential side effects of therapy
- Pregnant women: 110-135/85 mmHg
- Recommend against targeting <120/80 mmHg due to increase in adverse events

Lifestyle interventions such as a dietary changes (sodium restriction to <2300 mg/day), weight loss (sustaining 3-7% weight reduction), and exercise (≥150 minutes/week of moderate intensity aerobic exercise) are important nonpharmacological methods of hypertension management (54, 58). These interventions typically do not cause significant adverse effects and may enhance the effectiveness of some antihypertensive medications.

The initiation of pharmacotherapy depends on the degree of hypertension and the individual's risk factors (54):

Blood pressure 130/80 mmHg to 150/90 mmHg
- Counsel on lifestyle changes
- Initiate 1 agent
  - ▪ Albuminuria or coronary artery disease (CAD): start angiotensin converting enzyme-inhibitor (ACE-I) or angiotensin receptor blockers (ARB)
Blood pressure ≥150/80 mmHg
- Counsel on lifestyle changes
- Start 2 agents
  - ▪ Albuminuria or CAD: start ACE-I/ARB + dihydropyridine calcium channel blocker or thiazides

The use of ACE-I/ARB as first-choice agents in individuals with type 2 diabetes and CAD is also supported by the AHA (59).

Lipids

Several national and international societies have published guidelines for the management of hyperlipidemia in patients with diabetes.

Targets slightly differ between the ADA, the AACE, and the American College of Cardiology (ACC). For primary prevention, the ADA and ACC recommend low-density lipoprotein cholesterol (LDL-C) reduction by ≥50% or LDL-C < 70 mg/dL (54, 60) in patients 40-75 years with ≥1 ASCVD risk factor other than diabetes. The AACE includes additional targets for cholesterols other than LDL-C. In individuals with type 2 diabetes and <2 additional risk factors, LDL-C < 100 mg/dL, apo B < 90 mg/dL, non-HDL-C < 130 mg/dL is recommended. If there are ≥2 ASCVD risk factors, LDL-C < 70 mg/dL, apo B < 80 mg/dL, non-HDL-C < 100 mg/dL are the targets (61). For adults >75 years of age, it is reasonable to continue treatment if the individual is already on treatment or initiation of moderate intensity statin can be discussed with the patient (54, 60).

For secondary prevention, the ACC recommends to target a LDL-C reduction by ≥50% with consideration to additional lipid-lowering therapies if LDL-C remains >70 mg/dL (60). The ADA and AACE recommend an LDL-C target of <55 mg/dL (54, 61).

Managing LDL cholesterol

The recommended lifestyle interventions are similar to hypertension management. The 3 core principles are diet (Dietary Approach to Stop Hypertension diet, Mediterranean, reduce intake of saturated and trans fats), weight loss (sustain 3-7% weight loss), and exercise (≥150 minutes/week of moderate intensity aerobic exercise) (54, 58).

The first-choice class of drugs for primary and secondary prevention of ASCVD are statins. The primary goal is to lower LDL-C to target. When and in whom to initiate therapy depends on age, ASCVD risk factors, and whether therapy is for primary or secondary prevention. For primary prevention in the 40- to 75-year-old population without ASCVD, initiation of a moderate intensity statin is recommended. In the same population with ≥1 ASCVD risk factors, a high intensity statin should be initiated (54, 60). If target LDL-C is not met with high intensity statin, the addition of ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors should be considered (54). Moderate intensity statins will typically achieve a LDL-C reduction of 30% to 49% and high intensity will achieve ≥50% reduction (60). For secondary prevention, initiation of a high-intensity statin is recommended for all ages. Ezetimibe and/or PCSK-9 inhibitors are added if target LDL-C is not achieved and bempedoic acid and inclirisan can also be considered for individuals with statin intolerance (54).

Managing hypertriglyceridemia

Evidence demonstrating that cardiovascular risk remains high despite optimal treatment with statins is strong. Elevated triglyceride (TG) levels have been shown to be an independent risk factor in these individuals (62-64).

As with LDL-C-lowering interventions, lifestyle modifications are first-line therapy for any individual with any degree of hypertriglyceridemia; however, when pharmacotherapy is indicated, initiation depends on severity (65).

Currently, icosapent ethyl is the only approved pharmacotherapy for the treatment of hypertriglyceridemia that has been shown to reduce cardiovascular risk in individuals on statin therapy. Here, we will focus on the pharmacological management of hypertriglyceridemia in individuals with diabetes.

TG ≥150 and <500 mg/dL

When to consider pharmacotherapy:

Age ≥50 years old with diabetes mellitus AND
Additional ASCVD risk factors

The addition of icosapent ethyl in this population is supported by data from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (66). Their secondary prevention cohort (age ≥45 years old and established ASCVD) saw a 27% risk reduction (HR 0.73; 95% CI 0.65-0.8) in the icosapent ethyl group for the primary end point of cardiovascular death, nonfatal MI, nonfatal stroke, coronary artery revascularization, and unstable angina. The trial also observed a small but significantly higher rates of hospitalizations for atrial fibrillation in the icosapent ethyl group vs placebo group (3.1% vs 2.1%, respectively; P = .004) and bleeding (2.7% vs 2.1%, respectively; P = .06). It is recommended to discuss these potential risks and benefits with the individual prior to initiating therapy.

Of note, both the Fenofibrate Intervention and Event Lowering in Diabetes study and a randomized controlled clinical trial conducted by the ACCORD Study Group showed no benefit of adding fenofibrate to a statin in reducing cardiovascular outcomes (67, 68). More recently, a large-scale clinical trial investigated pemafibrate in individuals with type 2 diabetes, mild to moderate hypertriglyceridemia, and low HDL-C and LDL-C levels and found that cardiovascular events were not lower in the pemafibrate group compared with placebo (69). Niacin has also not been shown to reduce cardiovascular outcomes in clinical trials (70, 71). Therefore, fibrates and niacin are not recommended as combination therapy for the treatment of moderate hypertriglyceridemia (TG <500 mg/dL) in patients with diabetes.

What about individuals with fasting TG ≥150 and <500 mg/dL who are <50 years of age with diabetes or ≥50 years of age without additional ASCVD risk factors? There is not enough evidence to support the use of icosapent ethyl in this population. The American College of Cardiology recommends focusing on LDL-C lowering therapy and subsequent shared decision-making regarding hypertriglyceridemia-lowering therapy. When TG is persistently ≥500 mg/dL, the use of icosapent ethyl with the addition of fibrates can be considered to prevent TG-induced pancreatitis (65).

TG ≥1000 mg/dL

These individuals are at high risk of developing pancreatitis. A very low–fat diet (10-15% of calories) and elimination of added sugars and alcohol is recommended (Table 2).

Table 2.

Nutrition recommendations for varying severities of hypertriglyceridemia. Reproduced with permission from Virani et al (2021) (65)

	TG <500 mg/dL	TG 500-999 mg/dL	TG ≥1000 mg/dL^a	Patient Messages
Alcohol	Restrict Do not exceed limits: 2 drinks/day for women	Abstain completely	Abstain completely	For patients with TG <500 mg/dL, if alcohol is consumed, wine or beer with lower alcohol content is recommended over beverages with higher alcohol content. Alcohol content is listed on packaging and patients are encouraged to select beverages with lower alcohol content should they chose to consume alcohol
Sugar-sweetened beverages	Restrict	Abstain completely	Abstain completely	Recommend plain or sparkling water, unsweetened tea, or coffee
Fruits^b	Okay to include but individualize-3-4 servings/day	Limit to 3-4 servings/day and individualize. Avoid fruits with high glycemic index (ie, pineapples, mangoes, watermelon, ripe bananas)	Limit to 1 serving/day. Recommend individualized medical nutrition therapy with a registered dietician nutritionist	Consume whole fruit and avoid fruit juices when possible. Emphasize fresh fruits without added sugar or salt
Vegetables	Emphasize vegetables	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Avoid canned vegetables with salt and vegetables frozen with sauces. Avoid vegetable juices. Recommend 2.5 cups/day (72)^c
Legumes (beans, lentils, chickpeas, tofu, and so on)	Emphasize	Emphasize	Emphasize	Avoid added salt. Emphasize plant-based proteins instead of red meat. Avoid utlraprocessed meat alternatives
Fish/seafood	Emphasize fatty fish Recommend at least 2 servings/week	Emphasize either fatty or lean fish Recommend 2 (or more) servings/week	Emphasize lean fish Recommend 2 (or more) servings/week	Examples of fatty fish include salmon, farmed rainbow trout, and tuna. Examples of lean fish or seafood include cod, tilapia, haddock, flounder, and shrimp. Prioritize fresh, frozen, or packaged without sodium
Poultry/lean meats	Encourage	Encourage	Limit to the very leanest meats	Substitute poultry and lean meats in place of red meat. Avoid processed meats
Dairy products	Limit full-fat dairy products. Avoid sugar-sweetened dairy products	Limit full-fat dairy products. Avoid sugar-sweetened products	Eliminate full-fat dairy products and sugar-sweetened dairy products	Consume fat-free dairy products. Avoid any dairy products and added sugars
Fiber-rich whole grains	Emphasize 6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize 4-6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize individualized medical nutrition therapy with are registered dietician nutritionist	Replace refined grains (white bread, white rice, pasta) with fiber-rich whole-grain cereals, bread, brown rice
Nuts and peanuts	Emphasize	Consume in moderation	Limit	Preferably plain without added sugars or sodium
Total fat Type of fat	Moderate fat (30-35% of calories) Limit SFA and emphasize unsaturated fat	Low fat (20-25% of calories)^e Limit SFA and emphasize unsaturated fat	Very low fat (10-15% of calories or less) Limit fats to 20-30 g/day or less Meet essential fatty acid requirements For patients who need extra calories, add MCT oil gradually	Emphasize liquid oils (soybean, canola, corn, olive) instead of solid fats, butter, lard, and tropical oils (coconut, palm, and palm kernel)
Cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol
Desserts (sweets, cookies, cakes, pies, other pastries, ice cream, candy)	Occasional indulgence	Occasional indulgence	Abstain completely
Added sugars (table sugar, jams/jellies, honey)	Occasional indulgence (<6% of calories)	Occasional indulgence (<5% of calories)	Abstain completely/eliminate

	TG <500 mg/dL	TG 500-999 mg/dL	TG ≥1000 mg/dL^a	Patient Messages
Alcohol	Restrict Do not exceed limits: 2 drinks/day for women	Abstain completely	Abstain completely	For patients with TG <500 mg/dL, if alcohol is consumed, wine or beer with lower alcohol content is recommended over beverages with higher alcohol content. Alcohol content is listed on packaging and patients are encouraged to select beverages with lower alcohol content should they chose to consume alcohol
Sugar-sweetened beverages	Restrict	Abstain completely	Abstain completely	Recommend plain or sparkling water, unsweetened tea, or coffee
Fruits^b	Okay to include but individualize-3-4 servings/day	Limit to 3-4 servings/day and individualize. Avoid fruits with high glycemic index (ie, pineapples, mangoes, watermelon, ripe bananas)	Limit to 1 serving/day. Recommend individualized medical nutrition therapy with a registered dietician nutritionist	Consume whole fruit and avoid fruit juices when possible. Emphasize fresh fruits without added sugar or salt
Vegetables	Emphasize vegetables	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Avoid canned vegetables with salt and vegetables frozen with sauces. Avoid vegetable juices. Recommend 2.5 cups/day (72)^c
Legumes (beans, lentils, chickpeas, tofu, and so on)	Emphasize	Emphasize	Emphasize	Avoid added salt. Emphasize plant-based proteins instead of red meat. Avoid utlraprocessed meat alternatives
Fish/seafood	Emphasize fatty fish Recommend at least 2 servings/week	Emphasize either fatty or lean fish Recommend 2 (or more) servings/week	Emphasize lean fish Recommend 2 (or more) servings/week	Examples of fatty fish include salmon, farmed rainbow trout, and tuna. Examples of lean fish or seafood include cod, tilapia, haddock, flounder, and shrimp. Prioritize fresh, frozen, or packaged without sodium
Poultry/lean meats	Encourage	Encourage	Limit to the very leanest meats	Substitute poultry and lean meats in place of red meat. Avoid processed meats
Dairy products	Limit full-fat dairy products. Avoid sugar-sweetened dairy products	Limit full-fat dairy products. Avoid sugar-sweetened products	Eliminate full-fat dairy products and sugar-sweetened dairy products	Consume fat-free dairy products. Avoid any dairy products and added sugars
Fiber-rich whole grains	Emphasize 6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize 4-6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize individualized medical nutrition therapy with are registered dietician nutritionist	Replace refined grains (white bread, white rice, pasta) with fiber-rich whole-grain cereals, bread, brown rice
Nuts and peanuts	Emphasize	Consume in moderation	Limit	Preferably plain without added sugars or sodium
Total fat Type of fat	Moderate fat (30-35% of calories) Limit SFA and emphasize unsaturated fat	Low fat (20-25% of calories)^e Limit SFA and emphasize unsaturated fat	Very low fat (10-15% of calories or less) Limit fats to 20-30 g/day or less Meet essential fatty acid requirements For patients who need extra calories, add MCT oil gradually	Emphasize liquid oils (soybean, canola, corn, olive) instead of solid fats, butter, lard, and tropical oils (coconut, palm, and palm kernel)
Cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol
Desserts (sweets, cookies, cakes, pies, other pastries, ice cream, candy)	Occasional indulgence	Occasional indulgence	Abstain completely
Added sugars (table sugar, jams/jellies, honey)	Occasional indulgence (<6% of calories)	Occasional indulgence (<5% of calories)	Abstain completely/eliminate

Abbreviations: MCT, medium-chain triglycerides; SFA, saturated fatty acid; TG, triglycerides.

^aNutrition resources for patients are available from the National Lipid Association: https://www.lipid.org/sites/default/files/when_your_tgs_are_over_1000_mgdl.pdf and https://www.learnyourlipids.com/heart-healthy-resources/fcs-cookbook/

^bOne serving of fruit = 1 small piece of fruit (apple, orange, pear) or 1/2 cup chopped.

^cRecommendations are based on a 2000-calorie diet (72).

^dExamples include a patient with diabetes or obesity. For these individuals, fewer servings may be indicated.

^eClinicians may opt to reduce total fat as percent of calories in some of these patients to 10-15% (examples include those with a history of pancreatitis or those at the higher end of this range).

Table 2.

Nutrition recommendations for varying severities of hypertriglyceridemia. Reproduced with permission from Virani et al (2021) (65)

	TG <500 mg/dL	TG 500-999 mg/dL	TG ≥1000 mg/dL^a	Patient Messages
Alcohol	Restrict Do not exceed limits: 2 drinks/day for women	Abstain completely	Abstain completely	For patients with TG <500 mg/dL, if alcohol is consumed, wine or beer with lower alcohol content is recommended over beverages with higher alcohol content. Alcohol content is listed on packaging and patients are encouraged to select beverages with lower alcohol content should they chose to consume alcohol
Sugar-sweetened beverages	Restrict	Abstain completely	Abstain completely	Recommend plain or sparkling water, unsweetened tea, or coffee
Fruits^b	Okay to include but individualize-3-4 servings/day	Limit to 3-4 servings/day and individualize. Avoid fruits with high glycemic index (ie, pineapples, mangoes, watermelon, ripe bananas)	Limit to 1 serving/day. Recommend individualized medical nutrition therapy with a registered dietician nutritionist	Consume whole fruit and avoid fruit juices when possible. Emphasize fresh fruits without added sugar or salt
Vegetables	Emphasize vegetables	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Avoid canned vegetables with salt and vegetables frozen with sauces. Avoid vegetable juices. Recommend 2.5 cups/day (72)^c
Legumes (beans, lentils, chickpeas, tofu, and so on)	Emphasize	Emphasize	Emphasize	Avoid added salt. Emphasize plant-based proteins instead of red meat. Avoid utlraprocessed meat alternatives
Fish/seafood	Emphasize fatty fish Recommend at least 2 servings/week	Emphasize either fatty or lean fish Recommend 2 (or more) servings/week	Emphasize lean fish Recommend 2 (or more) servings/week	Examples of fatty fish include salmon, farmed rainbow trout, and tuna. Examples of lean fish or seafood include cod, tilapia, haddock, flounder, and shrimp. Prioritize fresh, frozen, or packaged without sodium
Poultry/lean meats	Encourage	Encourage	Limit to the very leanest meats	Substitute poultry and lean meats in place of red meat. Avoid processed meats
Dairy products	Limit full-fat dairy products. Avoid sugar-sweetened dairy products	Limit full-fat dairy products. Avoid sugar-sweetened products	Eliminate full-fat dairy products and sugar-sweetened dairy products	Consume fat-free dairy products. Avoid any dairy products and added sugars
Fiber-rich whole grains	Emphasize 6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize 4-6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize individualized medical nutrition therapy with are registered dietician nutritionist	Replace refined grains (white bread, white rice, pasta) with fiber-rich whole-grain cereals, bread, brown rice
Nuts and peanuts	Emphasize	Consume in moderation	Limit	Preferably plain without added sugars or sodium
Total fat Type of fat	Moderate fat (30-35% of calories) Limit SFA and emphasize unsaturated fat	Low fat (20-25% of calories)^e Limit SFA and emphasize unsaturated fat	Very low fat (10-15% of calories or less) Limit fats to 20-30 g/day or less Meet essential fatty acid requirements For patients who need extra calories, add MCT oil gradually	Emphasize liquid oils (soybean, canola, corn, olive) instead of solid fats, butter, lard, and tropical oils (coconut, palm, and palm kernel)
Cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol
Desserts (sweets, cookies, cakes, pies, other pastries, ice cream, candy)	Occasional indulgence	Occasional indulgence	Abstain completely
Added sugars (table sugar, jams/jellies, honey)	Occasional indulgence (<6% of calories)	Occasional indulgence (<5% of calories)	Abstain completely/eliminate

	TG <500 mg/dL	TG 500-999 mg/dL	TG ≥1000 mg/dL^a	Patient Messages
Alcohol	Restrict Do not exceed limits: 2 drinks/day for women	Abstain completely	Abstain completely	For patients with TG <500 mg/dL, if alcohol is consumed, wine or beer with lower alcohol content is recommended over beverages with higher alcohol content. Alcohol content is listed on packaging and patients are encouraged to select beverages with lower alcohol content should they chose to consume alcohol
Sugar-sweetened beverages	Restrict	Abstain completely	Abstain completely	Recommend plain or sparkling water, unsweetened tea, or coffee
Fruits^b	Okay to include but individualize-3-4 servings/day	Limit to 3-4 servings/day and individualize. Avoid fruits with high glycemic index (ie, pineapples, mangoes, watermelon, ripe bananas)	Limit to 1 serving/day. Recommend individualized medical nutrition therapy with a registered dietician nutritionist	Consume whole fruit and avoid fruit juices when possible. Emphasize fresh fruits without added sugar or salt
Vegetables	Emphasize vegetables	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Emphasize vegetables but avoid vegetables with high glycemic index (ie, carrots, potatoes, sweet potatoes, yams, parsnips)	Avoid canned vegetables with salt and vegetables frozen with sauces. Avoid vegetable juices. Recommend 2.5 cups/day (72)^c
Legumes (beans, lentils, chickpeas, tofu, and so on)	Emphasize	Emphasize	Emphasize	Avoid added salt. Emphasize plant-based proteins instead of red meat. Avoid utlraprocessed meat alternatives
Fish/seafood	Emphasize fatty fish Recommend at least 2 servings/week	Emphasize either fatty or lean fish Recommend 2 (or more) servings/week	Emphasize lean fish Recommend 2 (or more) servings/week	Examples of fatty fish include salmon, farmed rainbow trout, and tuna. Examples of lean fish or seafood include cod, tilapia, haddock, flounder, and shrimp. Prioritize fresh, frozen, or packaged without sodium
Poultry/lean meats	Encourage	Encourage	Limit to the very leanest meats	Substitute poultry and lean meats in place of red meat. Avoid processed meats
Dairy products	Limit full-fat dairy products. Avoid sugar-sweetened dairy products	Limit full-fat dairy products. Avoid sugar-sweetened products	Eliminate full-fat dairy products and sugar-sweetened dairy products	Consume fat-free dairy products. Avoid any dairy products and added sugars
Fiber-rich whole grains	Emphasize 6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize 4-6 servings/day unless a lower-carbohydrate diet is indicated^d	Emphasize individualized medical nutrition therapy with are registered dietician nutritionist	Replace refined grains (white bread, white rice, pasta) with fiber-rich whole-grain cereals, bread, brown rice
Nuts and peanuts	Emphasize	Consume in moderation	Limit	Preferably plain without added sugars or sodium
Total fat Type of fat	Moderate fat (30-35% of calories) Limit SFA and emphasize unsaturated fat	Low fat (20-25% of calories)^e Limit SFA and emphasize unsaturated fat	Very low fat (10-15% of calories or less) Limit fats to 20-30 g/day or less Meet essential fatty acid requirements For patients who need extra calories, add MCT oil gradually	Emphasize liquid oils (soybean, canola, corn, olive) instead of solid fats, butter, lard, and tropical oils (coconut, palm, and palm kernel)
Cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol	Choosing healthy protein foods, dairy products, and fats will limit cholesterol
Desserts (sweets, cookies, cakes, pies, other pastries, ice cream, candy)	Occasional indulgence	Occasional indulgence	Abstain completely
Added sugars (table sugar, jams/jellies, honey)	Occasional indulgence (<6% of calories)	Occasional indulgence (<5% of calories)	Abstain completely/eliminate

Abbreviations: MCT, medium-chain triglycerides; SFA, saturated fatty acid; TG, triglycerides.

^aNutrition resources for patients are available from the National Lipid Association: https://www.lipid.org/sites/default/files/when_your_tgs_are_over_1000_mgdl.pdf and https://www.learnyourlipids.com/heart-healthy-resources/fcs-cookbook/

^bOne serving of fruit = 1 small piece of fruit (apple, orange, pear) or 1/2 cup chopped.

^cRecommendations are based on a 2000-calorie diet (72).

^dExamples include a patient with diabetes or obesity. For these individuals, fewer servings may be indicated.

^eClinicians may opt to reduce total fat as percent of calories in some of these patients to 10-15% (examples include those with a history of pancreatitis or those at the higher end of this range).

If glycemic control is poor, treatment with insulin infusion should be prioritized and hypertriglyceridemia reassessed. Of note, when TG ≥1000 mg/dL, the efficacy of TG-lowering agents is limited. Therefore, strict dietary fat restriction is crucial until TG <1000 mg/dL, at which point fenofibrate or icosapent ethyl can be introduced, if needed (65).

It is important to note that the only omega-3 fatty acid that has been proven to reduce cardiovascular risk when added to statin therapy is icosapent ethyl. The data from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial cannot be extrapolated to other fatty acids. Icosapent ethyl is a single, purified form of the omega-3 fatty acid (eicosapentaenoic acid) and does not contain any other fatty acids. Therefore, caution is warranted to ensure isocapent ethyl is used and not any other form of omega-3 fatty acid for cardiovascular risk reduction.

Metabolic Dysfunction–Associated Steatotic Liver Disease

Nonalcoholic fatty liver disease was renamed metabolic dysfunction–associated steatotic liver disease (MASLD) in June 2023. The prevalence of MASLD is high with 65% of people with type 2 diabetes having this condition worldwide (73). MASLD is diagnosed when there is evidence of hepatic steatosis based on histology, imaging, or blood biomarker in addition to the presence of 1 of the following: overweight/obesity, type 2 diabetes, or metabolic dysregulation (74). Obesity and diabetes are major risk factors for the development and progression of MASLD (72, 75). The AACE states that individuals with obesity and/or features of metabolic syndrome, prediabetes, type 2 diabetes, hepatic steatosis on any imaging study and/or persistently elevated plasma aminotransferase levels over 6 months is at high risk for disease progression, so screening for liver fibrosis is recommended (76). The fibrosis-4 index, a liver fibrosis prediction calculation tool using age, aspartate aminotransferase, alanine aminotransferase, and platelet count is the preferred initial test to evaluate for fibrosis (76, 77).

While type 2 diabetes is a known risk factor for the development of MASLD, whether glycemic control effects the progression of MASLD or not remains controversial. A retrospective study including 713 participants with biopsy proven MASLD evaluated the association between HbA1c and progression of disease. The authors found that every 1% increase in HbA1c was associated with 15% higher odds of increased fibrosis stage (78). Another small prospective study of 39 participants with biopsy proven MASLD demonstrated that reduction in HbA1c was associated with improved liver fibrosis (79). On the other hand, a large cross-sectional study using data from the National Health and Nutrition Examination Survey showed no correlation between glycemic control and severity of liver steatosis (80).

At present, there are no MASLD-specific glycemic targets; however, the mainstay of treatment is managing obesity and diabetes. Hannah and Harrison proposed that ≥3% weight loss improves hepatic steatosis, ≥5% weight loss improves inflammation, and ≥10% improves fibrosis (81). Although there are no pharmacological agents approved for the treatment of MASLD, there is evidence to support the use of certain diabetes medications to improve MASLD. The AACE and the American Association for the Study of Liver Diseases recommend the use of pioglitazone, liraglutide, or semaglutide when treating patient with obesity, prediabetes, or type 2 diabetes (76, 77).

MASLD has a bidirectional association with cardiometabolic risk factors and conditions. It has become apparent that individuals with type 2 diabetes are at increased risk for developing MASLD and disease progression. As clinicians, acknowledging MASLD as a complication of type 2 diabetes is the first step to improving screening for this very prevalent complication.

Glycemic Targets: CGM

CGM devices have become a widely used tool for monitoring blood glucose levels in individuals with diabetes. Unlike the HbA1c, CGM systems provide information regarding acute glycemic changes and glycemic variations during and between days (82). The ADA, AACE, and NICE all recommend the use of these devices in patients who are on insulin therapy, have recurrent hypoglycemia, or hypoglycemia unawareness (7, 83, 84). Although hemoglobin A1c has been the primary metric for assessing the risk of chronic complications, new metrics specifically used with CGM systems have emerged.

CGM Ambulatory Glucose Profile Goals for Nonpregnant Adults With Diabetes

The goals (based on percent of readings and time) for nonpregnant adults with diabetes (5, 6, 82) are:

70% or greater time in range (TIR) between 70 and 180 mg/dL
<4% time below range between 54 and 69 mg/dL
<1% time below range <54 mg/dL

CGM Metrics and Chronic Complications

The expert panel from the international consensus on the use of CGM, identified 10 core CGM metrics that are useful in clinical practice (82, 85): number of days CGM worn, percentage of time CGM is active, mean glucose, glucose management indicator, glycemic variability, time above range (% of readings and time >250 mg/dL), time above range (% of readings and time 181-250 mg/dL), TIR (% of readings and time 70-180 mg/dL), time below range (% of readings and time 54-69 mg/dL), and time below range (% of readings and time <54 mg/dL) (81). TIR has been demonstrated to correlate with HbA1c and has been identified as the single most important CGM metric (82). There is growing evidence to support the association between TIR and development of microvascular complications.

Beck et al evaluated the association between TIR and development or progression of retinopathy and microalbuminuria using the data set from the DCCT (86). TIR was calculated from the trial's 7-point blood glucose tests performed daily. The hazard rate for the development of retinopathy increased by 64% and development of microalbuminuria by 50% for every 10% increase in TIR (86). A literature review of 34 publications including 20 852 participants investigating the association between diabetes complications and CGM metrics concluded that TIR and glycemic variability are strongly associated with retinopathy and nephropathy. Lower TIR and glycemic variability were risk factors for neuropathy. Evidence also supports that lower TIR is a risk factor for macrovascular disease but the effect of glycemic variability is still uncertain (87).

Acute Complications

CGM devices have also been shown in real-world studies to reduce acute complications of diabetes such as severe hypoglycemia, diabetic ketoacidosis, and hospitalizations for hypoglycemia and hyperglycemia. In a large retrospective study of 74 011 participants with type 1 diabetes and type 2 diabetes who initiated a flash glucose monitoring system, diabetic ketoacidosis decreased by 56.2% in type 1 diabetes and 52.1% in type 2 diabetes after 1 year. Hospitalizations for hypoglycemia and hyperglycemia deceased in type 2 diabetes by 10.8% and 26.5%, respectively (88). In a large cohort of type 1 diabetes patients, the use of flash glucose monitoring decreased rates of severe hypoglycemia by 21% compared with the conventional self-monitoring of blood glucose (89). More recently, The ALERTT1 trial compared the flash glucose monitoring system (ie, intermittently scanned CGM) without alerts for high and low blood glucose levels to real-time CGM systems with alerts in the type 1 diabetes population and found that the real-time CGM group spent less time in hyperglycemia without an increase in hypoglycemia. There was also a sustained reduction in severe hypoglycemia rates in the real-time CGM group (90). Real-time CGM with alerts may be protective against severe hypoglycemia and should be a factor in deciding the optimal CGM for patients with hypoglycemia awareness.

Summary

Diabetes is a chronic condition with the potential to affect multiple organ systems and significantly decrease quality of life. Glycemic targets were created in order to prevent long-term complications of this disease. Early and life-long achievement of glycemic goals, timely screening and treatment of microvascular complications, and management of risk factors for ASCVD, CKM syndrome, and MASLD are crucial for the prevention and delaying progression of diabetes-related complications.

Acknowledgments

The authors sincerely thank Christine G. Holzmueller, MS, for editing this manuscript.

Supplement Sponsorship

This article appears as part of the supplement “Guidebook for Providers on Comprehensive Diabetes Care,” sponsored by the University Hospitals Mary B. Lee Chair in Adult Endocrinology endowment, and by the Ratner Family Fund.

Funding

There is no funding for this paper.

Disclosures

The authors have no conflicts of interest to disclose.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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