Clinical Feature: The Intersection of Diabetes, Obesity, and Dyslipidemia

Introduction/Magnitude of The Problem

Diabetes mellitus (DM) is a systemic disease of abnormal carbohydrate metabolism leading to chronic hyperglycemia. It is a major contributor to chronic disease and death, both in the United States (U.S.) and globally. Notably, more than 37 million U.S. adults have diabetes mellitus with type 2 diabetes accounting for approximately 90-95% of this population. Moreover, diabetes is the 8^th leading cause of death in the nation and is the number 1 cause of kidney failure, lower limb amputation and adult blindness.¹ Strikingly, the number of cases of diabetes in the young has drastically increased over the years as well. Those with type 1 diabetes aged 19 years or younger drastically increased from 1.48 per 1000 to 2.15 per 1000 between 2001-2017 and the prevalence of type 2 diabetes in those aged 10-19 increased from 0.34 per 1000 youths to 0.67 per 1000 in the same time frame.² These startling statistics highlight the importance of diabetes education for patients, parents and providers as well as lifestyle and medication optimization when able.

Classification

Diabetes can be classified into several categories and among the most common are type 1 and type 2 diabetes. However, there are also more rare forms of diabetes that are related to specific patient populations including but not limited to: gestational diabetes of pregnancy, cystic fibrosis related diabetes, glucocorticoid induced diabetes, post-transplantation diabetes and Maturity Onset Diabetes of the Young (MODY) which classically occurs before age 25. However, these exceptional cases will not be discussed in this article.

People who suffer from chronic hyperglycemia but do not qualify for a diagnosis of diabetes have a high likelihood of having prediabetes. According to the CDC, 1 in 3 American adults have prediabetes, yet 80% of them do not even know they have it. There are 3 diagnostic criteria for prediabetes: (1) Fasting plasma glucose of 100 mg/dL – 125 mg/dL; OR (2) A glucose level of 140 mg/dL-199 mg/dL two hours after an oral glucose tolerance test; OR (3) an A1c 5.7-6.4%. A diagnosis of prediabetes should not be considered an entity of its own but rather a risk factor for developing diabetes.

Criteria for diagnosis of diabetes includes: (1) Fasting plasma glucose of >126 mg/dL; OR (2) Glucose level >200 mg/dL two hours after an oral glucose tolerance test; OR (3) an A1c >6.5%; OR (4) a random plasma glucose >200 in a patient with classic hyperglycemic symptoms or in a hyperglycemic crisis.³

Type 1 diabetes mellitus is an autoimmune disease manifested by destruction of the pancreatic beta cells, thus causing insulin deficiency and hyperglycemia.  

Type 2 diabetes mellitus also leads to chronic hyperglycemia, however instead of an autoimmune destructive process taking place, type 2 diabetes mellitus involves the simultaneous and progressive loss of pancreatic insulin secretion as well as insulin resistance of skeletal muscle, adipose, and liver cells. This leads to a functional decrease in insulin levels.^4,5 

Screening for prediabetes and type 2 diabetes should be considered in asymptomatic people of any age who are overweight or obese (BMI 25 kg/m²) with one or more risk factor including a first degree relative with diabetes, history of cardiovascular disease, hypertension, HDL <35 mg/dL and/or triglyceride level >250 mg/dL, polycystic ovary syndrome, physical inactivity, HIV, or other conditions associated with insulin resistance. Otherwise, screening in prediabetics should start at age 35 and should be repeated annually to assess for progression to diabetes. In patients >35 without prediabetes, testing should be repeated at a minimum of 3-year intervals.³

Clinical Features of Type 1 Diabetes Mellitus 

Type 1 diabetes mellitus typically presents during childhood in one of three ways: (1) New onset polyuria, polydipsia and weight loss with hyperglycemia and ketonemia; (2) New onset diabetic ketoacidosis (DKA); or (3) Incidental discovery without symptoms. 

Polyuria occurs when serum glucose concentrations rise, typically >180 mg/dL, and ultimately cause an increase in urinary glucose excretion as the kidney threshold for glucose absorption is surpassed. In turn, glucosuria leads to osmotic diuresis and hypovolemia and finally serum osmolality from hyperglycemia results in polydipsia. Furthermore, insulin deficiency impairs glucose metabolism in skeletal muscle and leads to increased fat loss and breakdown of muscle, which correlates to weight loss in children. Also, the high glucose levels fuel fungal growth and can lead to perineal candidiasis, another common presenting symptom in children.6

Clinical Features of Type 2 Diabetes Mellitus

In contrast to type 1 diabetes mellitus, type 2 diabetes mellitus most commonly affects adults, however the incidence in youth is rising. Patients frequently are asymptomatic at diagnosis and are only screened for the disease after hyperglycemia is found on routine testing. However, when patients are symptomatic, they present similarly to type 1 diabetics with polyuria, polydipsia, etc. Additionally, patients may present in a hyperosmolar hyperglycemic state (HHS) characterized by severe hyperglycemia, dehydration, and obtundation without the ketoacidosis that is noted in DKA.⁷

Interrelationship of Obesity & Diabetes

Importantly, obesity is a chief risk factor for developing insulin resistance, prediabetes and type 2 diabetes mellitus. In fact, obese patients are up to 80 times more likely to develop type 2 diabetes.⁵

Given the significant pathophysiological association with diabetes and obesity, the term ‘diabesity’ was coined in 1973. Unfortunately, the prevalence of obesity only continues to rise. In fact, between 1999-2000 the prevalence of obesity⁸ was 30.5%. This increased to nearly 42% between 2017-2020, according to the National Health and Nutrition Examination Survey (NHANES) pre-COVID 19 pandemic prevalence estimates. Additionally, the prevalence of diabetes was nearly 15% in adults 20 years of age and older.⁹

Also, a significant increase in the prevalence of overweight and obesity amongst children has been linked to higher incidence and complications of diabetes in this population.¹⁰ Increased body weight is associated with higher cardiometabolic risk which in turn contributes to worse cardiovascular complications compared to patients with normal body weight.⁶ Insulin resistance created as a part of metabolic complications from obesity increases insulin requirements and makes weight loss more challenging. 

Phenotypic Association

People who are obese with a predominant increase in upper body fat (abdominal subcutaneous and intra-abdominal fat), intrahepatic triglyceride content, intramyocellular lipid content, and pancreatic fat, are at higher risk of developing type 2 diabetes than those with a lower body (gluteofemoral) fat phenotype.¹¹ In addition, insulin resistance and hyperinsulinemia can contribute to the development of obesity.

Mechanism

The cellular and physiological mechanisms responsible for the link between obesity and type 2 diabetes are complex and involve adiposity-induced alterations in β cell function, adipose tissue biology, and multi-organ insulin resistance, which are often ameliorated and can even be normalized with adequate weight loss. The alteration in adipose tissue includes adipose tissue fibrosis (increased rates of fibrogenesis and expression of genes involved in extracellular matrix formation), inflammation (increased proinflammatory macrophage and T cell content and the production of plasminogen activator inhibitor-1), and the production of exosomes that can induce insulin resistance.¹² When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells, then failure to control blood glucose levels results. Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes.¹³

One of the most widely accepted theories explaining the association between obesity and type 1 diabetes is the “accelerator hypothesis”.¹⁴ It proposes that a higher body mass creates increased need for insulin peripherally, which leads to increased stress on the β cell. This in turn makes the B-cells more susceptible to environmental and genetic insults. Also, physical deposition of lipids on B cells can lead to triggered apoptosis of B cells and increased cytokine production, thus exacerbating B-cell injury through islet inflammation. Increased production of adipokines adds further insult by generating reactive oxygen species and creating insulin resistance which could lead to prediabetes and diabetes.¹⁵

What leads to Obesity in Patients with Diabetes?

Environmental factors including unhealthy diet and sedentary lifestyle have been thought to be key factors promoting obesity in patients with diabetes. Other factors such stress, altered sleep behavior and psychosocial characteristics affect weight gain in this population. Insulin treatment has also been considered a major factor in adding extra weight, especially since intensive insulin therapy has been widely adopted as a standard of care in patients with type 1 diabetes and in most patients with advanced type 2 diabetes.¹⁶

Diabetes and Cardiovascular Disease

Diabetes is commonly associated with dyslipidemia and hypertension. These comorbidities can further lead to atherosclerotic cardiovascular disease (ASCVD) and heart failure, amongst other things. Therefore, it is incredibly important to mitigate these risk factors before they progress.

Dyslipidemia is one of the strongest factors leading to an increased risk for adverse cardiovascular effects in patients with diabesity. Dyslipidemia observed in patients with diabesity is not only due to increased levels of some of the lipoprotein particles but also from qualitative changes leading to increased atherogenicity of these lipid particles. Although the exact pathophysiology for dyslipidemia is not clear, both insulin deficiency and insulin resistance have been considered to play a significant role. Increased levels of some adipocytokines such as retinol binding protein 4 in patients with obesity have been associated with metabolic syndrome and diabetes.

The primary lipid abnormality is increased triglyceride levels along with decreased HDL-cholesterol. Most patients have an increased proportion of small dense LDL particles and large, very low-density lipoproteins (VLDL). The glycation of apolipoproteins and increased susceptibility of LDL-cholesterol (LDL-c) to oxidation has been described. Most patients with diabesity have increased VLDL1 production along with increased HDL degradation and reduced clearance of VLDL. On routine laboratory testing, even though the LDL-c levels are usually in the normal range, these LDL particles in patients with diabesity are highly atherogenic and have reduced catabolism.¹⁷

Fortunately, evidence has shown that a Mediterranean diet, which is rich in monounsaturated fats from olive oil and low in saturated fat, meat, and dairy products, is associated with improved cardiovascular outcomes and should be considered to improve the lipid profile and reduce the risk of developing ASCVD in diabetics. In their 2023 ‘Standards of Care in Diabetes-2023’ article, the American Diabetes Association (ADA) also recommends starting a moderate intensity statin in addition to lifestyle therapies in diabetic patients 40-75 years old without ASCVD as primary prevention. Consideration to high intensity statins can be given to diabetics at a high cardiovascular risk to a target LDL <70 mg/dL. Additionally, for all patients with diabetes and ASCVD, high intensity statins should be used for secondary preventive therapy with a target LDL <55 mg/dL. The addition of ezetimibe or a PCSK9 inhibitor if goal isn’t achieved can be considered.

Hypertension in people with diabetes and a blood pressure >130/80 but <160/100 mmHg, treatment with one agent should be considered, preferably with an ACE inhibitor or ARB if the patient has a history of CAD or albuminuria. If the blood pressure is >160/100 mmHg, two agents can be started including an ACE inhibitor/ARB (especially if the patient has CAD or albuminuria), calcium channel blocker or a diuretic.³

Management

When to consider starting treatment in prediabetes to prevent progression to diabetes

Prediabetes is a strong risk factor for developing diabetes and should be addressed at diagnosis. Patients who are found to be prediabetic are highly encouraged to adjust their lifestyle and include 60 minutes/day or more of at least moderate aerobic activity at least 3 days/week. Aggressive lifestyle modification has been correlated with reduced progression to full-blown type 2 diabetes. Additionally, starting metformin may be considered in prediabetics at high-risk of developing type 2 diabetes. For example, patients aged 25-59 with a BMI >35 kg/m², a high fasting plasma glucose >110 mg/dL and an A1c > 6.0 or in individuals with a history of gestational diabetes mellitus.¹⁸

Treatment of Obesity in Patients with Diabesity

Diet and exercise are fundamental in achieving weight loss and better glycemic control. Consideration should be given to achieving a weight reduction of 7% of initial body weight in patients who are overweight/obese and at risk of developing type 2 diabetes. Moreover, obesity treatment with pharmacologic options is indicated with BMI ≥30 kg/m² or BMI ≥27 kg/m² in the presence of concomitant complications. However, pharmacotherapy is effective as an adjunct only for selected people¹⁹ with type 2 diabetes and BMI ≥27 kg/m².

Weight loss Medications

The FDA has approved Orlistat, Naltrexone-Bupropion, Liraglutide 3.0 mg, and Phentermine–Topiramate combination for achieving weight loss.²⁰ Improvement in metabolic profile has been demonstrated with the use of these drugs but it is important to note that there is a lack of data on the effect of these drugs in patients with type 1 diabetes.

Role of SGLT2i and GLP-1 Receptor Agonists in Treating Diabetes & Obesity

Two classes of drugs, sodium glucose co transporter 2 inhibitor (SGLT2i) and glucagon-like peptide 1 receptor agonist (GLP-1 RA), are attractive agents which target both hyperglycemia and weight loss with resultant favorable effects on cardiovascular profile. Semaglutide (GLP-1 receptor agonist) and tirzepatide (GLP-1 receptor agonist/glucose–dependent insulinotropic polypeptide receptor agonist) have proven high efficacy in achieving significant weight loss, followed by (SGLT2i) and other GLP-1 RA which have intermediate efficacy.²¹  

GLP-1 RA acts on GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release-responses that are both glucose-dependent-with a consequent low risk for hypoglycemia. Effects on GLP-1 receptor agonist activation in the central nervous system and the gastrointestinal tract cause reduced appetite and delayed glucose absorption due to slower gastric emptying.²² 

Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glycosuria. This reduces glycemia and lowers HbA1c by ~1.0%. Caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity.

The 2023 “Standards of Care” document from the American Diabetes Association recommended incorporating one of the SGLT2 inhibitors and/or GLP-1 RAs in people with type 2 diabetes and established ASCVD or indicators of high ASCVD risk. Combination therapy with an SGLT2 inhibitor and a GLP-1 RA may be considered to provide complementary outcome benefits.

GLP-1 RA and SGLT-2i inhibitors are not U.S. FDA-approved for patients with type 1 diabetes, therefore the role of these drugs in type 1 diabetes remains unclear. The largest clinical trials of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in type 1 diabetes with Liraglutide 1.8 mg daily, showed modest A1C reductions (0.4%), decreases in weight (5 kg), and reductions in insulin doses but with higher rates of hyperglycemia with Ketosis.²³ Similarly, clinical trials of SGLT2i in patients with type 1 diabetes, showed improvements in A1C, reduced body weight, and improved blood pressure but with an increased rate of diabetic ketoacidosis.²⁴ The 2023 “Standards of Care” document from the American Diabetes Association does not advocate their use in type 1 diabetes; it states that, “the risks and benefits of adjunctive agents continue to be evaluated, with consensus statements providing guidance on patient selection and precautions.”

GLP-1 RAs are associated with Gastrointestinal (GI) adverse effects which often limits their use in clinical practice. This is typically temporary and tends to resolve over time. Rates of severe nausea and vomiting vary depending on the dose and type of GLP-1 RAs but are generally 10% or less.²⁵ Patients should be provided guidance on dietary modification including reduction of meal size, mindful eating practices, decreasing intake of high fat or spicy foods. Other side effects are gallbladder disease (cholelithiasis, cholecystitis) and pancreatitis. Carefully monitored use in patients with prior history of pancreatitis is prudent. There is also an increased risk of all thyroid cancer including medullary thyroid cancer.²⁶ They should not be used in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B. Most experts would not prescribe any GLP-1 receptor agonist in this population.

SGLT2i are associated with Diabetes Ketoacidosis (DKA) risk, mostly in type 1 DM and rarely in type 2 DM. So, the clinician should be aware of the predisposing risk factor and clinical presentation including euglycemic DKA. To mitigate potential DKA risk, SGLTi should be discontinued 3-4 days prior to the scheduled surgery, during critical illness or during prolonged fasting. There is an increased risk of genital mycotic infection, perineal necrotizing fasciitis and bone fracture. Patients should be monitored closely for the volume status and blood pressure and if necessary other volume contracting agents should be adjusted. This should not be used in the patient²⁷ with eGFR <30 ml/min/1.73m².

Role of SGLT2i and GLP Agonists in Treating Obesity or Overweight without Diabetes

Various Clinical trials (SCALE program, STEP program, SURMOUNT-1) with GLP‐1 RAs have also been shown to be effective for weight management and maintenance of weight loss in the treatment of people who are overweight or suffer from obesity without diabetes. Absolute weight losses are greater for individuals without diabetes than with diabetes in these trials. These studies also showed improvement in various cardiometabolic risk factors, such as reduction in systolic and diastolic blood pressure, total cholesterol, and triglyceride levels.^28-30

The results of a recent meta‐analysis also support that treatment with GLP‐1 RAs is associated with cardiovascular risk reduction in adults with obesity but without diabetes.³¹ Both liraglutide and semaglutide have been approved by the FDA for chronic weight management in patients with obesity or overweight in the setting of having one weight‐related comorbidity, i.e., type 2 DM, hypertension, or dyslipidemia. Tirzepatide has been approved for the treatment of type 2 DM but has not yet received FDA approval for chronic weight management. However, it has received fast‐track designation by the FDA for use in obesity or overweight with weight related comorbidities.

Only a few studies have looked at the effects of SGLT2 inhibitors in weight loss in obese subjects without diabetes. The results of network meta-analyses show SGLT2 inhibitor monotherapy does not provide sufficient weight loss for successful treatment of obesity. However, it has other benefits in obese patients with comorbidities such as atherosclerotic cardiovascular disease, heart failure, and renal disease. Co-administration of SGLT2 inhibitors together with agents that reduce food intake target complementary mechanisms and may represent an effective weight loss therapy.³² Meta-analysis has also shown that treatment with SGLT2 inhibitors was associated with a reduction in systolic blood pressure, and fasting plasma glucose, compared with placebo. However, there were no differences in waist circumference, diastolic blood pressure, serum HbA1c, LDL-C level.³³

Summary

To prevent or delay development and progression of prediabetes to diabetes, we must understand the importance of the link between obesity and diabetes, especially since these two conditions are rapidly increasing in incidence and prevalence across the globe. Fortunately, there are a wide range of treatment options available including lifestyle education and modification, as well as an evolving landscape of pharmacotherapies that jointly target both obesity and diabetes. These recent advances in pharmacotherapy also offer effective and sustained reduction in blood sugars and weight loss subsequently leading to lower cardiovascular morbidity and mortality. 

 

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