Transforming Type 2 Diabetes Care: What Patients Need to Know with Dr. Tim Garvey

This article was written in collaboration with Dr. Timothy Garvey, Associate Director, Professor, Department of Nutrition Sciences, School of Health Professions, Senior Scientist, UAB Nutrition Obesity Research Center

Type 2 diabetes (T2DM) comprises 90% of the diabetes population and is usually caused by insulin resistance coupled with a “relative” insulin deficiency, resulting in elevated glucose levels. A fasting glucose level >126 mg/dL is diagnostic of diabetes. Guidelines also consider HbA1c >6.5% as diagnostic of diabetes mellitus. Living with diabetes presents a myriad of challenges, and one of the most significant concerns is the heightened risk of cardiovascular diseases (CVD) and related complications. Patients with diabetes face an increased risk of conditions such as coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF), atrial fibrillation (AF), cerebrovascular accidents (CVA), and peripheral vascular disease (PVD). Moreover, diabetes itself is a major risk factor for the development of chronic kidney disease (CKD), further entwining the intricate web of health concerns. In light of these interconnected risks, a paradigm shift in the treatment of diabetes is imperative, emphasizing the prevention and management of cardiovascular manifestations to safeguard both the heart and kidneys.

Numerous studies have underscored the intricate relationship between diabetes and cardiovascular disease. Individuals with T2DM are at a two- to four-fold higher risk of developing CVD during their lifetime. Recently, in a cohort study of all Danish patients with newly diagnosed T2DM, the risk of MI was increased by 30%, CVA by 21%, and CV death by 35%. In patients between 50-59 years of age, new onset DM increases the risk of CVD by 50%. In younger patients with new-onset T2DM, CVD occurs 12 years earlier than in patients without DM.

Shifting the Focus: Prevention and Management:

In light of this intricate web of risks, a fundamental shift in the approach to diabetes management is crucial. Rather than merely addressing blood sugar levels, physicians and allied professionals must adopt a comprehensive strategy that prioritizes the prevention and management of cardiovascular manifestations. This holistic approach not only aims to mitigate the risk of CVD but also recognizes the symbiotic relationship between cardiovascular health and target organ damage. Target organ damage is defined as an abnormal renal function (GFR <59 ml/min/1.73m2), microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g), and presence of microvascular disease (proteinuria, retinopathy, and neuropathy).

In patients aged >40 years with T2DM without overt ASCVD or severe target organ damage, it is recommended to estimate 10-year ASCVD risk using the Pooled cohort equation. Patients with T2DM are considered at very high risk if they have established ASCVD, severe organ damage, or 10-year risk >20 %. High-risk T2DM have a 10-year CVD risk of 10 to <20%, moderate-risk T2DM with a 10-year CVD risk of 5 to <10%, and low-risk T2DM with a 10-year CVD risk of <5%.

Diabetes as a Catalyst for Chronic Kidney Disease (CKD):

Beyond the cardiovascular realm, diabetes is a major catalyst for the onset and progression of CKD with approximately 30-40% of patients with DM will develop CKD. The kidneys, vital organs responsible for filtering waste from the blood, are particularly vulnerable to diabetes. Persistent high blood sugar levels can damage the intricate filtering units of the kidneys, leading to CKD. Importantly, CKD itself is intricately linked with cardiovascular complications, creating a cyclical relationship where each condition exacerbates the other. Nearly half of all patients with CKD stages 4 and 5 will develop cardiovascular disease and 40-50% of all deaths in this population are associated with atherosclerotic cardiovascular mortality and heart failure.

CARDIOVASCULAR RISK REDUCTION IN PATIENTS WITH T2DM:

Integrating Lifestyle Modification and Medication:

An effective strategy starts with lifestyle modifications. Encouraging a heart-healthy diet, regular physical activity, and smoking cessation can significantly impact cardiovascular risk factors. In the LookAHEAD study, 5,145 type 2 DM patients underwent lifestyle intervention with nutritional counseling and exercise. This resulted in an average of 8.6% weight loss which was associated with a reduction in HbA1c and blood pressure in the first year. After 10 years, the effect of the intervention had attenuated to a reduction of CKD. Further analysis revealed that patients who had lost >10% of their weight at 1 yr. had a 21% reduced risk of mortality. In patients with obesity and T2DM, reducing weight by >5% improves glucose control, lipid levels, and blood pressure. In general, patients with T2DM should follow nutritional recommendations that reduce body weight and improve outcomes. A Mediterranean-style eating pattern improves glucose control, lipid, and blood pressure. Supplementing with olive oil or nuts, as done in the PREDIMED study for patients with high-risk DM can result in a 30% reduction of ASCVD risks. Regular moderate to vigorous physical activity has favorable effects on glucose control and CV risk factors in type 2 DM patients. Compared to sedentary, a high level of physical activity is associated with a 40% reduction in all-cause mortality. Of course, smoking cessation is a key lifestyle intervention in patients with T2DM with evidence demonstrating a 35% reduction in mortality particularly in patients who have pre-existing cardiovascular disease.

Previously, diabetes management was focused primarily on the control of blood sugar levels. Following the much-publicized safety concerns with rosiglitazone (Avandia with black box warning in 2007) causing an increased risk of heart attacks and heart failure, the FDA mandated in 2008 that all new diabetes drugs conduct studies demonstrating CV safety. Clinical trials must have a parallel arm for major adverse CV events versus the control group. This led to recent advancements in pharmacotherapy and provided opportunities for dual-action medications that not only regulate blood sugar levels but also address cardiovascular risk factors.

Glucose-lowering medication with cardiovascular and renal benefits:

1. SGLT-2 inhibitors: Four Sodium-Glucose coTransporter 2 inhibitor agents have been approved for the treatment of T2DM in the US. Empagliflozin (Jardiance), Dapagliflozin (Farxiga), Canagliflozin (Invokana) and Ertugliflozin (Steglatro). They work at the level of the proximal tubule of the kidneys and enhance urinary glucose excretion, promoting the loss of 400 plus calories in the urine and the excretion of sodium resulting in weight reduction, intravascular volume contraction, decreased renal glomerular pressure, blood pressure reduction, and HbA1c reduction (0.5-1%). The results of 6 cardiovascular outcome trials, involving 47,000 patients, demonstrated a 17-38% reduction in CV death and a 7-14% reduction in CV death, MI, or stroke, particularly in patients with pre-existent cardiovascular disease. Patients with heart failure, peripheral artery disease, atrial fibrillation, chronic kidney disease, and obesity will benefit the most. In patients with T2DM without ASCVD or advanced target organ damage, but with an ASCVD risk >10%, treatment with SGLT2 inhibitors may be used to reduce the CV risk as well as blood sugar control. A meta-analysis of 13 trials involving over 90,000 patients demonstrated that SGLT-2 inhibitors slow the progression of CKD by 37%. In 4 CKD trials, they reduced the risk of acute kidney injury by 23%. The most common side effects include hypotension, a temporary rise in Creatinine, and urinary tract and vaginal yeast infections. They do not cause hypoglycemia unless combined with sulfonylurea (Glipizide, Glimepiride, or Glyburide) or insulin. It is therefore important to emphasize hygiene, hydration, adjusting the dose of diuretics, and monitoring the renal function every 3-6 months after starting an SGLT2 inhibitor. It is best to avoid it in patients with marginal BP with postural hypotension and patients with dehydration. Rarely (<0.1%), SGLT2 inhibitors can cause euglycemic diabetic ketoacidosis.
2. GLP-1 Receptor Agonists: Seven Glucagon-Like Peptide 1 receptor agonists have been approved for the treatment of T2DM in the US. Exenatide (Byetta/Bydureon), Liraglutide (Victoza), Lixisenatide (Lyxumia/Aslyxin), Dulaglutide (Trulicity), Semaglutide (Ozempic), Oral semaglutide (Rybelsus) and Albiglutide (Tanzeum). They work at the level of the brain by decreasing appetite and how much you eat, at the level of the pancreas by stimulating insulin secretion and lowering the blood sugar (HbA1c reduction of 1-1.5%), and at the level of the stomach by slowing the movement of food through the stomach and decreasing appetite. Eight cardiovascular outcome trials studied the safety and efficacy of GLP-1 RAs in 60,000 patients with T2DM. LEADER (Liraglutide/Victoza) demonstrated a 13% reduction in outcomes of CV death, MI, or stroke (13% vs 14.9%). REWIND (dulaglutide/Trulicity) found a 12% reduction in primary outcome (12% vs 13.4%) without a mortality advantage. SUSTAIN-6 (Semaglutide/Ozempic) demonstrated a 26% reduction respectively in CV death, MI, or stroke. HARMONY (Albiglutide/Tranzeum) demonstrated a 22% reduction in CV death, MI, or stroke (7% vs 9%). Albiglutide has been discontinued due to the limited prescribing of the drug. PIONEER-6 studied oral semaglutide (Rybelsus): MACE occurred in 3.8% in the treatment group vs 4.8% in the placebo group, a 21% difference that was significant for noninferiority. Overall the benefits of GLP-1s were present whether SGLT2 inhibitors were given at baseline or not. Cardioprotective effects are likely modulated through renal protection, lowering chronic inflammation, glucose reduction, and reduction of ectopic, visceral fat deposition which is known to affect insulin resistance and is associated with cardiovascular risk. GLP-1 receptor agonists also decrease the amount of albumin in the urine and can prevent a deterioration in kidney function and progression to end-stage kidney disease. Their main side effects consist of nausea (25-60%) and vomiting (5-15%) and tend to be transient for most patients as they are started on a very low dose. Patients may be advised to eat smaller meals, eat slowly, stop before feeling full, and avoid fatty, spicy, or strongly favored food. Occasionally, a short-term course of proton inhibitors can help.
3. Tirzepatide (dual GIP/GLP-1 Receptor Agonists): a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonist recently approved in the US to treat T2DM is being studied for its effects on cardiovascular outcomes (SURPASS-CVOT) with the results available later in 2024. A pre-specified meta-analysis of phases 2 and 3 of the SURPASS trials including 7,000 patients indicated that tirzepatide is safe and has the potential for cardiovascular benefits with a 10% reduction of CV death and a 20% in all-cause death.
4. Pioglitazone. The PROactive trial evaluated the effect of pioglitazone in patients with T2DM and ASCVD. It failed to achieve its primary composite outcome of all CV death, MI, stroke, unstable angina, coronary or peripheral revascularization. However, there was a 16% relative risk reduction in CV death, MI, or stroke compared to placebo. Pioglitazone can cause fluid retention and increase the risk of heart failure. The HbA1c is reduced by 1-1.5% on average. It can also induce weight gain.

Safe Glucose-lowering medications but without cardiovascular benefits:

1. Metformin: Considered first-line therapy, particularly for T2DM with obesity (HbA1c reduction 1-1.5%) and without ASCVD or severe target organ damage and at low- to moderate risk of ASCVD. In a meta-analysis of 13 randomized trials, there was no statistical difference in CV outcomes: all-cause mortality was reduced by 4%, CV death by 3%, MI by 11%, PVD by 19%, and a slight increase in stroke by 4%.
2. Sulfonylureas (Glimepiride/amaryl): Based on the UK Prospective Diabetes Study, intense blood sugar lowering using sulphonylureas (HbA1c reduction 1-1.5%) or insulin was similar to placebo with regards to CV safety (6% lower mortality (NS)) but with a 25% reduction in microvascular disease, namely diabetic retinopathy.
3. Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors): Five randomized trials have studied the CV safety of DPP-4 inhibitors: Saxagliptin/Onglyza, alogliptin/Nesina, sitagliptin/Januvia or Zituvio, and linagliptin/Tradjenta. When compared to the placebo, they demonstrated non-inferiority but not superiority for the primary CV endpoint. In SAVOR-TIMI 53, saxagliptin significantly increased the risk of heart failure hospitalization. (HbA1c reduction 0.5-1%)
4. Insulin: Degludec and Glargine insulin (Lantus or Toujeo) have been studied in ORIGIN and DEVOTE clinical trials in T2DM. There was no significant difference in the primary outcome of CV death, MI, or stroke.

Regular Monitoring and Timely Intervention:

Regular monitoring of cardiovascular and renal health is paramount in the care of individuals with diabetes. Routine screenings for blood pressure, cholesterol levels, and kidney function can detect early signs of complications. Targeting blood sugar, blood pressure, and lipid, can lower mortality and end-stage renal disease by 60%. A moderate-intensity statin (atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, or pravastatin 40-80 mg) can lower the risk of MI, stroke, and mortality by 30%. Patients with ASCVD and T2DM are at very high risk and their LDL cholesterol target should be <55 mg/dL. In T2DM patients at high risk ( ASCVD 10-yr score between 10 and 20), their LDL target should be <70 mg/dL. All available BP-lowering medications can be used to lower blood pressure to a target of 120/70, but renin-angiotensin inhibitors (ACE inhibitors or ARBs) are preferred, particularly if evidence of end-organ damage. Timely intervention, whether through medication adjustments or other therapeutic measures, can halt or slow the progression of both cardiovascular and renal issues.

In summary, to reduce CV risk independent of glucose control, a GLP-1 receptor agonist and/or SGLT2 inhibitor should be used independently of their HbA1c and independently of concomitant glucose-lowering medication. For additional glucose control, pioglitazone or metformin should be used. Other agents such as DPP-4, sulfonylureas such as glimepiride, or insulin can be used but can result in weight gain.

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