What are the management and mechanisms of acute and chronic complications of Diabetes Mellitus (DM)?

From the Guidelines

The management of diabetes mellitus should prioritize careful glycemic control, lifestyle modifications, and targeted interventions to prevent acute and chronic complications, with a focus on reducing morbidity, mortality, and improving quality of life. The most recent and highest quality study 1 emphasizes the importance of modifying glycaemic control, blood pressure control, and further cardiovascular risk management to dramatically reduce cardiovascular complications. Key aspects of management include:

• Glycemic control: aiming for HbA1c <7% through gradual reduction, avoiding too rapid reduction which can cause microvascular complications 1
• Lifestyle modifications: reduced calorie intake, Mediterranean diet, moderate-to-vigorous physical activity, and weight loss for obese patients 1
• Cardiovascular disease prevention: statin therapy, aspirin 81mg daily for secondary prevention, and consideration of SGLT-2 inhibitors for their cardiovascular and renal benefits 1
• Management of chronic complications:
  • Nephropathy: ACE inhibitors or ARBs, such as lisinopril 10-40mg daily 1
  • Retinopathy: regular ophthalmologic screening and possible laser photocoagulation
  • Neuropathy: pregabalin 150-300mg daily or duloxetine 60-120mg daily
  • Cardiovascular disease: statin therapy, aspirin 81mg daily for secondary prevention It is essential to consider the individual patient's needs, preferences, and comorbidities when developing a treatment plan, and to regularly monitor and adjust the plan as needed to prevent complications and improve quality of life 1.

From the FDA Drug Label

5.2 Lower Limb Amputation An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4. 2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes mellitus who had either established cardiovascular disease or were at risk for cardiovascular disease.

5.6 Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA

5.4 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving INVOKANA.

5.3 Volume Depletion INVOKANA can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine

5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue

5.7 Genital Mycotic Infections INVOKANA increases the risk of genital mycotic infections.

5.8 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with INVOKANA.

The management of acute and chronic complications of diabetes mellitus with canagliflozin (INVOKANA) involves monitoring for and mitigating the risk of several potential complications, including:

• Lower limb amputation: Counsel patients about the importance of routine preventative foot care and monitor for signs and symptoms of infection.
• Necrotizing fasciitis of the perineum (Fournier's gangrene): Assess patients for signs and symptoms of this condition, including pain or tenderness, erythema, or swelling in the genital or perineal area.
• Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly.
• Volume depletion: Assess and correct volume status before initiating INVOKANA, and monitor for signs and symptoms of volume depletion after initiating therapy.
• Hypoglycemia: Inform patients using concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms.
• Genital mycotic infections: Monitor and treat appropriately.
• Hypersensitivity reactions: Discontinue use of INVOKANA if hypersensitivity reactions occur, and treat and monitor until signs and symptoms resolve 2.

Metformin's mechanism of action is to decrease hepatic glucose production, decrease intestinal absorption of glucose, and improve insulin sensitivity by increasing peripheral glucose uptake and utilization 3.

From the Research

Acute and Chronic Complications of Diabetes Mellitus

• Diabetes mellitus (DM) is a major metabolic disorder that can lead to various complications if left untreated, including neuropathy, angiopathy, and dysfunction of cells, tissues, and organ systems 4
• The chronic complications of DM are caused largely by hyperglycemia-induced cellular and molecular impairment of neural and vascular structure and function 4
• Hyperglycemia-induced oxidative stress is a major contributor to the development of long-term complications of DM 4

Management of Diabetes Mellitus

• Lifestyle modifications, such as diet and exercise, can help achieve better management of diabetes 5
• The employability of phytoconstituents as multitargeting molecules and their potential use as effective therapeutic adjuvants to first-line hypoglycemic agents can help prevent side effects caused by synthetic drugs 5
• Sodium glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin, are effective and generally well-tolerated antihyperglycemic agents that can be used as monotherapy or as part of combination therapy 6, 7
• Combination therapy with SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) may improve long-term outcomes for patients with type 2 diabetes by addressing multiple facets of the disease 8

Mechanisms of Diabetes Mellitus

• Resistance to insulin action is the major cause of chronic hyperglycemia in diabetic patients 5
• The etiology of type 2 diabetes mellitus (T2DM) involves the complex interplay between genetics and environmental factors, which can be governed efficiently by lifestyle modifications 5
• T2DM is the consequence of activation of multiple pathways and factors involved in insulin resistance and β-cell dysfunction 5
• SGLT2 inhibitors, such as empagliflozin, work by increasing urinary glucose excretion and exerting favorable effects beyond glucose control, including reductions in body weight and blood pressure 6, 7