Diabetes Mellitus Management

Principles of Therapy

The overall target of diabetes mellitus management is to improve the quality of life and prevent complications and early death. The short-term goal is to relieve symptoms and acute complications, while the long-term goals include achieving target blood sugar levels, reducing concurrent risk factors, and identifying and treating chronic complications.  

Diabetes mellitus is a progressive disease where pharmacologic agents are likely to become a necessity in most patients even if they are compliant with dietary and physical activity recommendations. Fasting hyperglycemia should be controlled and is necessary for stabilizing HbA1c in poorly controlled patients with diabetes. Postprandial hyperglycemia should be identified and managed in patients with suboptimal glycemic control (HbA1c 6.5-7.5%). Regular reassessment and modification of the patient's treatment every 3-6 months should be done to prevent therapeutic inertia. Treatment plan must be individualized based on the patient’s age, cognitive abilities, school or work schedule and conditions, health beliefs, support systems, eating patterns, physical activity, social situation, financial situation, cultural factors, literacy including mathematical literacy, diabetes history, comorbidities, disabilities, health priorities, preferences for care, access to health care services, and life expectancy.  

Treatment types and devices prescribed depend on the patient's specific needs, preferences, and the patient's or caregiver's skill level.   

The choice of treatment is influenced by the following factors:

• Individualized glycemic and weight goals
• Access, cost, availability of medication, lifestyle choices
• Impact on weight, hypoglycemia and cardiorenal protection
• Underlying physiological factors
• Adverse effects of medications
• Complexity of regimens (eg frequency, mode of administration)
• Regimen choice to optimize medication use and reduce treatment discontinuation

Type 1 Diabetes Mellitus  

Therapy for type 1 diabetes mellitus consists of intensive insulin therapy which administers multiple-dose prandial (injected or inhaled) and basal insulin injections or continuous subcutaneous insulin infusion (CS II) therapy, matching prandial insulin to carbohydrate intake, premeal glucose, and expected activity, and using rapid-acting insulin analogs in reducing the risk of hypoglycemia. Insulin analogs (or inhaled insulin) are preferred over injectable human insulins to minimize risk of hypoglycemia. Teplizumab-mzwv infusion should be considered in patients ≥8 years old with stage 2 type 1 diabetes mellitus to delay the onset of symptomatic stage 3 type 1 diabetes.  

Type 2 Diabetes Mellitus  

The goals of pharmacological therapy for type 2 diabetes mellitus include:

• Achieving patient-individualized glucose targets:
  • HbA1c goal of ≤6.5-7% is recommended for most individuals
  • HbA1c goal may be less stringent if the risk of hypoglycemia is high, in the presence of comorbidities, with a long duration of diabetes mellitus, in frail or old adults, or if life expectancy is short
• Reducing the risk of hypoglycemia
• Facilitating weight loss in obese or overweight patients and preventing additional gain in weight
• Prevention of cardiovascular disease and other comorbidities, including reduction of cardiorenal risk in high-risk patients with type 2 diabetes mellitus

Based on the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) 2022 consensus report, and the 2025 ADA guideline, choosing the appropriate pharmacologic treatment for diabetes mellitus and subsequent treatment intensification should utilize shared decision-making and should have a patient-centered approach that includes considering significant comorbidities such as atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure (HF). The risk of hypoglycemia, effects on body weight, side effects of medications, costs, availability and access to medication, patient preferences, management needs, and drug regimen that optimizes medication adherence should also be considered. The selection of antidiabetic medications for cardiovascular and renal outcome improvement is the same with older people.  

Lifestyle modification with Metformin is recommended for newly diagnosed individuals with diabetes mellitus or those with mild hyperglycemia. Metformin may be used as background therapy and may be combined with other medications in cases when the therapeutic goal is not achieved with monotherapy alone. Other therapeutic agents (eg glucagon-like peptide-1 [GLP-1] agonists, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose linked transporter 2 [SGLT2] inhibitors, alpha-glucosidase inhibitors, and sulfonylureas) may be used in patients who are intolerant or have contraindications to Metformin.  

Combination therapy, which is usually Metformin plus another antidiabetic (antihyperglycemic) agent, may be started in young adults (<40 years old) with type 2 diabetes mellitus or in patients with HbA1c of ≥1.5% above glycemic target at diagnosis according to the ADA and EASD 2022 consensus report, and 2024 ADA guideline, or those who are not able to reach the therapeutic goal with monotherapy alone.  

Fixed-dose formulations can improve medication compliance when combination therapy is used and can help achieve target glucose levels more rapidly. Triple therapy is recommended for patients with suboptimal response to dual combination therapy. Consider early combination therapy in individuals less than 40 years old with diabetes.  

Early introduction of insulin is considered if there is a presence of ongoing catabolism (weight loss), symptoms of hyperglycemia, or very high HbA1c levels (>10%) or blood glucose levels (≥16.7 mmol/L or ≥300 mg/dL). Insulin is recommended in patients with extreme and symptomatic hyperglycemia.  

Combination injectable therapy is initiated when basal insulin has been titrated to an acceptable fasting blood glucose level and HbA1c remains above normal, or the dose of basal insulin is >0.5 U/kg/day. This approach involves using GLP-1 receptor agonists or dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist added to basal insulin or multiple doses of insulin. When initiating combination injectable therapy, Metformin therapy should be continued while dosages of other medications are adjusted or discontinued.  

A network meta-analysis showed that among the antidiabetic agents, GLP-1 receptor agonists and insulin regimens have the greatest reductions in HbA1c levels. GLP-1 receptor agonists including dual GIP and GLP-1 receptor agonist are preferred to insulin in most patients who need the greater glucose-lowering effect of an injectable medication and should be considered in all individuals without contraindications prior to initiating insulin therapy.  

GLP-1 receptor agonists or SGLT2 inhibitors with proven benefit should be considered in patients with multiple risk factors for or with established cardiovascular disease, heart failure, or CKD independent of background Metformin use and independent of baseline HbA1c.  

Consider using a GLP-1 receptor agonist with proven benefit to reduce major adverse cardiovascular events (MACE), or an SGLT2 inhibitor with proven benefit to reduce major adverse cardiovascular events and heart failure and improve renal outcomes in individuals with established cardiovascular disease to reduce cardiovascular risk independent of baseline glucose control, those without established cardiovascular disease but with multiple cardiovascular risk factors (eg ≥55 years old, smoking, hypertension, dyslipidemia, obesity, or albuminuria), or with coronary artery disease (CAD).  

An SGLT2 inhibitor with proven benefit to reduce major adverse cardiovascular events and heart failure and improve renal outcomes should be used in patients with heart failure to reduce heart failure hospitalization or cardiovascular death and those with CKD or an eGFR of ≥20 mL/min/1.73 m² and a urinary albumin/creatinine ratio (UACR) of ≥22.6 mg/mmol (>200 mg/g) to reduce cardiovascular and kidney failure risk.  

A GLP-1 receptor agonist with proven cardiovascular benefit to reduce major adverse cardiovascular events could be considered and should be continued until kidney transplantation is indicated in individuals with CKD in whom an SGLT2 inhibitor is not tolerated or is contraindicated. It is recommended in patients with CKD with eGFR >15 mL/min/1.73 m² to achieve adequate glycemic control due to its low risk of hypoglycemia and beneficial effects on weight, CV risk and albuminuria.  

In individuals who are overweight and obese, weight management through lifestyle modification, medications, and/or surgery serves as a cornerstone for the treatment of diabetes mellitus. Reduction in body fat mass leads to better secretory function of Insulin and effectively reduces morbidity and mortality in patients with type 2 diabetes mellitus. Clinical evidence shows that GLP-1 receptor agonists, SGLT2 inhibitors, and Tirzepatide are the most effective medications for reducing body weight.

Guidelines for Oral Antidiabetic (Antihyperglycemic) Agents  

Therapeutic goals and drug choices should be individualized in patients with comorbidities. Start oral antidiabetic agents at a low dose while stressing the need for a diet and physical activity. The daily dosing of oral antidiabetic agents may improve compliance.  In individuals with diabetes mellitus under stress (eg infection), short-term insulin therapy is recommended until recovery. When treatment with a single oral antidiabetic agent fails to achieve the therapeutic goal, a combination with another class of oral antidiabetic agents or basal insulin may be given.  

Intercurrent Illness (eg Any Illness, Trauma, and/or Surgery)  

Stress can aggravate glycemic control and may precipitate a hyperglycemic crisis. Hence, frequent blood glucose monitoring is required, and urine and blood ketone levels should also be checked in ketosis-prone patients. Temporary adjustment of treatment is needed in patients with a hyperglycemic crisis. Adequate fluid and caloric intake should be provided, and insulin may be temporarily needed by patients on non-insulin therapy or medical nutrition therapy alone.  

Hypoglycemia

Hypoglycemia is the primary limiting factor in the glycemic management of type 1 and Insulin-treated type 2 diabetes mellitus. It can be classified as follows:

• Level 1: Plasma glucose of ≥3.0 mmol/L (54 mg/dL) to <3.9 mmol/L (70 mg/dL)
• Level 2: Plasma glucose is <3.0 mmol/L (54 mg/dL)
• Level 3: Severe event characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia, irrespective of glucose level

Hypoglycemia should be treated with glucose (15-20 g) or any form of carbohydrate as an alternative. In cases of severe hypoglycemia, intravenous glucose may be administered. Intramuscular Glucagon is recommended for patients at risk of levels 2 or 3 hypoglycemia and may be given to patients for the treatment of severe hypoglycemia (eg unable or unwilling to take carbohydrates by mouth) and can also be given by family members or caregivers.

Immunization  

Common preventable infectious diseases such as influenza and pneumonia are associated with high mortality and morbidity in older people and in patients with chronic diseases like diabetes mellitus. It is advisable to give influenza vaccine yearly to all patients with diabetes mellitus. One dose of pneumococcal conjugate vaccine (PCV15 or PCV20) is given to patients aged 19-64 years old with underlying risk factors or other medical conditions whose vaccine status is unknown or who have not received a pneumococcal vaccine. If PCV15 was used, it is followed by a pneumococcal polysaccharide vaccine (PPSV23) ≥1 year later. For patients ≥65 years old with unknown vaccine status or who have not received a pneumococcal vaccine, one dose of PCV15 or PCV20 is given, if PCV15 was used, it is followed by PPSV23 ≥ 1 year later. Adults who received only PPSV23 may receive PCV15 or PCV20 ≥1 year later.  

Administer the 2- or 3-dose series of hepatitis B vaccine to unvaccinated individuals with diabetes mellitus aged 19-59 years old. Consider giving the hepatitis B vaccine to unvaccinated individuals with diabetes mellitus ≥60 years old. A single dose of respiratory syncytial virus (RSV) vaccine may be given in patients with diabetes mellitus ≥60 years old. A booster dose of tetanus, diphtheria, and pertussis (Tdap) in all adults is recommended every 10 years. Zoster vaccine is recommended in patients with diabetes mellitus ≥50 years old.  

COVID-19 and Diabetes Mellitus  

Individuals with diabetes mellitus with poor glycemic control are at high risk for severe illness or poor prognosis from COVID-19 disease.  

The mechanisms that can increase the ability of COVID-19 to impact patients with diabetes mellitus include decreased viral clearance, diminished function of T-cells, increased susceptibility to hyperinflammation and cytokine storm, and the presence of cardiovascular diseases.  

For patients with mild COVID-19 infection, glucose-lowering therapies should be continued, and blood glucose monitoring should be performed.  

Insulin treatment may or may not be given to patients with severe COVID-19 infection. Metformin should not be used, especially in patients with respiratory distress, renal impairment, or heart failure, due to an increased risk of lactic acidosis. DPP-4 inhibitor therapy (except Alogliptin and Saxagliptin) can be continued as it is associated with a low risk of hypoglycemia and can be used for a wide renal function range.  

Extreme caution should be observed in giving sulfonylureas and meglitinides as they have a hypoglycemic risk. The use of Pioglitazone and other thiazolidinediones is not ideal in hospitalized COVID-19 patients due to the risk of fluid retention and edema in hemodynamically unstable patients.  

SGLT2 inhibitors may increase the risk of volume depletion and ketoacidosis thus optimal hydration and proper adjustment of insulin doses are needed. GLP-1 receptor agonists should be discontinued in severely ill patients with COVID-19 infection due to the risk of aspiration pneumonia.  

COVID-19 vaccines are recommended for patients with diabetes mellitus. Recommended dosing and frequency vary depending on the vaccine product.

Pharmacological therapy

Antidiabetic (Antihyperglycemic) Agents  

Alpha-glucosidase Inhibitors  

Example Drugs: Acarbose, Miglitol, Voglibose  

This group of drugs is indicated in treating patients with type 2 diabetes mellitus as monotherapy or as a combination therapy. They may be used together with Insulin and have a synergistic effect when given with other oral antidiabetic agents. They are most suitable in patients with moderately elevated glucose and HbA1c.  

Alpha-glucosidase inhibitors reduce the digestion rate of polysaccharides in the proximal small intestine by inhibiting alpha-glucosidase enzymes, which are essential for the release of glucose from more complex carbohydrates. Additionally, they delay carbohydrate absorption, lowering postprandial glucose (PPG) and insulin levels.  

Thus, they are one of the agents that primarily affect postprandial glucose and they lower HbA1c by approximately 0.7-0.8% with monotherapy1. They are considered less effective than Metformin or sulfonylureas. They must be taken during meals as they may cause bloating.  

¹References: American Diabetes Association. Standards of medical care in diabetes - 2023. Diabetes Care. 2023; 2021 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Food and Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus.  

Biguanides  

Example Drug: Metformin  

Biguanides are the first-line treatment option for patients with type 2 diabetes mellitus due to their high efficacy, low cost, low side effects including hypoglycemia risk, and lack of associated weight gain. They lower blood glucose through a reduction in hepatic glucose production and do not stimulate insulin secretion thus, they are usually not associated with hypoglycemia. They affect both FPG and postprandial glucose and improve peripheral glucose disposal while suppressing appetite and promoting weight reduction. As monotherapy, it may decrease HbA1c by approximately 1%.¹ They have synergistic effect to further lower the blood glucose level when used in combination with other agents. They increase insulin sensitivity and lower insulin requirements and may cause modest weight loss or weight stability, as compared to other antidiabetic agents.  

Biguanides may be safely given to patients with eGFR of ≥30 mL/min/1.73 m², nevertheless, it is suggested to measure the patient’s eGFR prior to starting therapy. To reduce cardiovascular risk, Metformin may be used as an add-on therapy for patients with type 2 diabetes mellitus with ASCVD if additional glucose control is needed and in patients with type 2 diabetes mellitus without ASCD or severe target organ damage but with low or moderate risk.  

There are some studies that have shown beneficial effects on cardiovascular disease outcomes (ie reduction in LDL-C and TG levels). They may also be given to prevent type 2 diabetes mellitus in patients with impaired glucose tolerance, impaired fasting glucose, or HbA1C of 5.7-6.4%, especially if body mass index is ≥35 kg/m², age of <60 years, and in women with a gestational diabetes mellitus history. In the Asia-Pacific region, significant evidence supports the effectiveness of lifestyle intervention and pharmacologic therapy with Metformin in patients with impaired glucose tolerance.  

Periodic vitamin B12 measurement should be considered in patients who are on long-term treatment with Metformin as it is associated with biochemical vitamin B12 deficiency, especially in those patients with anemia or peripheral neuropathy.  

¹References: American Diabetes Association. Standards of medical care in diabetes - 2024. Diabetes Care. 2024; 2023 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Food and Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus.  

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors  

Example Drugs: Alogliptin, Evogliptin, Gemigliptin, Linagliptin, Saxagliptin, Sitagliptin, Teneligliptin, Trelagliptin, Vildagliptin  

This group of drugs is indicated as monotherapy or in combination with Metformin, sulfonylurea, or thiazolidinedione for patients with type 2 diabetes mellitus as an adjunct to diet and exercise. When used in combination with Insulin, the dose of Insulin or sulfonylurea should be decreased to lower the risk of hypoglycemia.  

They decrease the rate of incretin inactivation which is usually released in the gut throughout the day and increase after meals. Incretins increase the release of insulin from pancreatic β-cells and decrease the secretion of glucagon from pancreatic α-cells. It affects both FPG and postprandial glucose. Its glucose-lowering efficacy is intermediate, and it reduces HbA1c by approximately 0.5-0.8% with monotherapy.¹  

Concurrent use of DPP-4 inhibitors with a GLP-1 receptor agonist is not recommended due to a lack of additional glucose lowering effect beyond that of a GLP-1 receptor agonist alone. It was found in the VERIFY trial that the initial combination of Metformin and Vildagliptin had a slower decline of glycemic control compared with Metformin alone or Vildagliptin added sequentially to Metformin.  

Based on two large clinical trials involving patients with heart disease, it was found that Alogliptin and Saxagliptin may increase the risk of heart failure in patients with heart or kidney disease. On the other hand, based on the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, Sitagliptin was not found to be associated with an increased risk of heart failure.  

DPP-4 inhibitors do not cause hypoglycemia or weight gain. They may be given to patients if the further gain in weight would exacerbate or cause significant problems. They may be taken without regard to food.  

¹References: American Diabetes Association. Standards of medical care in diabetes - 2024. Diabetes Care. 2024; 2023 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Food and Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus.    

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists  

Example Drugs: Albiglutide², Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide  

GLP-1 receptor agonists possess endogenous GLP-1 activity but are resistant to DPP-4 enzyme breakdown, resulting in longer action. It increases insulin release when glucose concentration is elevated, alters gastric emptying, prevents the postprandial rise in plasma glucagon, and causes satiety leading to lower caloric intake and weight loss. GLP-1 receptor agonists have very high to very high glycemic efficacy as they approximately reduce HbA1c by 0.5 to 1.4% with monotherapy and lower predominantly fasting plasma glucose or postprandial glucose based on the type (short- or long-acting) of GLP-1 agonist.¹  

GLP-1 receptor agonists are recommended in patients with established cardiovascular disease due to their cardiovascular benefit and in those with symptomatic heart failure with preserved ejection fraction. Dulaglutide, Liraglutide, and Semaglutide are GLP-1 receptor agonists that have proven cardiovascular benefit.  

GLP-1 receptor agonists have intermediate to very high weight loss efficacy and therefore may also be used to treat obese patients with type 2 diabetes mellitus who are already on Metformin and/or sulfonylurea. Among GLP-1 agonists, weight loss efficacy is as follows: Semaglutide > Liraglutide > Dulaglutide > Exenatide > Lixisenatide. GLP-1 receptor agonists are recommended to patients with type 2 DM and advanced chronic kidney disease due to the lower risk of hypoglycemia and cardiovascular events.

They are used as an alternative to adding insulin therapy in patients who fail to reach the target glucose level on dual therapy with Metformin and/or sulfonylurea. The dose of sulfonylurea should be reduced to lower the risk of hypoglycemia when combined with GLP-1 agonist.  

Except for twice-daily Exenatide, all GLP-1 agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia (MEN) syndrome type 2.  

Liraglutide may be used to further improve blood glucose levels in obese patients with type 2 diabetes mellitus who fail to reach target glucose level even with Metformin and a thiazolidinedione. It should also be considered in patients with long-standing sub-optimally controlled type 2 diabetes mellitus and established atherosclerotic cardiovascular disease as it has been shown to reduce the risk of adverse cardiovascular events (eg heart attack, stroke, cardiovascular death) when added to standard care. Liraglutide is recommended in patients with type 2 diabetes mellitus and cardiovascular disease or with very high or high cardiovascular risk to reduce the risk of death.  

Exenatide immediate-release formulation must be given within 60 minutes before breakfast and dinner while Exenatide extended-release formulation can be given at any time of the day with or without meals. It is not recommended for patients with end-stage renal disease or severe renal impairment.  

Dulaglutide is useful as an add-on therapy for patients with inadequately controlled diabetes mellitus during oral monotherapy.  

Semaglutide is an oral and subcutaneous (SC) GLP-1 receptor agonist used as monotherapy when Metformin is intolerable or contraindicated. It can also be used as an add-on therapy for patients with diabetes mellitus treated with other antidiabetic agents.  

¹References: American Diabetes Association. Standards of medical care in diabetes - 2024. Diabetes Care. 2024; 2023 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Food and Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus. ²Albiglutide is currently not available in the market.  

GLP-1 Receptor and Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Agonist  

Example Drug: Tirzepatide  

Tirzepatide is a once-weekly dual GLP-1 receptor and GIP receptor agonist subcutaneously given as an addition to diet and exercise for glycemic control improvement in adults with type 2 diabetes mellitus. It has very high glucose- and weight-lowering efficacy.

In clinical trials comparing Tirzepatide with other antidiabetic agents, participants who were given the maximum recommended dose of 15 mg had their HbA1c lowered by 0.5% more than Semaglutide, 0.9% more than Insulin degludec, and 1% more than Insulin glargine.  

Results from a phase 3 trial (SURMOUNT-2) showed weight loss of 9.6% and 11.6% more than placebo and HbA1c lowering of 1.55% and 1.57% more than placebo after 72 weeks of therapy with 10 mg and 15 mg doses respectively.  

Meglitinides/Non-Sulfonylurea Insulin Secretagogues  

Example Drugs: Mitiglinide, Nateglinide, Repaglinide  

They are short-acting insulin secretagogues that bind to a different site within the sulfonylurea receptor and stimulate the secretion of insulin. They are useful in controlling postprandial glucose and approximately decrease HbA1c by 0.7-1.5% with monotherapy¹.  

Meglitinides must be administered more frequently because of their short half-life as compared with sulfonylureas and they have a fast absorption from the gastrointestinal tract. They reach peak level at 1-hour post-administration and are eliminated within 4-6 hours.  

They may be used in combination with Metformin, thiazolidinediones, or alpha-glucosidase inhibitors. Concomitant use of Repaglinide and Gemfibrozil should be avoided due to a higher risk of hypoglycemia. They should be taken within 10-15 minutes before main meals. They may cause weight gain similar to sulfonylureas but have a lower risk for hypoglycemia.  

Sodium-Glucose Linked Transporter/Co-transporter 2 (SGLT2) Inhibitors  

Example Drugs: Bexagliflozin, Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Luseogliflozin  

SGLT2 inhibitors reduce the reabsorption of glucose in the renal tubules leading to increased urinary excretion of glucose. SGLT2 inhibitors are indicated as monotherapy or in combination with Metformin, or as a second-line therapy, and in patients with atherosclerotic cardiovascular disease in whom heart failure is present or is of special concern. They are the preferred antidiabetic agents in overweight and obese patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.  

They have intermediate to high glucose-lowering efficacy as they approximately decrease HbA1c by 0.4-0.8% with monotherapy.¹ SGLT2 inhibitors (eg Canagliflozin, Dapagliflozin, Empagliflozin, and Sotagliflozin) have proven cardiovascular benefit and were shown to reduce heart failure and the progression of CKD in cardiovascular outcome trials.  

In the Canagliflozin Cardiovascular Assessment Study (CANVAS) program, results showed that patients with an established atherosclerotic cardiovascular disease treated with Canagliflozin had lower rates of major adverse cardiovascular events and a lower risk of hospitalization for heart failure.  

In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients - Remove Excess Glucose (EMPA-REG) clinical trial, individuals with type 2 diabetes mellitus with established cardiovascular disease who took Empagliflozin in addition to standard care have lower rates of major adverse cardiovascular events and all-cause mortality and lower risk of hospitalization for heart failure (when compared to those who took the placebo). Thus, SGLT2 inhibitors are recommended in patients with type 2 diabetes mellitus and cardiovascular disease to reduce the risk of death.  

It has been found in the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction (DECLARE-TIMI 58) trial that individuals with type 2 diabetes mellitus taking Dapagliflozin had a lower rate of cardiovascular death or hospitalization for heart failure. In this trial, individuals with type 2 diabetes mellitus who had multiple risk factors for or established atherosclerotic cardiovascular disease were randomly assigned to receive Dapagliflozin or placebo and results did not show any statistically significant difference in the overall rate of major adverse cardiovascular events between these 2 groups. The trial results also showed a decrease in the risk of heart failure and adverse renal outcomes in a broad population of patients with type 2 diabetes mellitus. Other beneficial effects of SGLT2 inhibitors include reduction of fasting and 2-hour postprandial glucose levels, body weight, and blood pressure, and increases in HDL levels.  

In general, SGLT2 inhibitors have been found to be associated with an increased risk of genitourinary infections and slightly increased LDL-C. Canagliflozin was found in clinical trials to have an increased incidence of bone fractures. Patients taking Canagliflozin and Bexagliflozin have a potentially increased risk of amputation of the lower limb (mostly toes).  

Bexagliflozin was recently approved for the treatment of type 2 diabetes mellitus. Studies have shown that Bexagliflozin significantly reduces HbA1c and was considered non-inferior compared to Glimepiride and Sitagliptin; however, it was not superior to placebo in terms of reducing major adverse cardiovascular events.    

¹References: American Diabetes Association. Standards of medical care in diabetes - 2024. Diabetes Care. 2024; 2023 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Food and Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus.  

Sulfonylureas or Insulin Secretagogues  

Example Drugs: First generation: Chlorpropamide, Tolazamide, Tolbutamide; Second generation: Glibenclamide, Gliquidone, Gliclazide, Glimepiride, Glipizide  

Sulfonylureas are used as second-line options in patients intolerant of or with contraindications to Metformin. They are one of the agents that primarily affects FPG. Sulfonylureas decrease plasma glucose up to 25% by increasing the secretion of insulin from pancreatic beta cells. Their glucose-lowering efficacy is high as they approximately reduce HbA1c by 0.4-1.3% with monotherapy.¹

The dose may be increased at intervals of 1-2 weeks until satisfactory glycemic control or a maximum dose is reached. They have similar effectiveness in controlling hyperglycemia and thus, one should not combine two different sulfonylureas. They may be used in combination with other antidiabetic agents or Insulin to improve glucose control.  

Sulfonylureas may increase appetite and lead to weight gain. They may cause hypoglycemia due to their glucose-independent stimulation of insulin secretion. The risk of hypoglycemia is higher in patients with renal impairment and liver cirrhosis and in the elderly.  

Glibenclamide causes the highest rate of hypoglycemia as compared to other sulfonylureas and is not recommended in patients >60 years of age. Glipizide, Glimepiride, and Gliclazide may have a lower risk of hypoglycemia compared to other sulfonylureas.  

Sulfonylureas must be taken 30 minutes before meals, although Glimepiride and Gliclazide may be taken just before meals.  

¹References: American Diabetes Association. Standards of medical care in diabetes - 2023. Diabetes Care. 2023; 2021 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Food and Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus.  

Thiazolidinediones  

Example Drug: Pioglitazone  

As peroxisome proliferator-activated receptor-gamma agonists, they increase insulin sensitivity of the muscle, adipose tissue, and liver to endogenous and exogenous insulin. They are one of the agents that primarily affect FPG. They have high glycemic efficacy as they reduce HbA1c by approximately 0.5-0.9% when used as monotherapy.¹ Thiazolidinediones elevate HDL-C, lower blood pressure, reduce inflammation markers, decrease hepatic steatosis, decrease carotid and coronary artery thickening, and prevent restenosis after percutaneous transluminal coronary angioplasty. Glycemic control may only be improved after 6 weeks, and maximal effect may be seen up to 6 months after starting therapy.  

Thiazolidinediones may be an option with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Pioglitazone may be used as an add-on therapy for patients with type 2 diabetes mellitus with atherosclerotic cardiovascular disease without heart failure if additional glucose control is required. Pioglitazone may also be given to patients with a history of stroke and evidence of insulin resistance and prediabetes to lower the risk of stroke and myocardial infarction. However, this benefit needs to be balanced with the increased risk of weight gain, edema, and fractures. They may be given in combination with sulfonylureas, Metformin, DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors.  

Thiazolidinediones may cause fluid retention that is associated with the risk of new or worsened heart failure. Thus, it is contraindicated in patients with a history of heart failure. Additionally, it should be used with caution in combination with insulin due to an accentuated heart failure risk. It may also cause weight gain or bone fracture, especially in the distal upper or lower limb but may not be a reason for discontinuation. Consider using lower doses and combination therapy with other antidiabetic agents that promote weight loss and sodium excretion to reduce weight gain and edema.  

In 2015, the United States Food and Drug Administration (US FDA) concluded that Rosiglitazone monotherapy did not show additional cardiovascular risks in comparison to Metformin and a sulfonylurea combination based on an independent review of the RECORD trial. Hence, the restriction on prescribing and dispensing the drug has been lifted. The US FDA also removed the Risk Evaluation and Mitigation Strategy (REMS) as it is no longer needed to ensure that the benefits of Rosiglitazone therapy outweigh the risks.  

¹References: American Diabetes Association. Standards of medical care in diabetes - 2023. Diabetes Care. 2023; 2021 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Food and Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus.

Other Antidiabetic (Antihyperglycemic) Agents  

Amylin Analogue  

Example Drug: Pramlintide  

Pramlintide is approved for the treatment of type 1 diabetes mellitus. It is a synthetic analog of human amylin that slows gastric emptying without altering overall nutrient absorption, suppresses the pancreatic secretion of glucagon, and enhances satiety which leads to a decrease in caloric intake. It has been shown to induce weight loss and lower insulin dose requirements. It is used as an adjunct treatment in patients with type 1 and 2 diabetes mellitus who use mealtime insulin or have failed to reach target glucose control despite optimal insulin therapy. It is indicated only in patients who are willing to add 2-4 injections and more frequent glucose monitoring to their regimen.  

Pramlintide may be used in addition to prandial insulin therapy which may lower postprandial hyperglycemia, HbA1c, and weight. It reduces HbA1c by 0.4% and weight by 1 kg after 6 months and results in a 50% reduction in pre-prandial, rapid-acting, or short-acting insulin dosages. It may be used in combination with sulfonylurea and/or Metformin in type 2 diabetes mellitus. It should be given immediately before each main meal.  

Pramlintide is contraindicated in patients who are non-compliant with the current insulin regimen and are poorly adherent to the prescribed self-monitoring of blood glucose (SMBG). It is also contraindicated in patients who have HbA1c >9%, recurrent severe hypoglycemia requiring assistance during the past 6 months, hypoglycemia unawareness, a confirmed diagnosis of gastroparesis, and in those who require the use of drugs that stimulate gastrointestinal motility or drugs that slow the intestinal absorption of nutrients.  

Bromocriptine  

Bromocriptine is a dopamine receptor agonist that modestly improves glycemic control in conjunction with diet and exercise.  

It may be used in specific situations, and it does not lead to hypoglycemia and is associated with decreased rates of cardiovascular events. Side effects may include orthostasis and nausea; not to be concomitantly used with antipsychotic agents.  

Colesevelam  

Colesevelam is a bile acid sequestrant that modestly improves glucose levels as an adjunct to diet and exercise. It may be used in specific situations, and it does not lead to hypoglycemia and it reduces LDL-C levels.  

Side effects may include gastrointestinal intolerance and an increase in triglyceride levels in patients with hypertriglyceridemia.  

Teplizumab  

Teplizumab is a monoclonal antibody that binds to CD3 of T cells which increases the proportion of regulatory T cells and exhausted CD8+ T cells in the peripheral blood. It has been recently approved to delay the onset of stage 3 type 1 diabetes mellitus in adults and pediatric patients ≥8 years old with stage 2 type 1 diabetes mellitus.  

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Nonpharmacological

Lifestyle Modifications

Medical Nutrition Therapy (MNT)  

Medical nutrition therapy focuses on how to improve metabolic outcomes of diabetes mellitus by modifying nutrient intake and lifestyle. It is important in preventing and managing hyperglycemia and preventing, delaying, and treating diabetic complications.  

In patients with pre-diabetes, medical nutrition therapy may help lower diabetes mellitus and cardiovascular disease risk by promoting healthy food choices and physical activity which will lead to moderate weight loss that is sustained. In patients with diabetes mellitus, medical nutrition therapy will help reach and maintain blood glucose, blood pressure, and lipid profile levels as close to normal. It deals with individual nutritional needs based on personal and cultural preferences, severity of disease, and patient’s readiness for change. It maintains eating pleasure by only restricting food choices that are necessary for metabolic control. In patients with diabetes mellitus treated with Insulin or insulin secretagogues, medical nutrition therapy provides self-management training for the safe performance of exercise, preventing and treating hypoglycemia, and managing acute hyperglycemia. Adjustment of Insulin dose should match carbohydrate intake with specific reference to sucrose-containing or high glycemic index food.  

Studies had shown that after 3-6 months of medical nutrition therapy, HbA1c is decreased by 1% in type 1 diabetes mellitus and 1-2% in type 2 diabetes mellitus, and LDL-C is reduced by 0.4-0.6 mmol/L (15-25 mg/dL). There is no recommendation on nutrition that can prevent type 1 diabetes mellitus.  

Diet or Eating or Meal Plan

Diet modification is the cornerstone of diabetes mellitus management. Patients should be advised to avoid missing meals and it should be synchronized with the time actions of the medication. A balanced diet is recommended and should be individualized based on glucose and lipid targets. Lower fat intake, especially saturated fat, may decrease diabetes mellitus risk by producing an energy-dependent improvement in insulin resistance and promoting weight loss. A Mediterranean or plant-based diet rich in unsaturated fat is recommended to reduce cardiovascular risk.  

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