INTRODUCTION
Diabetes mellitus is a metabolic disease that requires ongoing medical attention and family support in order to reduce complications and maintain glycemic control. Patients must be educated about self-management and support in order to reduce the risk of long-term consequences and avoid acute ones.
TREATMENT GOALS TO PREVENT COMPLICATIONS AND OPTIMIZE THE QUALITY OF LIFE
|
BMI category (kg/m2) Treatment
(or 23.0–“ 26.9*)
(or 27.5–“ 32.4*)
(or 32.5–“ 37.4*) ≥40 (or ≥37.5*) Diet, physical activity + + + + + Pharmacotherapy + + + + Metabolic surgery + + + *Cut-off for Asians. +Treatment may be indicated for selected motivated patients. Since there is no one optimal dietary distribution of calories across proteins, lipids, and carbs, meal plans should be customized while keeping in mind metabolic objectives and total caloric intake. Complex, high-fiber sources of carbohydrates should be consumed, such as fruits, vegetables, whole grains, legumes, and some dairy products. To improve glycemic control, patients with type 1 and type 2 diabetes receiving insulin therapy should be taught how to count carbohydrates and how to calculate insulin dosage at mealtimes by taking protein and fat content into account. The most effective way to enhance glycemic control is to eat a balanced diet. Certain diets, such as the Paleo and ketogenic diets, can only be followed for brief periods of time under close supervision and in institutional settings, and they must be well watched for any negative consequences. Adult men and women are allowed to consume one drink and two drinks, respectively. However, alcohol reduction must be recommended for people with fatty livers. Exercise The best exercise for patients with diabetes is a combination of aerobic and resistance training. The muscle mass increases with resistance training which contributes to blood glucose uptake without altering the muscle's intrinsic capacity to respond to insulin. The aerobic exercises on the other hand enhance glucose uptake via an enhanced insulin action, and this is independent of changes in muscle mass or aerobic capacity. Pharmacological Therapy for Type 1 Diabetes Insulin for Type 1 Diabetes Mellitus People with type 1 DM should be continued on basal bolus insulin therapy. Insulin requirements are estimated based on weight. The typical doses range from 0.4 units/kg/day to 1.0 units/kg/day. Higher amounts of insulin need to be given during puberty, pregnancy, and medical illness. The insulin dose can be divided conventionally into one half as prandial for mealtime glucose and the rest as basal to control glycemia in the periods between meal absorption. Non-insulin Treatment for Type 1 Diabetes Mellitus Metformin (Not approved): There are some studies with metformin where its addition helped in causing body weight and lipid levels reductions to a small extent but did not improve A1c. Presently metformin is not approved to use in type 1 diabetes mellitus. PramlintidePramlintide is an analogue of naturally occurring β-cell peptide amylin and is approved for use in adults with type 1 diabetes. Studies showed variable reductions of A1c (0–“0.3%) and body weight (1–“2 kg) with the addition of pramlintide to insulin. GLP1 Agonists (Not Approved): The glucagon-like peptide 1 (GLP-1) receptor agonists liraglutide and exenatide added to insulin therapy have shown small reductions in A1c about 0.2% compared with insulin alone in people and also reduced body weight by 3 kg.SGLT2 Inhibitor (Not Approved Presently): Sodium–“glucose cotransporter 2 (SGLT2) inhibitor added to insulin therapy has shown improvements in A1c and body weight when compared with insulin alone, but the risk of ketoacidosis is very high.7 Sotagliflozin which is a dual SGLT1/2 inhibitor, is currently under consideration by the FDA.Surgical Treatment for Type 1 Diabetes MellitusPancreas and Islet TransplantationPancreas and islet transplantation is a surgical option to normalize glucose levels but is associated with problems like lifelong immunosuppression and recurrence of autoimmune islet destruction. This candidates for pancreas transplantation include patients with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or those who have recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management.Pharmacotherapy for Type 2 Diabetes MellitusMetforminIt is one of the preferred initial pharmacologic agents for the treatment of type 2 diabetes as per all international and national guidelines. The gastrointestinal side effets are common and are dose-dependent and do improve with time. The dose reduction may be needed for some patients because of these side effects. It is not approved for use in patients with an eGFR < 30 ml/min/1.73 m2 and dose reduction should be considered when the eGFR is <45 ml/min/1.73 m2. It has high efficacy, low cost, minimal hypoglycemia risk when used as monotherapy, and the potential for some weight loss. This makes it the preferred agent of choice for patients with type 2 diabetes mellitus. There is no conclusive evidence on reduction of CVD but as compared to sulfonylureas, the risk for cardiovascular mortality is lower. There is a risk of vitamin B12 deficiency with long-term use and patients need to be supplemented with vitamin B12 if they have a deficiency or symptoms of peripheral neuropathy.11 The risk of lactic acidosis is very miniscule and is seen mostly within the setting of severe illness or acute kidney injury.SGLT2 InhibitorsSGLT2 inhibitors are one of the latest oral antidiabetic medications that reduce plasma glucose by enhancing urinary excretion of glucose. All SGLT2 inhibitors have the advantage of reducing weight and blood pressure. Figure 1. Glucose lowering in type 2 diabetes mellitusAnti-diabetic drugs (OADs) like sulfonylureas and insulin the risk can be increased. Empagliflozin, dapagliflozin and canagliflozin have cardiac and renal benefits in patients with established or at high risk of ASCVD. The lower approved eGFR cut- off for the use of SGLT2 inhibitors 45 mL/min/1.73 m2 but latest data has shown efficacy till eGFR of 30 mL/min/1.73 m2 along with glycemic control. They are associated with increased risk for mycotic genital infections (mostly vaginitis in women, balanitis in men).SGLT2 inhibitors can cause diabetic ketoacidosis but it can be avoided by not using it during stress states and to not use it in other types of diabetes. CANVAS study showed that canagliflozin is associated with increased risk for lower limb amputations and fractures whereas CREDENCE study didn't indicate any increased risk for amputations and fractures. It is uncertain whether amputation and fractures are class effects.GLP-1 Receptor AgonistsThese medications help in stimulating insulin secretion and reducing glucagon secretion in a glucose-dependent manner, improve satiety and promote weight loss. The duration of action is related to the structural differences among GLP-1 receptor agonists, and their efficacy, weight losing effects, side-effect profile and cardiovascular benefit is dependent on formulation and dosing.There are once weekly formulations like dulaglutide, exenatide extended-release and semaglutide and daily formulations like liraglutide. GLP-1 receptor agonists have high glucose-lowering efficacy, but with variation within the drug class. The weight reduction with all GLP-1 receptor agonists ranges from about 1.5 kg to 6.0 kg over about 6–“7 months of therapy.GLP-1 receptor agonists delivered by subcutaneous injection but oral formulations are under research.Liraglutide, semaglutide and dulaglutide have been shown to improve cardiovascular outcomes. The common side effects are nausea, vomiting and diarrhea, though these tend to lessen over time. The patients are told to avoid heavy and fatty meals when they start taking it as it may exacerbate nausea and vomiting. GLP-1 receptor agonists when used with metformin or alone have a minimal risk for hypoglycemia, but when combined with insulin and sulfonylureas, the risk increases. An increased risk of gallbladder events is seen. Semaglutide was shown to be with increased retinopathy complications in the SUSTAIN 6 trial, and it is seen in those with baseline retinopathy who had rapid improvement of glycemic control. GLP-1 receptor agonists have not been shown to substantially increase the risk for pancreatitis, pancreatic cancer or bone disease.DPP-4 InhibitorsDPP-4 inhibitors are oral medications which agument the increase in insulin secretion by blocking the DPP-4 enzymes and reduce glucagon secretion in a glucose-dependent manner. They have moderate glucose-lowering efficacy. DPP-4 inhibitors are weight neutral and have minimal risk of hypoglycemia when used as monotherapy but when used in combination with agents like sufonyureas and insulin, the risk increases. The dose of DPP-4 inhibitor needs to be adjusted based on renal function; linagliptin is the exception as it has minimal renal excretion. Teneligliptin also does not need dose adjustment based on renal function. Some causes of pancreatitis have been reported but most of the real world studies have not confirmed that some studies have also shown increased musculoskeletal side effects. DPP4 inhibitors are cardioneutral though some studies showed increased hospitalization for heart failure for saxagliptin.ThiazolidinedionesThiazolidinediones (TZDs) (pioglitazone) are oral medications that increase insulin sensitivity and are of high glucose-lowering efficacy. They are most useful for young individuals who are not overweight or obese. Thiazolidinediones increase HDL-cholesterol, and pioglitazone has been shown to reduce cardiovascular endpoints, and hepatic steatohepatitis. Thiazolidinediones have good glycemic durability. However, the safety concerns regarding fluid retention and congestive heart failure, weight gain, bone fracture and, possibly, bladder cancer have limited their extensive use.SulfonylureasSulfonylureas are inexpensive medications with good glycemic efficacy and they lower glucose by stimulating insulin secretion from pancreatic beta-cells. Sulfonylureas have demonstrated good effect on reduction in microvascular complications in the UKPDS and ADVANCE trials. Sulfonylureas cause weight gain and increase the risk for hypoglycemia though lower than seen with insulin. Glibenclamide has a higher risk of hypoglycemia compared with other sulfonylureas. Glipizide, glimepiride and gliclazide may have a lower chance for hypoglycemia compared with other sulfonylureas. Glibenclamide abolishes ischemic preconditioning and should be avoided. The other sulfonylureas in use are cardioneutral. Greatest caution is warranted for people at high risk of hypoglycemia, such as older patients and those with CKD. Gliclazide is approved for use across all stages of diabetic kidney disease.Insulin–˜Human' insulins (NPH, regular [R], and premixed combinations of NPH and R) are recombinant DNA-derived human insulin, while insulin analogues have been designed to change the onset or duration of action. Insulin lowers glucose in a dose-dependent manner, to almost any glycemic target . There is an increased risk of hypoglycemia with the use of insulin and also other disadvantages include weight gain and the need for injections, frequent titration for optimal efficacy and glucose monitoring. The intermediate- and long-acting insulins differ in timings of onset, durations of action and risks of hypoglycemia. The treating physician should ensure whether insulin administration, rotation and storage are correctly followed and also check for any hypertrophy or lipoatrophy at insulin injection sites at each visit.Basal InsulinBasal insulins are longer-acting insulin which cover the body's basal metabolic insulin requirement (Fig. 2). There are various options which include once- or twice- daily administration of intermediate-acting NPH or detemir insulin and the once- daily administration of glargine (U100 or U300) or degludec (U100 or U200). The advantage of long-acting insulin analogues like degludec, glargine [U100 and U300 and detemir are that they have a modestly lower absolute risk for hypoglycemia compared with NPH insulin, but the cost is more. Biosimilar formulations are also available for glargine and have shown similar efficacy with lower cost. Insulin has not been shown to reduce the risk for CVD, but data suggest that glargine U100 and degludec do not increase the risk for MACE. Figure 2. Algorithm for titration of insulin. The advantage of glargine (U300) are available that allow injection of a reduced volume and is convenient for patients on higher doses. Not all patients have their blood glucose adequately controlled with basal insulin. The patients require intensification of therapy with prandial insulin if glucose values are not controlled with basal insulin therapy. Prandial Insulin Formulations The patients who are not adequately controlled (Table 2) with basal insulin therapy require intensification with meal-time administration of short- or rapid-acting or ultrarapid-acting insulin formulations. There are various options like human regular insulin, different analogues (aspart, glulisine and lispro), formulations (faster insulin aspart, lispro U200). The rapid-acting insulin analogues have a modestly lower risk for hypoglycemia, provide more flexibility as compared with human regular insulin but the cost is higher. Various premixed formulations of human and analogue insulins are available and continue to be widely used in India as patients comply better with them because of one type of insulin with lesser prick (Fig. 2). Table 2. Glycemic targets as recommended by various organisations
|
