Type 2 diabetes mellitus

What it is

Diabetes is classified into four main categories: type 1 diabetes, type 2 diabetes, gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation), and specific types of diabetes. Type 2 diabetes accounts for 90% of cases. It is characterized by:

• Obesity, global or abdominal
• Features of insulin resistance
• Hyperinsulinemia, which then progresses to relative insulin deficiency

How it is treated

Metformin is the first medication prescribed when an oral agent is required, and first-line therapy to reduce microvascular complications, assist in weight management, reduce the risk of cardiovascular events, and reduce mortality. It reduces glycemic levels, is linked to weight loss and fewer occurrences of hypoglycemia, and is less expensive than most other options. It decreases food intake by about 250-300 kcal per day and gives moderate weight loss in the range of 2-4 kg. If more than one agent is required, metformin is continued and one or more of the following is added: a sulfonylurea such as glipizide, a thiazolidinedione such as pioglitazone, an SGLT2 inhibitor such as empagliflozin, or a DPP-4 inhibitor such as alogliptin. Weight is part of that choice. Sulfonylureas, including glimepiride, are associated with weight gain. Empagliflozin, liraglutide, metformin and sitagliptin are not, and SGLT2 inhibitors and GLP1 agonists give clinically significant weight loss. A patient who is intolerant of metformin is unlikely to be successful with a third trial of that agent; empagliflozin is then a second-line choice. Sitagliptin and liraglutide should be avoided or used with caution after pancreatitis.

How the control is measured is set out with the same care as what is given. The HbA1C test is the most important test for assessment of glycemic control; it should be done at diagnosis, and during follow up every 6 months if glycemia is controlled and stable, or every 3 months if therapy has been changed or the glycemic target is not met. So a woman whose therapy has not been changed and whose HbA1c is at target is seen at 6 months, not at 3. For most non-pregnant adults the target is an HbA1C below 7.0%, made more or less stringent according to hypoglycemia risk, disease duration, life expectancy, important comorbidities, established vascular complications, patient preference and resources. The two ends it moves between are a more stringent A1C <6.5% and a less stringent A1C <8%, and every factor has a direction: hypoglycemia risk low against High; disease duration Newly diagnosed against Long standing; life expectancy Long against short; important comorbidities Absent against Severe; established vascular complications Absent against Severe; patient preference Highly motivated against Not motivated; resources Readily available against Limited.

In a child or adolescent with type 2 diabetes the comorbidities are checked at set times. Urine ACR should be obtained at the time of diagnosis and annually, an elevated ACR above 30 mg/g creatinine confirmed on two of three samples; blood pressure is monitored at every visit; retinal examination is performed at diagnosis and annually thereafter; and ALT and AST are measured at diagnosis and annually thereafter to evaluate for NAFLD and non-alcoholic Steatohepatitis. Testing for dyslipidemia is the one item that runs on a different clock: it is repeated once glycemic control has been achieved or after 3 months of initiation of medication, and annually thereafter.

When insulin is started is set out as a list, and it is not only the end of the road. Insulin is for all T1DM, and it is considered for T2DM at any stage of the disease if there is ongoing catabolism, meaning unintentional weight loss; if severe symptoms of hyperglycemia are present; if the HbA1C level is above 10% or the blood glucose readings are very high; or if glycemic targets are not achieved with the other anti-hyperglycemic medications. So a patient with unintentional weight loss, or one sitting above 10%, is put on insulin even while the other medications continue.

The classes are worth holding as one table, by mechanism, route and main side effect.

• Insulin: direct replacement for endogenous insulin, subcutaneous; hypoglycaemia, weight gain and lipodystrophy. Used in all patients with T1DM and some patients with poorly controlled T2DM, and classified by source, that is analogue, human sequence and porcine, and by duration of action, short, immediate and long-acting.
• Metformin: increases insulin sensitivity and decreases hepatic gluconeogenesis, oral; gastrointestinal upset and lactic acidosis. First-line medication in the management of T2DM. In one source it cannot be used in patients with an eGFR of less than 30 ml/min.
• Sulfonylureas: stimulate pancreatic beta cells to secrete insulin, oral; hypoglycaemia, weight gain and hyponatraemia. Examples include gliclazide and glimepiride.
• Thiazolidinediones: activate the PPAR-gamma receptor in adipocytes to promote adipogenesis and fatty acid uptake, oral; weight gain and fluid retention. The only currently available thiazolidinedione is pioglitazone.
• DPP-4 inhibitors, the gliptins: increase incretin levels, which inhibit glucagon secretion, oral; generally well tolerated but with an increased risk of pancreatitis.
• SGLT-2 inhibitors, the gliflozins: inhibit reabsorption of glucose in the kidney, oral; urinary tract infection. They typically result in weight loss.
• GLP-1 agonists, the tides: incretin mimetic which inhibits glucagon secretion, subcutaneous; nausea and vomiting, and pancreatitis. They typically result in weight loss.

In pregnancy the two that are used together are named. A 30 year old G2P1 woman with a history of type 2 diabetes mellitus at 40 weeks, managing her diabetes on a regimen of metformin and insulin, with good glycemic control and HbA1c maintained below 6.5%, and an estimated fetal weight of 4200 grams on the last ultrasound, is the setting in which the mode and timing of delivery are then weighed.