Effective Utilization of Oral Hypoglycemic Agents to Achieve Individualized HbA1c Targets in Patients with Type 2 Diabetes Mellitus

Metformin is the only biguanide available, and one of the oldest treatments for diabetes, dating back to the 1960s. Metformin reduces gluconeogenesis in the liver, lessening the amount of glucose released by the liver, particularly overnight. Additionally it increases the sensitivity of muscle cells to insulin, improving peripheral glucose uptake and utilization. Due to its mode of action, metformin rarely causes hypoglycemia.

The National Institute for Health and Care Excellence [3] pathway for blood-glucose-lowering therapy for type 2 diabetes recommends that metformin is initiated as first-line therapy in asymptomatic patients with a HbA1c greater than 48 mmol/mol, or higher than an agreed individualized target despite changes to lifestyle. Metformin should be commenced with a starting dose of 500 mg once daily after food with active titration over a 4-week period to the maximum tolerated dose or maximum dose of 2 g daily. Adopting this approach reduces the common side effects of nausea, vomiting, diarrhea, and abdominal pain. Slow-release preparation of metformin could be trialed if side effects mean that standard release preparations cannot be tolerated.

If renal function declines below 45 mL/min/1.73 m² [8], a dose review should occur, with a maximum dose of 1 g being prescribed. Metformin should be discontinued in patients whose eGFR is less than 30 mL/min/1.73 m². Due to an increased risk of lactic acidosis if a sudden deterioration in renal function occurs, metformin should be withheld prior to general anesthesia, procedures requiring contrast medium, and episodes of acute deterioration in eGFR until the renal function normalizes. Dehydration increases the risk of deterioration in renal function; therefore, patients should be aware that they should stop taking metformin if they become unwell with diarrhea and vomiting.

Commonly prescribed sulfonylureas include glimepiride and gliclazide; their mode of action requires a degree of beta-cell function, as they stimulate the pancreas to increase insulin secretion and as a result have a significant risk of inducing hypoglycemia and can potentially cause weight gain. NICE 2015 [3] recommends their use as first-line therapy in symptomatic patients, and should be titrated weekly whilst osmotic symptoms are present based on blood glucose self-monitoring results. Prescribing sulfonylureas in the elderly population and in people who drive requires caution because of the associated risk of hypoglycemia.

Pioglitazone is the only thiazolidinedione currently prescribable in Europe. It acts directly at the cellular level, increasing the sensitivity of the hepatic and muscle tissue to endogenous insulin, and is particularly efficacious in patients whose underlying pathophysiology is insulin resistance. As pioglitazone does not impact on insulin secretion, the hypoglycemia risk is low unless used in combination with a sulfonylurea or insulin. Pioglitazone should be initiated at 15 mg, increasing to 30 mg after 3 months if there has not been a response. Increasing to 45 mg would only be indicated if there was a reduction in HbA1c with 30 mg but the target HbA1c was not reached. If no additional response is noted with 45 mg, the dose should be reduced back to 30 mg [9]. If a 6 mmol/mol drop is not achieved after 6 months on 30 mg it should be stopped. Due to an increased risk of fluid retention, which could exacerbate or precipitate heart failure, pioglitazone is contraindicated in patients with or a history of heart failure. Advice in relation to signs and symptoms of heart failure such as edema should be part of the patient consultation on initiating treatment, and treatment should be stopped if any symptoms develop. Liver function tests should be carried out prior to initiation and periodically thereafter due to a rare potential risk of liver toxicity. If the alanine aminotransferase (ALT) level remains more than three times the upper limit of normal, pioglitazone should be discontinued. Suggestions have been made that pioglitazone potentially increases the risk of bone fractures and bladder cancer in a recent multi-population pooled cumulative-exposure analysis; however, it showed that there was no association with the cumulative use of pioglitazone and the associated incidence of bladder cancer [10]. Recent studies in individuals without diabetes but with diagnosed insulin resistance and a history of ischemic stroke or transient ischemic attacks treated with pioglitazone showed a significant reduction in the relative risk of nonfatal heart attack or fatal and nonfatal stroke, suggesting that addressing insulin resistance though treatment with pioglitazone could improve cardiovascular outcomes [19].

There are five different DPP4 inhibitors currently on the market: alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin. They work by inhibiting DPP4, which is an enzyme that destroys the hormone GLP-1. GLP-1 aids glucose-dependent insulin production, in particular first-phase insulin release. Due to the glucose-dependent mode of action, they are unlikely to cause hypoglycemia unless used concomitantly with a sulfonylurea or insulin. These groups of drugs are weight neutral which, combined with the low risk of hypoglycemia, means they are a suitable treatment option for the elderly and occupational drivers. If used as second-line therapy with metformin, patients are not required to undertake glucose self-monitoring due to the low risk of hypoglycemia. DPP4 inhibitors have the associated increased risk of pancreatitis and should be avoided in patients with high triglycerides. Patients require counseling on initiation about the signs and symptoms of pancreatitis, with instructions for when and how to seek urgent medical advice. The majority of DPP4 inhibitors are taken once daily and the doses need to be adjusted according to renal function, with the exception of linagliptin, which has no restriction based on eGFR as it is excreted in the bile. Post-surveillance trials have highlighted that DPP4 inhibitors can cause severe and disabling joint pain. It was found that when DPP4 inhibitors were stopped, the pain and symptoms resolved. Therefore, it would be appropriate to consider a trial without the DPP4 inhibitor if patients report joint pains [11]. Concerns relating to DPP4 inhibitors and increased heart failure risk have been raised in cardiovascular safety studies for a number of treatments. The SAVOR-TIMI 53 trial [12] found an increased risk of admission to hospital for heart failure with saxagliptin. The EXAMINE trial [13], which reviewed alogliptin, and the TECOS trial [14], which reviewed sitagliptin, did not identify any statistically significant effect on hospital admissions for heart failure. More recently, a further safety review from the US Food and Drug Administration [15] found that saxagliptin and alogliptin may increase the risk of heart failure, especially in patients where heart failure or kidney disease is already present. Patients therefore should be warned of the signs and symptoms of heart failure and advised to seek urgent medical advice if concerned, and healthcare professionals should contemplate stopping the treatment if patients develop heart failure. Applying these findings to clinical practice would mean exercising caution when utilized in patients with type 2 diabetes with heart and kidney disease, paying particular attention to ensuring correct dosage based on a current eGFR result. Response to treatment initiation must be reviewed, and if the HbA1c has not reduced by 6 mmol/mol from when the treatment was initiated it should be discontinued [3].

These are the newest group of oral hypoglycemic agents, and include dapagliflozin, canagliflozin, and empagliflozin. SGLT2 is a protein which encourages glucose reabsorption in the proximal tubule in the kidney. The SGLT2 inhibitors block the receptor site, preventing activation of the glucose channel and glucose reabsorption, so the glucose remains in the renal filtrate and ultimately the urine. As the filtrate passes through the loop of Henle, water is reabsorbed by osmosis, but as a result of the elevated levels of glucose in the filtrate, reduced water reabsorption occurs, resulting in increased urine production. The loss of glucose in the urine and thus calories can result in weight loss. However, the side effects due to the glycosuria include increased risk of urinary tract infections and thrush/balanitis. For SGLT2 inhibitors to be effective, good renal function is required, and they should not be prescribed to patients whose eGFR is less than 60 mL/min/1.73 m². The increased diuresis that can result from glycosuria can potentially cause hypotension, and SGLT2 inhibitors should be used with caution in combination with a loop diuretic. The three SGLT2 inhibitors vary in their licensing guidance. Dapagliflozin is not licensed with pioglitazone, is not recommended in triple therapy, and should be stopped if eGFR drops below 60 mL/min/1.73 m². Canagliflozin and empagliflozin are both licensed for triple therapy and with pioglitazone. They can be continued at the lower prescribable dose even if eGFR drops below 60 mL/min/1.73 m² if a therapeutic benefit has been noted, but are stopped if eGFR drops below 45 mL/min/1.73 m². SGLT2 inhibitors are taken once daily, with canagliflozin and empagliflozin having the option of a titrating dose. If the HbA1c has not reduced by 6 mmol/mol following the initiation of treatment, it should be discontinued. Unless prescribed in combination with a sulfonylurea or insulin, then the risk of hypoglycemia is low.

As with all new diabetes oral therapies, they require the study of cardiovascular endpoints to assess safety. Empagliflozin, the most recent SGLT2 inhibitor on the market, was found to have added benefits of reducing the relative risk of cardiovascular death, nonfatal heart attack, or nonfatal stroke by 14% and a significant 38% relative risk reduction in cardiovascular death rate. These positive results come from the EMPA-REG OUTCOME trial [16], but it still needs to be determined if this relates to the class of drugs, as cardiovascular outcome studies are still in progress for canagliflozin and dapagliflozin.

A number of clinical concerns have been raised with this group of drugs. An increased risk of acidosis with euglycemia has been noted, particularly during the first 2 months of treatment [17]. Whilst the case numbers were low and a third were identified as having type 1 diabetes, clear guidance has been issued that—particularly when used in combination with insulin or a sulfonylurea, where doses have been reduced—vigilance for ketosis must be high. Patients therefore should be informed of the signs and symptoms of diabetic ketoacidosis (DKA), and healthcare professionals still need to consider DKA in patients who present with the symptoms but whose glucose levels are within the normal range and, as with metformin treatment, should be suspended in patients hospitalized for major surgical procedures or acute medical illness and restarted once the patient’s condition has stabilized.

Concerns in relation to an increased frequency of fractures with canagliflozin compared to placebo and links to reduced bone mineral density have resulted in changes to the drug label “warning and precaution” and “adverse reactions” [18]; further concerns have been highlighted in the CANVAS study in relation to increased amputation rates in those patients with a high cardiovascular risk, particularly those with a previous history of amputation [20]. In clinical practice, this requires healthcare professionals to be mindful of patient risk factors before commencing this treatment, and to consider if it actually the most appropriate treatment choice for that patient. Reporting side effects is an important way of establishing any adverse impacts from new drugs, and all healthcare professionals need to be involved in this process when appropriate. The importance of ensuring that patients maintain good levels of hydration when treated with SGLT2 inhibitors in order to minimize the risk of potential adverse outcomes is being increasingly being stressed [20].

A DPP4 inhibitor. With an eGFR of 49 mL/min/1.73 m², alogliptin, saxagliptin, sitagliptin, and vildagliptin could be used at a reduced dose. Linagliptin would not need adjusting according to eGFR as the dose is not affected by eGFR results, so this could be used at the maximum dose. The eGFR would need to be closely monitored because the metformin dose would need halving if the eGFR drops below 45 mL/min/1.73 m².

Table 2 shows the treatment decisions and rationales for this patient.

An SGLT2 inhibitor. His eGFR is within the normal range. His weight is his main concern. Pioglitazone was shown to have a good therapeutic effect at 30 mg, and his HbA1c reduced by another 7 mmol/L when the dose was increased to 45 mg, so pioglitazone would be continued. Dapagliflozin is not licensed with pioglitazone so it would not be appropriate in this case, but empagliflozin and canagliflozin would be an option for third-line therapy.

Table 3 shows the treatment decisions and rationales for this patient.

Pioglitazone 15 mg (titrated to 30 mg at 3 months if HbA1c remains above target) or SGLT2 inhibitor. Insulin resistance is the primary pathology of type 2 diabetes in this patient due to his ethnic origin and raised BMI. Pioglitazone has the potential to improve his insulin sensitivity. A SGLT2 inhibitor will potentially result in weight loss, and a 5–10% weight loss would have a positive impact on insulin sensitivity. As the patient is an occupational driver with potentially erratic meal patterns, it is important to minimize the risk of hypoglycemia. Whichever treatment is commenced first should be agreed upon following discussion with the patient. The unused treatment should be added if triple therapy is indicated or the first choice is stopped due to lack of impact on control or side effects.

Table 4 shows the treatment decisions and rationales for this patient.

Glimepiride with blood glucose self-monitoring to facilitate dose titration. A sulfonylurea will have the quickest impact on symptoms, as it will stimulate increased insulin production if sufficient beta-cell function remains. Blood glucose self-monitoring will be required to facilitate rapid dose titration to correct high blood glucose levels and in turn resolve symptoms. If there is no response to glimepiride in the first couple of weeks, rapid referral to the specialist diabetes team for insulin therapy is indicated. Metformin could be added as second-line treatment if there is a positive response to glimepiride but the HbA1c target is not achieved. Due to BMI, the third-line treatment should be insulin.

Table 5 shows the treatment decisions and rationales for this patient.