Dr Larry Distiller, specialist physician, endocrinologist at the Centre for Diabetes and Endocrinology in Johannesburg, gave a practical overview of the 2018 American Diabetes Association (ADA) Standards of Medical Care in Diabetes for the SA market.

With all the emphasis on newer medication, we often forget that the cornerstone of therapy remains lifestyle improvement, and this is given extensive coverage in the 2018 ADA Guidelines

The management of diabetes is changing rapidly as new treatment options, technologies and the outputs of research continue to snowball. While many of these emerging treatment strategies are now available in South Africa, local affordability issues make the majority of these newer options inaccessible to the public sector and limit inclusion on the baskets of care for medical schemes in the private health sector. Diabetes, together with its co-morbidities, has always been an expensive and complex condition to manage, requiring on-going medical care, with multifactorial risk-reduction strategies beyond glycaemic control.

Treatment costs have increased exponentially if one is to use many of the newer treatments and technologies recommended in the guidelines promulgated in developed economies. In South Africa, we have the paradox of trying to deliver best-practice medicine in a developing economy. This places a large burden on the heath care practitioner who needs to weigh up the scientific and clinical advantages of anything new with the cost implications for the patient, the Medical Schemes and the country. The result is often an ethical conflict regarding clinical-efficacy versus cost-efficacy.

With all the emphasis on newer medication, we often forget that the cornerstone of therapy remains lifestyle improvement, and this is given extensive coverage in the 2018 ADA Guidelines.

Once again, the need for input from the entire diabetes team is stressed. The reason for this is clear. Without appropriate lifestyle adjustment, no medication, new or old, will improve control. Too often patients and health care providers alike will target a ‘new pill’ in the hope of improving outcomes, whilst foundational lifestyle therapies are ignored. Particular emphasis is placed on weight loss where applicable. Lowering caloric intake is the main driver for weight loss irrespective of the dietary approach chosen and patients should be referred to a registered dietician who ideally has specific training in diabetes and cardiovascular risk factor management.

With recent interest in low-carbohydrate diets, the ADA has added a section on this in which they state that the role of low-carbohydrate diets in patients with diabetes remains unclear. Part of the confusion is due to the wide range of definitions for a ‘low-carbohydrate diet’. While some literature has shown benefits of low-carbohydrate diets, the results seem to be short term and, over time, these effects are not maintained.

With regard to exercise, it is recommended that a physical activity regimen should involve at least 150 minutes per week of moderate-intensity physical activity such as brisk walking and strength training. Of interest, the ADA have now added the need for seven hours of ‘good’ sleep per night as a requirement for satisfactory life style adjustment, and recommend excluding obstructive sleep apnoea in patients who cannot achieve this.

The ADA document stresses that providers should assess social context, including potential food insecurity, housing stability, and financial barriers, and apply that information to treatment decisions. As always, this is even more applicable in the South African context.

Finally, the ADA document devote far more space than previously to the importance of controlling other co-morbidities such as dyslipidaemia and hypertension, and attempt to place glycaemic control and targets into perspective when providing holistic treatment for the metabolically at-risk patient.

“The Standards of Medical Care in Diabetes includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care,” stated the authors.

Pharmacologic therapy for type 1 diabetes

Recommendations

  • Most people with type 1 diabetes should be treated with multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion.
  • Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycaemia risk.
  • Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, pre-meal blood glucose levels, and anticipated physical activity.
  • Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age.

Insulin therapy

Insulin should be the mainstay of therapy for individuals with type 1 diabetes, the authors recommended. “Generally, the starting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/day of total insulin with higher amounts required during puberty.”

According to Wolpert et al, Dietary fat acutely increases glucose concentrations and insulin requirements in patients with type 1 diabetes: implications for carbohydrate-based bolus dose calculation and intensive diabetes management. (2013), “Education regarding matching prandial insulin dosing to carbohydrate intake, pre-meal glucose levels, and anticipated activity should be considered, and selected individuals who have mastered carbohydrate counting should be educated on fat and protein gram estimation.

Yeh et al, Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis (2012), stated that although most studies of multiple daily injections versus continuous subcutaneous insulin infusion (CSII) have been small and of short duration, a systematic review and meta-analysis concluded that there are minimal differences between the two forms of intensive insulin therapy in A1C (combined mean between-group difference favouring insulin pump therapy –0.30% [95% CI –0.58 to –0.02]) and severe hypoglycaemia rates in children and adults.

A three-month randomised trial by Bergenstal et al, ASPIRE In-Home Study Group. Threshold-based insulin-pump interruption for reduction of hypoglycaemia (2013), found, “In patients with type 1 diabetes with nocturnal hypoglycaemia reported that sensor-augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycaemia without increasing glycated haemoglobin levels.”

“Intensive management using CSII and continuous glucose monitoring should be encouraged in selected patients when there is active patient participation,” the guidelines encouraged.

“The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive therapy with multiple daily injections or CSII delivered by multidisciplinary teams of physicians, nurses, dietitians, and behavioural scientists improved glycaemia and resulted in better long-term outcomes,” Diabetes Care (2016). The study was carried out with short-acting and intermediate-acting human insulins. Despite better microvascular, macrovascular, and all-cause mortality outcomes, intensive therapy was associated with a high rate of severe hypoglycaemia (61 episodes per 100 patient-years of therapy).

“Since the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed. These analogs are associated with less hypoglycaemia, less weight gain, and lower A1C than human insulins in people with type 1 diabetes. Longer-acting basal analogs (U-300 glargine or degludec) may additionally convey a lower hypoglycaemia risk compared with U-100 glargine in patients with type 1 diabetes.” Tricco et al, Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis. (2014.)

Pramlintide

“Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is FDA-approved for use in adults with type 1 diabetes. It has been shown to induce weight loss and lower insulin doses. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycaemia,” the American Diabetes Association recommended.

Investigational Agents

Metformin

Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in patients with type 1 diabetes. In one study, metformin was found to reduce insulin requirements (6.6 units/day, P < 0.001), Vella et al. The use of metformin in type 1 diabetes: a systematic review of efficacy. (2010), and led to small reductions in weight and total and LDL cholesterol, but not to improved glycaemic control (absolute A1C reduction 0.11%, P = 0.42).

A randomised clinical trial, Libman et al T1D Exchange Clinic Network Metformin RCT Study Group. Effect of metformin added to insulin on glycaemic control among overweight/obese adolescents with type 1 diabetes: a randomised clinical trial, (2015), similarly found that, among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycaemic control and increased risk for gastrointestinal adverse events after six months compared with placebo.

The Reducing With Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) trial investigated the addition of metformin therapy to titrated insulin therapy in adults with type 1 diabetes at increased risk for cardiovascular disease. The guidelines found that, “Metformin did not significantly improve glycaemic control beyond the first three months of treatment and that progression of atherosclerosis (measured by carotid artery intima-media thickness) was not significantly reduced, although other cardiovascular risk factors such as body weight and LDL cholesterol improved.”

Incretin-based therapies

“Due to their potential protection of β-cell mass and suppression of glucagon release, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are being studied in patients with type 1 diabetes, but are not currently FDA-approved for use in patients with type 1 diabetes,” said the authors.

Sodium–Glucose Cotransporter 2 Inhibitors

Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2. These agents provide modest weight loss and blood pressure reduction in type 2 diabetes. The FDA issued a warning about the risk of ketoacidosis occurring in the absence of significant hyperglycaemia (euglycaemic diabetic ketoacidosis) in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors. “Symptoms of ketoacidosis include dyspnoea, nausea, vomiting, and abdominal pain. Patients should be instructed to stop taking SGLT2 inhibitors and seek medical attention immediately if they have symptoms or signs of ketoacidosis,” US Food and Drug Administration. SGLT2 inhibitors: drug safety communication – labels to include warnings about too much acid in the blood and serious urinary tract infections, 2015.

Pharmacologic therapy for type 2 diabetes

Guideline recommendations:

  • Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes.
  • Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anaemia or peripheral neuropathy.
  • Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic and/or have A1C ≥10% (86mmol/mol) and/or blood glucose levels ≥300mg/dl (16.7mmol/l).
  • Consider initiating dual therapy in patients with newly diagnosed type 2 diabetes who have A1C ≥9% (75mmol/mol).
  • In patients without atherosclerotic cardiovascular disease, if monotherapy or dual therapy does not achieve or maintain the A1C goal over three months, add an additional antihyperglycaemic agent based on drug-specific and patient factors.
  • A patient-centred approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycaemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side-effects, renal effects, delivery method (oral versus subcutaneous), cost, and patient preferences.
  • In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycaemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors.
  • In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, after lifestyle management and metformin, the antihyperglycaemic agent canagliflozin may be considered to reduce major adverse cardiovascular events, based on drug-specific and patient factors.
  • Continuous re-evaluation of the medication regimen and adjustment as needed to incorporate patient factors and regimen complexity is recommended.
  • For patients with type 2 diabetes who are not achieving glycaemic goals, drug intensification, including consideration of insulin therapy, should not be delayed.
  • Metformin should be continued when used in combination with other agents, including insulin, if not contraindicated and if tolerated.

Initial therapy

Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. “Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death. Compared with sulfonylureas, metformin as first-line therapy has beneficial effects on A1C, weight, and cardiovascular mortality. Metformin may be safely used in patients with estimated glomerular filtration rate (eGFR) as low as 30ml/min/1.73 m2,” stated the American Diabetes Association.

Patients should be advised to stop the medication in cases of nausea, vomiting, or dehydration. Metformin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study (DPPOS) suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anaemia or peripheral neuropathy.

Combination therapy

Although there are numerous trials comparing dual therapy with metformin alone, few directly compare drugs as add-on therapy. A comparative effectiveness meta-analysis, Bennett et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations (2011), suggested that each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0.7–1.0%. If the A1C target is not achieved after approximately three months and patient does not have atherosclerotic cardiovascular disease (ASCVD), consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin.

According to the guideline, “The choice of which agent to add is based on drug-specific effects and patient factors.”

Insulin therapy

Many patients with type 2 diabetes eventually require and benefit from insulin therapy. The authors said that the progressive nature of type 2 diabetes should be regularly and objectively explained to patients. “Providers should avoid using insulin as a threat or describing it as a sign of personal failure or punishment. Equipping patients with an algorithm for self-titration of insulin doses based on self-monitoring of blood glucose improves glycaemic control in patients with type 2 diabetes initiating insulin,” stated the American Diabetes Association.

Basal insulin

Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 units per day or 0.1–0.2 units/kg/day, depending on the degree of hyperglycaemia. Basal insulin is usually prescribed in conjunction with metformin and sometimes one additional noninsulin agent.

According to Hermansen et al, A 26-week, randomised, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes (2006), when basal insulin is added to antihyperglycaemic agents in patients with type 2 diabetes, long-acting basal analogs (U-100 glargine or detemir) can be used instead of NPH to reduce the risk of symptomatic and nocturnal hypoglycaemia. Further, “Longer-acting basal analogs (U-300 glargine or degludec) may additionally convey a lower hypoglycaemia risk compared with U-100 glargine when used in combination with oral antihyperglycemic agents, said Zinman et al, (BEGIN Once Long) Trial Investigators. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomised, treat-to-target trial (2012).

Bolus insulin

According to the authors of the guidelines, many individuals with type 2 diabetes may require mealtime bolus insulin dosing in addition to basal insulin. “Rapid-acting analogs are preferred due to their prompt onset of action after dosing. The recommended starting dose of mealtime insulin is 4 units, 0.1 units/kg, or 10% of the basal dose. If A1C is <8% (64 mmol/mol) when starting mealtime bolus insulin, consideration should be given to decreasing the basal insulin dose.”

Premixed insulin

“Premixed insulin products contain both a basal and prandial component, allowing coverage of both basal and prandial needs with a single injection. NPH/Regular 70/30 insulin, for example, is composed of 70% NPH insulin and 30% regular insulin,” the guidelines suggested.

Concentrated insulin products

“Several concentrated insulin preparations are currently available. U-500 regular insulin, by definition, is five times as concentrated as U-100 regular insulin and has a delayed onset and longer duration of action than U-100 regular, possessing both prandial and basal properties. U-300 glargine and U-200 degludec are three and two times as concentrated as their U-100 formulations and allow higher doses of basal insulin administration per volume used. U-300 glargine has a longer duration of action than U-100 glargine,” stated the American Diabetes Association.

Inhaled insulin

Inhaled insulin is available for prandial use with a more limited dosing range. “It is contraindicated in patients with chronic lung disease such as asthma and COPD disease and is not recommended in patients who smoke or who recently stopped smoking. It requires spirometry (FEV1) testing to identify potential lung disease in all patients prior to and after starting therapy,” stated the guideline.

Combination injectable therapy

“If basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is >0.5 units/kg/day) and A1C remains above target, consider advancing to combination injectable therapy. When initiating combination injectable therapy, metformin therapy should be maintained while other oral agents may be discontinued on an individual basis to avoid unnecessarily complex or costly regimens,” the authors recommended.

In general, GLP-1 receptor agonists should not be discontinued with the initiation of basal insulin.

“Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are typically stopped once more complex insulin regimens beyond basal are used. In patients with suboptimal blood glucose control, especially those requiring large insulin doses, adjunctive use of a thiazolidinedione or SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed, though potential side effects should be considered,” American Diabetes Association stated.

Beyond the hype – A practical overview of the 2018 American Diabetes Association (ADA) Standards of Medical Care in Diabetes