How to improve long-term glycemic control in the real world



by S. Chatterjee, M. J. Davies,
and K. Khunti, United Kingdom

Kamlesh KHUNTI, PhD1,2

Sudesna CHATTERJEE, MD1,2
Melanie J. DAVIES, MD1,2
1Leicester Diabetes Centre
Leicester General Hospital
University of Leicester
Leicester, UNITED KINGDOM
2Diabetes Research Centre
College of Medicine, Biological
Sciences and Psychology
University of Leicester
Leicester, UNITED KINGDOM

Type 2 diabetes represents over 90% of the global population with diabetes. The incidence and prevalence continue to rise unrelentingly due to a lifestyle of sedentary behavior and energy-dense nutrition, which leads to obesity and metabolic dysregulation and places a severe psychosocial and economic burden on the patient, family, community, and health care system. Translating the benefits of diabetes prevention, glucose-lowering, and cardiovascular outcome trials can be challenging in the real world when faced with barriers such as therapeutic inertia by health care professionals to adequately intensify medication and patient adherence and persistence with recommended treatment. Traditional and newer glucose-lowering therapies need to be combined safely and effectively to achieve individualized treatment targets based on factors such as age, duration of diabetes, cardiovascular risk factors, and risk of hypoglycemia or adverse events. Both biomedical (HbA1c, weight) and psychosocial (illness beliefs, medication adherence) factors are improved when patients participate in structured education programs, which should be offered to all at diagnosis. Unwelcome side effects of intensive therapy, including hypoglycemia and weight gain, must be balanced carefully against the need to optimize glycemic control. Type 2 diabetes can be especially complex when managing younger (<25 years) and older (>65 years) patients, emphasizing the need for collaborative care planning and individualized targets and taking into account the patient’s circumstances and risk of complications.

Type 2 diabetes mellitus (T2DM) is characterized by relative insulin deficiency associated with insulin resistance, and accounts for over 90% of patients with diabetes worldwide. In 2015, 415 million people were diagnosed with diabetes globally, with the majority (80%) in low-to-middle-income countries, and it is estimated that there were a further 193 million people with diabetes who were undiagnosed.1 Major risk factors are obesity and a sedentary lifestyle associated with excessive carbohydrate and fat intake. Although usually lifelong, T2DM is preceded by a reversible preclinical phase of impaired glucose regulation which responds to lifestyle modification and pharmacotherapy, reducing future diabetes risk.2 Up to 50% of people have microvascular and macrovascular complications at diagnosis.3 Once diagnosed, patients with T2DM need early and appropriate risk factor control including blood glucose, HbA1c, and lipids, supported by structured education and self-management and psychological input, to reduce the development and progression of microvascular (retinopathy, neuropathy, nephropathy) and macrovascular (cardiovascular, cerebrovascular, and peripheral vascular disease) complications.4 Cardiovascular disease (CVD) is the most significant cause of morbidity and mortality, and intensive management of CVD risk factors is critical to achieving optimal care and should replace the current glucocentric approach.5 Large international multicenter randomized controlled trials (RCTs) have demonstrated the benefits of intensive glycemic control in reducing complications and mortality.6 However, challenges lie in translating these findings into real world clinical settings and nonstudy populations where financial and manpower resources are unlikely to match research trials and patients may lack the motivation to adhere to evidence-based interventions. This review will examine and discuss strategies to translate research evidence and improve long-term glycemic control, and reduce development and progression of complications especially cardiovascular outcomes in the real world.

Table I. Landmark trials in type 2 diabetes.
Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified
Release Controlled Evaluation; CV, cardiovascular; DM, diabetes mellitus; T2DM, type 2 diabetes mellitus; UKPDS, United Kingdom Prospective Diabetes Study;
VADT, Veterans Association Diabetes Trial.

Rationale for improving long-term glycemic control in type 2 diabetes

International multicenter RCTs and subsequent meta-analyses have conclusively demonstrated that intensive glycemic control leads to reduced microvascular and macrovascular complications (Table I).7,8 The United Kingdom Prospective Diabetes Study (UKPDS) was the first to show that decade long treatment with sulfonylureas, metformin, and insulin with target HbA1c<7% (53 mmol/mol) resulted in a significant reduction in microalbuminuria, retinopathy, and neuropathy, but there was less confirmatory evidence of a reduction in macrovascular complications.9 Patients included in the UKPDS study were within 12 months of diabetes diagnosis. Subsequent RCTs including ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation),10 ACCORD (Action to Control Cardiovascular Risk in Diabetes),11 and Veterans Association Diabetes Trial (VADT)12 demonstrated similar findings although participants generally had diabetes for longer and were more likely to have preexisting macrovascular disease. Rosiglitazone was used in up to 90% of patients in the intensive arm of ACCORD, whereas less than 20% of patients received these agents in ADVANCE and neither study incorporated intensive lifestyle modification with diet and physical activity. Early termination of ACCORD due to increased mortality with intensive treatment raised concerns that lowering HbA1c targets to near-normal (HbA1c<6.1% [43 mmol/mol]) should not be advocated due to increased hypoglycemia risk, and as a result, individualized HbA1c targets are now recommended according to diabetes duration, age, and comorbidities.

Follow-up studies confirmed that a period of intensive glycemic control, even when not sustained, leads to better long-term outcomes than continuous poor control (“glycemic legacy”).<sup<13</sup< This legacy effect was first reported after the 10-year follow-up of UKPDS participants showed that despite a narrowing of the separation in glycemic control between the intensive and standard arms, previously intensively managed patients had an ongoing reduction in microvascular risk and a new reduction in the risk of myocardial infarction (MI) and all-cause mortality.9 ADVANCE-ON (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation posttrial ObservatioNal study) demonstrated long-term reduction in end-stage kidney disease in the intensive group following a median of 5.4 years of further follow-up.14 Ten years after a median follow-up of 5.6 years, patients in the VADT cohort who received intensive therapy developed 8.6 fewer major CV events per 1000 person-years but no improvement in CV mortality.15

The importance of intensive multifactorial CV risk factor management has been demonstrated in Steno-2, an RCT of 160 patients with T2DM and microalbuminuria, with statistically significant improvement in cardiovascular outcomes after a mean treatment duration of 7.8 years.16 After 21.2 years of further follow-up, a median gain of 7.9 years of life was observed in the intensively managed group.17 Improved cardiovascular risk profile and metabolic control were also seen with intensive multifactorial management of diabetes and microalbuminuria in the MEMO study (Microalbuminuria Education and Medication Optimisation).18

Translating trial findings to real world settings has been difficult as frequent encounters with health care professionals are part of these study protocols, and requires substantial investment and infrastructure in health care systems. Additionally, factors such as therapeutic inertia19 and iatrogenic hypoglycemia20 can limit optimization of treatment.

Meta-analysis of these major trials confirmed that intensive treatment reduced all CVD events and MI; on the other hand, there was no reduction in CVD mortality and the risk of hypoglycemia increased the risk (HR 2.48 [95% CI, 1.91-3.21]); however these findings may partly be explained by data from ACCORD, which was terminated early.7 Another meta-analysis demonstrated that intensive glycemic control combined with multifactorial interventions significantly improves nonfatal MI by 17% (OR 0.83; 95% CI, 0.75-0.93) and coronary heart disease events by 15% (OR 0.85; 95% CI, 0.77-0.93) but not strokes and all-cause mortality.21

Nevertheless, the current consensus remains that intensive glycemic control with individualized glycemic targets combined with other CVD risk factor management is important and needs to be sustained to reduce adverse outcomes.22

Screening and early diagnosis of type 2 diabetes

Diagnosis of T2DM can be delayed by up to 12 years, predisposing to the development of microvascular and macrovascular complications.23 Opportunistic screening using validated risk scores can improve detection, enabling early treatment and prevention of complications.24-26 For diagnosis of T2DM, using glycated hemoglobin (HbA1c) is advocated, as it is equivalent to fasting plasma glucose and superior to oral glucose tolerance testing in detecting retinopathy,27 and is convenient, cost-effective, and obviates the need for fasting.28 HbA1c is not suitable for diagnosis in pregnancy, children, and in conditions with abnormal red cell turnover, and is also affected by race and increasing age.29 If the patient is asymptomatic a second diagnostic test must be performed within 2 weeks to confirm the diagnosis and the presence of complications must be established. T2DM is increasingly diagnosed in younger people who can often demonstrate characteristic features of extreme insulin resistance such as acanthosis nigricans. It can be difficult to differentiate between type 1 and type 2 diabetes, and autoantibodies at diagnosis and a genetic risk score are useful to aid correct diagnosis.30 Detectable C-peptide levels, a surrogate marker for circulating plasma insulin concentrations, after 3 years from diagnosis generally indicate T2DM.31

Following diagnosis, it is essential to devise a collaborative care plan with the patient, family, and carers, including an individualized HbA1c target depending on age, existing complications, especially CVD and other comorbidities. Quality outcomes are improved when a multidisciplinary approach32 is taken and structured education and self-management programs and psychological support are provided in the care plan.33 The care plan and HbA1c target should be reviewed with the patient at each clinic visit to ensure that care remains optimal and patient-centered. The increased prevalence of T2DM necessitates that more patients are seen in primary or community care by health care practitioners who should provide enhanced services for complex management including insulin initiation and appropriate screening and referral for complications (Figure 1, page 170).34

Structured education and self-management

At diagnosis, patients should be enrolled in an evidence based structured education and self-management program as there is evidence that this will improve biomedical factors including HbA1c, weight, and blood pressure, and psychosocial factors such as illness beliefs, quality of life, and medication adherence.35 Beneficial effects are lost after a few months or years and patients should be encouraged to attend refresher sessions at regular intervals (every 1 to 3 years).36 Uptake of education programs is variable, however, and there is a need for greater investment in promoting these courses, and health care professionals and patients should be advised on the advantages of attendance.37 Ideally they should be provided in patient-preferred venues and supported by additional media (web-based, text messaging). Offering psychological support can help patient acceptance and adjustment following diagnosis and improve adherence to advice and medication.38-40 Self-monitoring of blood glucose levels improves diabetes control even in patients not on insulin.41

Figure 1.
Enhanced care
in primary care
settings .
Abbreviation:
GLP-1 RA, glucagon-
like peptide-1
receptor agonist.
From reference
34: Seidu et al.
Diabet Med. 2017;
34(6):748-750.
© 2017, Diabetes
UK.

Lifestyle modification Lifestyle modification including weight management,42 healthy diet43 and increased physical activity44 in combination with pharmacological agents optimizes long-term glycemic control. In the 4-year Look AHEAD (Action for HEAlth in Diabetes) RCT of over 5000 patients with T2DM and CVD risk factors, greater weight loss (8.6% vs 0.7%) at 1 year was observed in the intensive lifestyle modification arm and was sustained at study end (6% vs 3.5%) with associated reductions in HbA1c, HDL-cholesterol, waist circumference and increased physical activity compared with standard care.45 However, this study did not result in improved CVD outcomes due partly to the relatively short study duration.

As overweight and obesity are major risk factors for the development of T2DM and are associated with poor control of T2DM as well as CVD, it is essential that patients are offered support with weight reduction and ongoing maintenance of ideal weight. Pharmacological agents licensed for weight loss include orlistat (a lipase inhibitor) and the glucagon-like peptide- 1 (GLP-1) receptor agonist, liraglutide. Orlistat is effective in appropriately selected patients although limited by gastrointestinal side effects.46 High-dose liraglutide (3.0 mg daily) is licensed in some regions including Europe, North America, and Australia for obesity treatment in patients with or without diabetes.47,48 For more extreme obesity (BMI>40 kg/m2), very low calorie diets (VLCD) <800 kCal per day in experimental conditions result in diabetes remission for up to 6 months, with responders typically having a short duration of diabetes and higher insulin levels at diagnosis.48 Bariatric surgery, in particular Roux-en-Y bypass or sleeve gastrectomy, is also associated with diabetes remission.50

The importance of physical activity must be highlighted to patients as it increases insulin sensitivity, helps with weight loss/maintenance and improves mood.44 Current recommendations suggest at least 30 minutes of moderate to vigorous physical activity five times a week. Both cardiovascular and resistance training are encouraged and patients should be guided to perform activities that are maintainable and suit their lifestyle. If patients are on glucose-lowering therapies that can increase the risk of hypoglycemia, advice must be given on appropriate adjustment of treatment when undergoing exercise and checking blood glucose levels before driving.

At diagnosis, patients should be referred to a dietitian for advice on portion size and reducing consumption of fat and sugar. The Mediterranean diet reduces CVD events by 30% in high risk CVD patients including in a diabetes subgroup.51 For weight reduction, calorie restriction is needed and patients should be given clear instructions on how this can be achieved with regular support from a dietitian. Enrolment in structured education programs such as DESMOND (Diabetes Education and Self-Management program for peOple with Newly diagnosed type 2 Diabetes mellitus) can support lifestyle modification.36,52

Appropriate initiation and selection of glucose-lowering therapies

In the last two decades, there has been a significant increase in new classes of glucose-lowering therapies, with varying characteristics including efficacy, cost, dosing schedule, side-effect profile, and contraindications. Newer therapies undergo rigorous testing in comprehensive RCT programs to confirm their efficacy and safety, providing a solid evidence base. Prescribing these agents in the real world requires a clear understanding of their mechanisms of action and other characteristics to ensure safety and efficacy. Post-marketing surveillance is critical to identify and monitor side effects.

Metformin remains first-line following diagnosis, with more than 50 years of safety and efficacy data and benefit on microvascular complications as well as possibly CV disease.53 Metformin offers durable control compared with sulfonylureas and may reduce the risk of cancer.54 Lactic acidosis is a rare side effect occurring mainly in patients with organ failure, whereas gastrointestinal side effects are commoner, and result in metformin discontinuation or failure of dose uptitration. Gastrointestinal side effects can be minimized by slow upward titration over several weeks or use of long-acting formulations. The position statement of the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) advocates the use of metformin as first-line therapy unless it is contraindicated or the patient is highly symptomatic at diagnosis.4

If metformin fails to achieve target HbA1c within 3 to 6 months of diagnosis, second-line glucose-lowering therapy is needed, and includes conventional choices such as sulfonylureas, thiazolidinediones (TZDs), meglitinides, and acarbose, and newer therapies such as dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists, and sodium glucose cotransporter- 2 (SGLT-2) inhibitors. In view of the number and complexity of drugs, decision-support tools potentially aid therapy choices.55 Basal insulin may also be added at this stage.

The second-line choice of agent depends on a number of patient factors including diabetes duration, age, and comorbidities, and drug characteristics such as hypoglycemia risk, effect on weight, dosing frequency, side effect profile, presence of renal or hepatic impairment, and cost.56 Although sulfonylureas, which increase insulin secretion, are cheap and effective, they are associated with weight gain and hypoglycemia, especially in older people.57 They also lack durability and potentially increase CVD risk.58 TZDs are equally effective at improving glycemic control but cause weight gain, partly through fluid retention, and are unsuitable in patients with heart failure or osteoporosis.59

Incretin therapies include oral DPP-4 inhibitors (sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin) and subcutaneous GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide). DPP-4 inhibitors are safe, well-tolerated, and do not cause weight gain or hypoglycemia.60 They are not as cheap as traditional agents or as effective as newer treatments such as GLP-1 receptor agonists and SGLT-2 inhibitors but are a convenient once- or twice-daily option, even in patients with severe renal impairment (eGFR<30 mL/ min/1.73 m2) with (sitagliptin) or without (linagliptin) dose reduction. GLP-1 receptor agonists are either exendin- or nonexendin- based, making them short- (exenatide, lixisenatide) or long-acting (liraglutide, albiglutide, dulaglutide), respectively, and are effective at reducing glucose levels and weight.60 Liraglutide has recently been shown to improve CV outcomes61 (see section on CV outcome trials). They are administered by subcutaneous injection although oral preparations (eg, semaglutide) are currently in phase 3 trials.62

SGLT-2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) are the newest glucose-lowering therapies and increase glycosuria, consequently improving glucose levels with weight reduction through urinary calorie loss of up to 320 kCal per day.63 Common side effects are genital and urinary tract infections, which can be limited by adequate fluid intake and good hygiene practice. Canagliflozin and empagliflozin remain effective with moderate renal impairment (eGFR 30-60 mL/min/1.73 m2), although dapagliflozin efficacy has shown to be diminished.64 SGLT-2 inhibitors should be discontinued during acute illness and hospitalization due to a potential risk of euglycemic ketoacidosis,5 and canagliflozin has been associated with bone fractures66 in clinical trials and amputation risk during postmarketing surveillance.67

The ADA and EASD provide guidance on combining glucose lowering therapies (Table II, page 172),4 which is determined by both patient factors and physician choice with efficacy and safety, key determinants in decision making supported by the UK National Institute for Care and Clinical Excellence (NICE). An ongoing RCT, GRADE (Glycemia Reduction Approaches in DiabEtes), comparing glimepiride, sitagliptin, liraglutide, or basal insulin to metformin treatment but not SGLT-2 inhibitors, will help determine optimal combinations in terms of efficacy and safety.68

Insulin initiation and optimal titration

Insulin therapy may be initiated at any treatment stage. Normalizing glucose levels can be beneficial in the first few weeks following diagnosis especially if the patient has had an MI or stroke as it reduces glucotoxicity, restores pancreatic β cell function,69 and improves insulin resistance, leading to longer drug-free remission.70 RCTs demonstrate that either basal or prandial insulin is the best option for initiation with regard to efficacy and risk of hypoglycemia,71 but adherence to insulin therapy is affected by fear of hypoglycemia, weight gain, and practical issues such as injecting.72 Insulin initiation may be delayed by physicians due to therapeutic inertia, patient fear of injections, or increased risk of hypoglycemia and weight gain. Delays in initiating insulin can be considerable and varies in different regions and countries.19Following initiation, there may also be “titration inertia.”19 Suboptimal titration of insulin limits efficacy and is improved by using patient self-managed titration algorithms.73

Table II.
Escalation of
glucose-lowering
therapy
according to
glycemic control
(based on
the EASD and
ADA consensus
guidelines)
Abbreviations:
DPP-4i, dipeptidyl
peptidase-4 inhibitor;
HbA1c, glycated
hemoglobin;
GLP-1 RA, glucagon-
like peptide-1
receptor agonist;
SGLT-2i, sodium
glucose co-transporter-
2 inhibitor;
SU, sulfonylurea;
TZD, thiazolidinedione.
Based on reference
4: Inzucchi
et al. Diabetologia.
2012;55(6):1577-
1596.

There is evidence that older basal insulins (NPH insulin) are as effective as newer basal insulin analogues (glargine U100 and U300, detemir, degludec) in improving glycemic control although hypoglycemia, especially nocturnal hypoglycemia, is less likely with analogues due to reduced variability in insulin action profiles.74-77 Newer basal insulins such as U300 glargine, which deliver more concentrated insulin in the same volume as other basal insulins, are useful in overcoming the challenges of glycemic management in highly insulin-resistant patients.78 Ultrarapid-acting insulins are in development.

The use of GLP-1 receptor agonists in combination with insulin can enhance efficacy and minimize hypoglycemia and weight gain, and several fixed combinations are available.79,80

Hypoglycemia and weight gain with glucose-lowering therapies

Hypoglycemia is a major factor that limits intensive glycemic control and achievement of treatment targets.81 It is often caused by polypharmacy, especially in the elderly or in people with comorbidities such as renal impairment.82-85 Adopting individualized HbA1c targets by taking into consideration factors such as duration of diabetes, age, comorbidities—especially CVD—has been recommended to minimize hypoglycemia risk.86 In patients at increased risk, it would be appropriate to consider combining metformin with DPP-4 inhibitors, thiazolidinediones, SGLT-2 inhibitors, and GLP-1 receptor agonists rather than sulfonylureas, meglitinides, and insulin if possible. Regular self-monitoring of blood glucose levels is essential when agents causing hypoglycemia are prescribed.

Weight gain is another often unavoidable consequence of glucose-lowering therapy, which affects intensification and optimization of treatment. Initiating insulin therapy can lead to approximately 6 kg in weight gain.87 Furthermore, a recent meta-analysis showed that every 1 kg increase in weight, especially with DPP-4 inhibitors and TZDs, elevated the risk of heart failure by 7.1% (95% CI, 1.0-13.6; P=0.022).88 GLP-1 receptor agonist and insulin combination therapy limits weight gain, resulting in lower insulin dosage.80 Improved glycemic control, weight loss, and systolic blood pressure have been reported in a phase 3 trial (DURATION-8), which compared dual therapy with dapagliflozin and once-weekly exenatide versus either drug alone, and showed that GLP-1 receptor agonists and SGLT-2 inhibitors are an effective therapeutic combination.89

Cardiovascular outcome trials

Since 2008, it has been a US Food and Drugs Administration (FDA) requirement that all glucose-lowering agents are tested against placebo in RCTs for cardiovascular safety, after a meta-analysis of rosiglitazone studies showed an increased risk of adverse CVD outcomes.90 Several agents have demonstrated noninferiority and safety with placebo for major cardiovascular events such as CVD and all-cause mortality, MI and stroke, and hospitalization for heart failure (Table III). Major trials showing noninferiority include SAVOR-TIMI 53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 (saxagliptin),91 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) (sitagliptin),92 and EXAMINE (The EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome) (alogliptin).93 However, increased hospitalization risk due to heart failure, as seen in SAVOR TIMI 53 and EXAMINE, has led to an FDA warning that these agents should be avoided in moderateto- severe heart failure.94

Table III. Cardiovascular outcome trials for new glucose-lowering therapies.
Abbreviations: CAD, coronary artery disease; CKD, chronic kidney disease; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; EMPA-REG, EMPAgliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes trial; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with
type 2 diabetes mellitus and acute coronary syndrome; GLP-1, glucagon-like peptide-1; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular
outcome Results; MI, myocardial infarction; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–
Thrombolysis in Myocardial Infarction (TIMI) 53; SGLT-2, sodium glucose co-transporter-2; SUSTAIN-6, trial to evaluate cardiovascular and other long-term outcomes
with semaglutide in subjects with type 2 diabetes; T2DM, type 2 diabetes mellitus; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.

EMPA-REG OUTCOME (EMPAgliflozin, cardiovascular outcomes, and mortality in type 2 diabetes trial) has demonstrated the superiority of empagliflozin compared with placebo with a 14% reduction in the composite primary end point of CV death, nonfatal MI, and nonfatal stroke.95 Other SGLT-2 inhibitor outcome studies, DECLARE (Dapagliflozin Effect on CardiovascuLAR Events) (dapagliflozin)96 and CANVAS (CANagliflozin cardioVascular Assessment Study) (canagliflozin),97 have not yet reported and therefore it is unclear whether this is a class effect. The mechanism may be diuretic-related, leading to plasma volume reduction as benefits are seen within three months of therapy initiation.98 Other possible mechanisms include cardiac remodeling, natriuresis, or cardiac ketone body oxidation.99 LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) has also showed superior outcomes with liraglutide 1.8 mg daily with a 13% risk reduction in the same primary outcome as EMPA-REG and a 2% reduction in CV mortality,61 and once weekly semaglutide demonstrated a 2.3% risk reduction in the primary end point and no difference in CV mortality compared with placebo (SUSTAIN-6 [trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes]).100 However, the temporal separation of the curves is different, with GLP-1 receptor agonists taking longer to demonstrate positive outcomes compared with empagliflozin. Studies on other GLP-1 receptor agonists such as lixisenatide (ELIXA [Evaluation of Lixisenatide in Acute Coronary Syndrome]) have only demonstrated noninferiority,101 or are yet to report (exenatide [EXSCEL: The EXenatide Study of Cardiovascular Event Lowering]).102

Need for cost-effective strategies

T2DM management confers considerable expense to health care economies and is globally estimated at $825 billion.103 Intensive management, even with only modest improvements in glycemic control, is associated with a significant reduction in adverse outcomes and corresponding financial gains, especially in patients with higher baseline HbA1c levels.104 In the UK, cost reductions in T2DM were significantly associated with reductions in neuropathy, foot ulcers, and amputations.104 Cost-effective patient care is essential and should be prioritized according to need, while addressing of barriers such as therapeutic inertia and patient noncompliance and developing newer models of care is also crucial. Implementation of the Chronic Care Model, which advocates an integrated, organized, and evidence-based approach to chronic disease management in primary care settings, has been shown to improve diabetes care.105

Newer therapies tend to be expensive, and there may not be sufficient evidence to justify their use compared with more traditional therapies. For example, NPH insulin may be as effective as more expensive basal insulin analogues in achieving glycemic targets and should only be discontinued if there are issues with nocturnal hypoglycemia or diurnal variability. Conversely, newer therapies should not be avoided simply on the basis of expense. Health care professionals must be aware of latest guidelines and evidence ensuring that the most effective and cost-effective treatments are used for their patients. Unnecessary adverse events due to medication such as hypoglycemia requiring hospitalization also increase health care costs.

Conclusion

Long-term glycemic management requires early detection and initiation of appropriate treatment with a focus on patient-centered collaborative care. Sustaining glucose control is challenging due to the inevitable deterioration in β cell function and insulin resistance with time. As yet, no pharmacological agents are able to reverse this process. Synergistic drug combinations should be commenced early to minimize long periods of suboptimal diabetes control. This requires regular monitoring by home glucose measurement as well as HbA1c checked at regular intervals and support from an integrated multidisciplinary team. ■

References
1. International Diabetes Federation. IDF Diabetes Atlas. 7th ed. International Diabetes Federation; 2015. http://www.diabetesatlas.org/ (2015). Accessed April 2, 2017.
2. Gillies CL, Abrams KR, Lambert PC, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: Systematic review and meta-analysis. BMJ. 2007;334(7588):299.
3. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care. 1992;15(7):815-819.
4. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: A patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European association for the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-1596.
5. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care. 1993;16(2):434-444.
6. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: A scientific statement from the american heart association and the american diabetes association. Diabetes Care. 2015;38(9):1777-1803.
7. Control Group, Turnbull FM, Abraira C, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288- 2298.
8. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: A metaanalysis of randomised controlled trials. Lancet. 2009;373(9677):1765-1772.
9. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577- 1589.
10. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
11. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
12. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139.
13. Cefalu WT, Rosenstock J, LeRoith D, Blonde L, Riddle MC. Getting to the “heart” of the matter on diabetic cardiovascular disease: “Thanks for the memory.” Diabetes care. 2016;39:664-667.
14. Wong MG, Perkovic V, Chalmers J, et al. Long-term benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON. Diabetes Care. 2016;39(5):694-700.
15. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372(23):2197- 2206.
16. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The steno type 2 randomised study. Lancet. 1999;353(9153):617-622.
17. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the steno-2 randomised trial. Diabetologia. 2016;59(11): 2298-2307.
18. Crasto W, Jarvis J, Khunti K, et al. Multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: The microalbuminuria education and medication optimisation (MEMO) study. Diabetes Res Clin Pract. 2011;93(3): 328-336.
19. Khunti K, Nikolajsen A, Thorsted BL, Andersen M, Davies MJ, Paul SK. Clinical inertia in intensifying therapy among people with type 2 diabetes treated with basal insulin. Diabetes Obes Metab. 2016;18(4):401-409.
20. Cryer PE. Glycemic goals in diabetes: Trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes. 2014;63(7):2188-2195.
21. Seidu S, Achana FA, Gray LJ, Davies MJ, Khunti K. Effects of glucose-lowering and multifactorial interventions on cardiovascular and mortality outcomes: A meta-analysis of randomized control trials. Diabet Med. 2015;33(3):280-239.
22. Authors/Task Force Members, Ryden L, Grant PJ, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The task force on diabetes, pre-diabetes, and cardiovascular diseases of the european society of cardiology (ESC) and developed in collaboration with the european association for the study of diabetes (EASD). Eur Heart J. 2013;34(39):3035-3087.
23. [No authors listed]. UK prospective diabetes study 6. complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res. 1990;13:1-11.
24. Webb DR, Gray LJ, Khunti K, et al. Screening for diabetes using an oral glucose tolerance test within a western multi-ethnic population identifies modifiable cardiovascular risk: The ADDITION-leicester study. Diabetologia. 2011;54(9):2237- 2246.
25. Simmons RK, Echouffo-Tcheugui JB, Sharp SJ, et al. Screening for type 2 diabetes and population mortality over 10 years (ADDITION-cambridge): A clusterrandomised controlled trial. Lancet. 2012;380(9855):1741-1748.
26. Black JA, Sharp SJ, Wareham NJ, et al. Change in cardiovascular risk factors following early diagnosis of type 2 diabetes: A cohort analysis of a clusterrandomised trial. Br J Gen Pract. 2014;64(621):e208-e216.
27. Colagiuri S, Lee CM, Wong TY, et al. Glycemic thresholds for diabetes-specific retinopathy: Implications for diagnostic criteria for diabetes. Diabetes Care. 2011;34(1):145-150.
28. Bonora E, Tuomilehto J. The pros and cons of diagnosing diabetes with A1C. Diabetes Care. 2011;34(suppl 2):S184-90.
29. Welsh KJ, Kirkman MS, Sacks DB. Role of glycated proteins in the diagnosis and management of diabetes: Research gaps and future directions. Diabetes Care. 2016;39(8):1299-1306.
30. Oram RA, Patel K, Hill A, et al. A type 1 diabetes genetic risk score can aid discrimination between type 1 and type 2 diabetes in young adults. Diabetes Care. 2016;39(3):337-344.
31. Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med. 2013;30(7):803-817.
32. Seidu S, Walker NS, Bodicoat DH, Davies MJ, Khunti K. A systematic review of interventions targeting primary care or community based professionals on cardio- metabolic risk factor control in people with diabetes. Diabetes Res Clin Pract. 2016;113:1-13.
33. Tricco AC, Ivers NM, Grimshaw JM, et al. Effectiveness of quality improvement strategies on the management of diabetes: A systematic review and meta-analysis. Lancet. 2012;379(9833):2252-2261.
34. Seidu S, Davies MJ, Farooqi A, Khunti K. Integrated primary care: is this the solution to the diabetes epidemic? Diabet Med. 2017;34(6):748-750.
35. Davies MJ, Heller S, Skinner TC, et al. Effectiveness of the diabetes education and self management for ongoing and newly diagnosed (DESMOND) programme for people with newly diagnosed type 2 diabetes: Cluster randomised controlled trial. BMJ. 2008;336(7642):491-495.
36. Khunti K, Gray LJ, Skinner T, et al. Effectiveness of a diabetes education and self management programme (DESMOND) for people with newly diagnosed type 2 diabetes mellitus: Three year follow-up of a cluster randomised controlled trial in primary care. BMJ. 2012;344:e2333.
37. Khunti K, Chatterjee S, Carey M, Daly H, Batista-Ferrer H, Davies MJ. New drug treatments versus structured education programmes for type 2 diabetes: Comparing cost-effectiveness. Lancet Diabetes Endocrinol. 2016;4(7):557-559.
38. Nicolucci A, Kovacs Burns K, Holt RI, et al. Diabetes attitudes, wishes and needs second study (DAWN2): Cross-national benchmarking of diabetes-related psychosocial outcomes for people with diabetes. Diabet Med. 2013;30(7):767-777.
39. Kovacs Burns K, Nicolucci A, Holt RI, et al. Diabetes attitudes, wishes and needs second study (DAWN2): Cross-national benchmarking indicators for family members living with people with diabetes. Diabet Med. 2013;30(7):778-788.
40. Peyrot M, Burns KK, Davies M, et al. Diabetes attitudes wishes and needs 2 (DAWN2): A multinational, multi-stakeholder study of psychosocial issues in diabetes and person-centred diabetes care. Diabetes Res Clin Pract. 2013;99(2): 174-184.
41. Zhu H, Zhu Y, Leung SW. Is self-monitoring of blood glucose effective in improving glycaemic control in type 2 diabetes without insulin treatment: A metaanalysis of randomised controlled trials. BMJ Open. 2016;6(9):e010524-2015- 010524.
42. Norris SL, Zhang X, Avenell A, et al. Long-term non-pharmacologic weight loss interventions for adults with type 2 diabetes. Cochrane Database Syst Rev. 2005;(2):CD004095.
43. Orozco LJ, Buchleitner AM, Gimenez-Perez G, Roque I Figuls M, Richter B, Mauricio D. Exercise or exercise and diet for preventing type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008;(3):CD003054.
44. Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006;(3):CD002968.
45. Look AHEAD Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2): 145-154.
46. Bray GA, Fruhbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016;387(10031):1947-1956.
47. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443- 1451.
48. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: The SCALE diabetes randomized clinical trial. JAMA. 2015;314(7):687-699.
49. Steven S, Hollingsworth KG, Al-Mrabeh A, et al. Very-low-calorie diet and 6 months of weight stability in type 2 diabetes: Pathophysiologic changes in responders and nonresponders. Diabetes Care. 2016;39(5):808-815.
50. Steven S, Carey PE, Small PK, Taylor R. Reversal of type 2 diabetes after bariatric surgery is determined by the degree of achieved weight loss in both short- and long-duration diabetes. Diabet Med. 2015;32(1):47-53.
51. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a mediterranean diet. N Engl J Med. 2013;368(14):1279-1290.
52. Chrvala CA, Sherr D, Lipman RD. Diabetes self-management education for adults with type 2 diabetes mellitus: A systematic review of the effect on glycemic control. Patient Educ Couns. 2016;99(6):926-943.
53. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK prospective diabetes study (UKPDS) group. Lancet. 1998;352(9131):854-865.
54. Soranna D, Scotti L, Zambon A, et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: A meta-analysis. Oncologist. 2012; 17(6):813-822.
55. Ampudia-Blasco FJ, Benhamou PY, Charpentier G, et al. A decision support tool for appropriate glucose-lowering therapy in patients with type 2 diabetes. Diabetes Technol Ther. 2015;17(3):194-202.
56. Cefalu WT, Buse JB, Del Prato S, et al. Beyond metformin: Safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: Reflections from a diabetes care editors’ expert forum. Diabetes Care. 2014;37(9):2647-2659.
57. Monami M, Dicembrini I, Kundisova L, Zannoni S, Nreu B, Mannucci E. A metaanalysis of the hypoglycaemic risk in randomized controlled trials with sulphonylureas in patients with type 2 diabetes. Diabetes Obes Metab. 2014;16(9): 833-840.
58. Vaccaro O, Masulli M, Bonora E, et al. Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: Impact on cardiovascular events. A randomized controlled trial. Nutr Metab Cardiovasc Dis. 2012;22(11):997-1006.
59. Consoli A, Formoso G. Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus? Diabetes Obes Metab. 2013;15(11):967-977.
60. Deacon CF, Mannucci E, Ahren B. Glycaemic efficacy of glucagon-like peptide- 1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis. Diabetes Obes Metab. 2012;14(8):762-767.
61. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016.
62. Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ. Benefits and harms of once-weekly glucagon-like peptide-1 receptor agonist treatments: A systematic review and network meta-analysis. Ann Intern Med. 2016;164(2):102-113.
63. Wilding JP. The role of the kidneys in glucose homeostasis in type 2 diabetes: Clinical implications and therapeutic significance through sodium glucose cotransporter 2 inhibitors. Metabolism. 2014;63(10):1228-1237.
64. Davies M, Chatterjee S, Khunti K. The treatment of type 2 diabetes in the presence of renal impairment: What we should know about newer therapies. Clin Pharmacol. 2016;8:61-81.
65. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687-1693.
66. Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38(3):403-411.
67. US Food and Drug Administration. FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (invokana, invokamet); FDA to investigate. May 18, 2016. https://www.fda.gov/Drugs/DrugSafety/ ucm500965.htm. Accessed April 2, 2017.
68. GRADE Study Group. A comparative effectiveness study of major glycemialowering medications for treatment of type 2 diabetes (GRADE). https://clinicaltrials. gov/ct2/results?term=NCT01794143. Updated 2015. Accessed October 21, 2015.
69. Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: A multicentre randomised parallel-group trial. Lancet. 2008;371(9626):1753-1760.
70. Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy in type 2 diabetes mellitus: A systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013;1(1):28-34.
71. Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361(18):1736-1747.
72. Davies MJ, Gagliardino JJ, Gray LJ, Khunti K, Mohan V, Hughes R. Real-world factors affecting adherence to insulin therapy in patients with type 1 or type 2 diabetes mellitus: A systematic review. Diabet Med. 2013;30(5):512-524.
73. Silva DD, Bosco AA. An educational program for insulin self-adjustment associated with structured self-monitoring of blood glucose significantly improves glycemic control in patients with type 2 diabetes mellitus after 12 weeks: A randomized, controlled pilot study. Diabetol Metab Syndr. 2015;7:2.
74. Horvath K, Jeitler K, Berghold A, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;(2):CD005613.
75. Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: A meta-analysis. Diabetes Res Clin Pract. 2008;81(2):184-189.
76. Swinnen SG, Simon AC, Holleman F, Hoekstra JB, Devries JH. Insulin detemir versus insulin glargine for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(7):CD006383.
77. Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN basal-bolus type 2): A phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825): 1498-1507.
78. Steinstraesser A, Schmidt R, Bergmann K, Dahmen R, Becker RH. Investigational new insulin glargine 300 U/ml has the same metabolism as insulin glargine 100 U/ml. Diabetes Obes Metab. 2014;16(9):873-876.
79. Gough SC, Bode B, Woo V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: Results of a phase 3, open-label, randomised, 26-week, treatto- target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014;2(11):885-893.
80. Gough SC, Bode BW, Woo VC, et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: Results of a 26-week extension to a 26-week main trial. Diabetes Obes Metab. 2015;17(10):965-973.
81. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a workgroup of the american diabetes association and the endocrine society. J Clin Endocrinol Metab. 2013;98(5):1845-1859.
82. Sinclair A, Dunning T, Rodriguez-Manas L. Diabetes in older people: New insights and remaining challenges. Lancet Diabetes Endocrinol. 2015;3(4):275-285.
83. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med. 2015;175(3):356-362.
84. Greco D, Pisciotta M, Gambina F, Maggio F. Severe hypoglycaemia leading to hospital admission in type 2 diabetic patients aged 80 years or older. Exp Clin Endocrinol Diabetes. 2010;118(4):215-219.
85. Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ. Rates of complications and mortality in older patients with diabetes mellitus: The diabetes and aging study. JAMA Intern Med. 2014;174(2):251-258.
86. International Hypoglycaemia Study Group. Minimizing hypoglycemia in diabetes. Diabetes Care. 2015;38(8):1583-1591.
87. Russell-Jones D, Khan R. Insulin-associated weight gain in diabetes—causes, effects and coping strategies. Diabetes Obes Metab. 2007;9(6):799-812.
88. Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose- lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: A meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3(5):356-366.
89. Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): A 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016.4(12):1004-1016.
90. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457- 2471.
91. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.N Engl J Med. 2013;369(14): 1317-1326.
92. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242. doi: 10.1056/NEJMoa1501352 [doi].
93. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: A multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067- 2076.
94. US Food and Drug Administration. Diabetes medications containing saxagliptin and alogliptin: Drug safety communication – risk of heart failure. May 4, 2016. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm494252.htm. Accessed April 2, 2017.
95. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
96. Astra Zeneca. Multicenter trial to investigate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). https://clinicaltrials.gov/ ct2/show/NCT01730534. Updated 2015. Accessed October 21, 2015.
97. Janssen Research and Development LLC. CANVAS – Canagliflozin cardiovascular assessment study. https://clinicaltrials.gov/ct2/show/NCT01032629. Updated 2015. Accessed October 21, 2015.
98. Sarafidis PA, Tsapas A. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2016;374(11):1092.
99. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: Lessons learned from the EMPA-REG OUTCOME study. Diabetes Care. 2016;39(5):717-725.
100. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834- 1844.
101. Pfeffer MA; ELIXA steering group. The evaluation of lixisenatide in acute coronary syndrome—the results of ELIXA [Abstract]. ADA Scientific Sessions. 2015; Abstract 3-CT-SY28.
102. Holman RR, Bethel MA, George J, et al. Rationale and design of the EXenatide study of cardiovascular event lowering (EXSCEL) trial. Am Heart J. 2016;174:103-110.
103. Seuring T, Archangelidi O, Suhrcke M. The economic costs of type 2 diabetes: A global systematic review. Pharmacoeconomics. 2015;33(8):811-831.
104. Baxter M, Hudson R, Mahon J, et al. Estimating the impact of better management of glycaemic control in adults with type 1 and type 2 diabetes on the number of clinical complications, and the associated financial benefit. Diabet Med. 2016;33(11):1575-1581.
105. Barletta V, Profili F, Gini R, et al. Impact of chronic care model on diabetes care in Tuscany: A controlled before-after study. Eur J Public Health. 2017;27(1): 8-13.

Keywords: cardiovascular outcomes; diabetes; glucose-lowering therapy; glycemic control