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Hypertension in type 2 diabetes

impact of glucose-lowering medications

Krentz, Andrew J.

Cardiovascular Endocrinology & Metabolism: December 2016 - Volume 5 - Issue 4 - p 137–143
doi: 10.1097/XCE.0000000000000100
Review Articles
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Hypertension often co-exists with hyperglycaemia to elevate the risk of vascular disease. The importance of treating hypertension in type 2 diabetes is well appreciated, the benefits of good glycaemic control and effective treatment of hypertension being additive. Treating hyperglyaemia on the one hand and hypertension on the other are usually considered separate strategies of a multifactorial approach to risk reduction requiring specific antihypertensive and glucose-lowering drugs. It is well appreciated that antihypertensive medications can have effects (prodiabetic, neutral, protective against diabetes, according to drug class) on blood glucose levels. Rather less attention has been paid to the effect of glucose-lowering drugs on blood pressure (BP). Positive, neutral and negative effects on BP have been reported for different classes, with some evidence of heterogeneity between individual drugs within certain classes. In this article, the effects of glucose-lowering medication on BP are reviewed. There is a paucity of head-to-head studies of the effects of glucose-lowering medications on BP. Although BP targets in type 2 diabetes continue to be debated, there is a case for more attention to be directed towards the impact of glucose-lowering drugs on BP control.

Institute for Translational Medicine, Clore Life Sciences, University of Buckingham, Buckingham, UK

Correspondence to Andrew J. Krentz, MD, FRCP, Institute for Translational Medicine, Clore Life Sciences, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK Tel/fax: +44 1280 820242; e-mail: andrew.krentz@buckingham.ac.uk

Received September 2, 2016

Accepted September 20, 2016

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Introduction

Hypertension often co-exists with other modifiable vascular risk factors (hyperglycaemia, complex dyslipidaemia and smoking) in patients with type 2 diabetes 1–5. Globally, hypertension rates are high in all regions, with most studies reporting rates above 50% and many above 75%. This situation has been described as a case of ‘bad companions’ in terms of the risk of microvascular and macrovascular disease 6. Observational studies have shown that the associations of blood pressure (BP) levels with measures of glycaemic control on the risks of mortality and coronary heart disease in type 2 diabetes are independent and additive 7,8. The presence of hypertension increases the risk of new-onset diabetes; conversely, type 2 diabetes promotes the development of hypertension. Plausible mechanisms to explain the strong association between hypertension and type diabetes include production of reactive oxygen species, insulin resistance in the nitricoxide pathway; the stimulatory effect of hyperinsulinaemia on sympathetic drive, smooth muscle growth, sodium-fluid retention; and the excitatory effect of hyperglycaemia on the renin–angiotensin–aldosterone system 6,9. The risk of cardiovascular disease is four-fold higher in patients with both hypertension and diabetes compared with normotensive nondiabetic control patients 9. In type 1 diabetes, hypertension is usually encountered in the context of diabetic renal disease, that is, albuminuria and/or declining glomerular filtration 10. Overweight or obesity, older age and longer diabetes duration may be associated with impaired insulin sensitivity and elevated BP in patients with type 1 diabetes 11. Although selected noninsulin glucose-lowering drugs may be combined with insulin in patients with type 1 diabetes. the focus of research interest in this context has largely been on glycaemic control rather than effects on BP 12.

The importance of treating hypertension in type 2 diabetes has been well appreciated since the results of United Kingdom Prospective Diabetes Study (UKPDS) 38 were reported 13. Patients in the intensive BP treatment arm of UKPDS 38 showed statistically significant reductions in death related to diabetes, as well as in stroke, heart failure and microvascular endpoints. However, even with the accumulation of additional trial-derived data, BP thresholds for treatment initiation and optimal BP targets for patients with type 2 diabetes continue to be debated 14–16.

Clinical studies of type 2 diabetes have shown that interventions to improve glycaemic control in concert with effective treatment of hypertension have an additive beneficial impact on the development of vascular complications 17,18. Management of BP in patients with diabetes includes both lifestyle modifications and pharmacological therapies 16. The treatment of hyperglycaemia on the one hand and hypertension on the other are usually considered separate therapeutic strategies requiring specific antihypertensive and glucose-lowering drugs, respectively. It is well appreciated that antihypertensive medications can have effects (prodiabetic or requiring increased glucose-lowering medication versus neutral versus protective against diabetes according to drug class) on blood glucose levels 19,20. Less attention has been paid to the effect of glucose-lowering drugs on BP. When considering BP-lowering effects, 24 h ambulatory BP readings are more reproducible than standard clinic BP measurements 21. The aim of this article is to briefly review the effects of glucose-lowering medications on BP in type 2 diabetes with an emphasis on clinical research studies.

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Sulfonylureas

Sulfonylureas stimulate the release of insulin from the β-cells of the pancreatic islets 22. This class of glucose-lowering drugs are generally considered to be neutral with respect to their effects on BP. Sulfonylurea-associated weight gain, predominantly adipose tissue, has been viewed as having the potential to increase BP (thiazolidinedione-induced weight gain; see below) 23. There have long been concerns that sulfonylureas may increase the risk of cardiovascular events through effects on the SUR1 of the cardiac K (ATP) channel 24. However, the clinical relevance of effect remains controversial and risk may differ between members of the class 25. Available data on the effects of sulfonylureas on BP range from neutral effects or nonsignificant decreases (glimepiride) to significant increases in BP during treatment with glibenclamide (glyburide) or glipizide 26.

As reported in UKPDS 33, the mean systolic and diastolic BP were significantly higher throughout the study in patients assigned chlorpropamide than in those assigned any of the other glucose-lowering therapies 27. Mean haemoglobin (Hb)A1c was significantly lower in the chlorpropamide group than in the glibenclamide group (P=0.008), although neither differed from the insulin treatment group 27. Interpretation of these data is hampered by the progressive addition of other glucose-lowering drugs over time in UKPDS.

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Meglitinides

Meglitinide derivatives include nateglinide and repaglinide. These drugs increase insulin secretion, in particular, the early phase of insulin release 22. The adverse event profile, including weight gain, is broadly similar to sulfonylureas 22. The effects of meglitinide derivatives on BP have not been well quantified 26. In a comparative study in nonobese patients with type 2 diabetes of nonglycaemic vascular risk biomarkers, levels of tumour necrosis factor-α, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide therapy for similar degrees of glycaemic control 28.

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Biguanides

Since the late 1970s, metformin has been the only biguanide available in many countries; the drug was introduced into clinical practice in the USA in 1995 22. In UKPDS 34, a relatively small group of overweight patients (n=342) with recently diagnosed type 2 diabetes who were randomized to metformin monotherapy had lower rates of myocardial infarction (39% reduction; P=0.01) and coronary deaths (50% reduction; P=0.02) together with decreased all-cause mortality relative to diet therapy 29. Whereas the mechanisms through which metformin was associated with cardioprotection in UKPDS 34 remain uncertain, improvements in lipids, thrombosis and blood flow have been postulated 30. Metformin is associated with weight neutrality or modest weight reduction 31. Insulin levels are reduced along with glucose and metformin is considered to have insulin-sensitizing properties. However, improved insulin action in skeletal muscle appears to be a secondary effect to lower glucose concentrations resulting from reductions in hepatic glucose production. A systematic review of metformin in patients with type 2 diabetes concluded that metformin had no intrinsic effects on BP 32. Among nondiabetic patients with ST elevation, myocardial infarction treatment with metformin for 4 months resulted in a modest improvement in the cardiovascular risk profile compared with placebo 33. No effect of metformin was observed on BP in the latter study 33. The cardiovascular effects of metformin are being re-examined in patients with nondiabetic hyperglycaemia and high cardiovascular risk (glucose lowering in nondiabetic hyperglycaemia trial, GLINT; https://www.dtu.ox.ac.uk/GLINT/).

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α-Glucosidase inhibitors

Acarbose, voglibose and miglitol are α-glucosidase inhibitors that retard glucose absorption from the intestine, thereby reducing postprandial glucose excursions in patients with type 2 diabetes 22. Data on the effects of α-glucosidase inhibitors on BP are largely confined to acarbose, which is credited with beneficial effects on body weight, triglycerides, markers of low-grade chronic inflammation and BP 34. In the Study to Prevent Noninsulin-Dependent-Diabetes-Mellitus (STOP-NIDDM) trial, acarbose significantly reduced progression of intima media thickness, incidence of cardiovascular events and the incidence of newly diagnosed hypertension (34% relative risk reduction in the incidence of new cases of hypertension [hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.49–0.89; P=0.006] in patients with impaired glucose tolerance (IGT) compared with placebo 35. A post-hoc analysis of STOP-NIDDM that found a relationship between the development of type 2 diabetes and hypertension in patients with IGT and treatment with acarbose led the investigators to speculate on a shared pathogenesis for type 2 diabetes and hypertension 36.

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Thiazolidionediones

Thiazolidionediones improve insulin action by effects considered to be mediated primarily by the widely expressed PPAR-γ nuclear receptor 22,37. Although differences may exist among the agents within the class, thiazolidinediones are associated with modest BP-lowering effects 26,38. Thiazolidinedione-mediated reductions in BP, which have been shown in animal models and clinical studies, are accompanied by favourable effects on other cardiovascular risk factors 39. However, body weight tends to increase with thiazolidinedione therapy as a class effect and particularly in combination with insulin therapy 40. Part of the gain in body weight is attributable to water retention, which can manifest as oedema with a risk of heart failure in vulnerable patients 41. Reductions of ~4–5 mmHg in systolic and 2–4 mmHg in diastolic BP have been reported 42. Troglitazone-induced improvements in BP in patients with type 2 diabetes were attributed to vasodilatory effects 43. BP reduction with pioglitazone is in the region of 3–5 mmHg after 12 months of therapy when added to either glimepiride or metformin 44. Similar effects have been reported for rosiglitazone in nondiabetic hypertensive patients and in patients with type 2 diabetes, which correlate with improvements in insulin sensitivity measured using the hyperinsulinaemic euglycaemic clamp technique 45,46.

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DPP-4 inhibitors

The dipeptidyl peptidase (DPP)-4 inhibitor class of glucose-lowering drugs contains several members including sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin 47,48. These drugs have general excellent tolerability profiles and are considered weight neutral 49. In addition to reducing the breakdown of the incretin hormones GLP-1 and GIP, DPP-4 inhibitors decrease the degradation of several vasoactive peptides including the vasodilator brain natriuretic peptide 50. Saxagliptin, alogliptin and sitagliptin have been studied in large Food and Drug Administration-mandated cardiovascular outcome trials (CVOTs) in patients with type 2 diabetes at high risk of cardiovascular events 51,52. Whereas early reports indicated that DPP-4 inhibitors decreased BP in patients with diabetes, these studies were not designed to assess BP effects 50,53. In a recent systematic review and meta-analysis of 15 trials, DPP-4 inhibitors achieved greater reductions for systolic BP (mean difference, −3.04 mmHg; 95% CI, −4.37 to −1.72; P<0.00001) and diastolic BP (mean difference, −1.47 mmHg; 95% CI, −1.79 to −1.15; P<0.00001) compared with placebo or no treatment 54. Whether differences in diurnal BP control are of relevance to the risk of developing heart failure between individual DPP-4 inhibitors reported in recent CVOTs (saxagliptin associated with an increased risk of hospitalization for heart failure) remains uncertain 55,56. More detailed evaluation using the gold standard of 24-h ambulatory BP measurements in carefully designed comparative studies would be required to test this hypothesis 57.

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SGLT-2 inhibitors

The sodium-glucose cotransporter (SGLT)-2 inhibitors are the most recent class of glucose-lowering drugs that have become available. These agents decrease glucose reabsorption by the kidneys by increasing renal glucose excretion, resulting in a diuresis and urinary calorie loss 58. The positive effects of SGLT-2 inhibitors on multiple cardiovascular risk factors including glucose, insulin, body weight, albuminuria and BP raised hopes for reductions in cardiovascular events 59. This potential was realized in the EMPA-REG OUTCOME, a CVOT of empagliflozin at 10 and 25 mg daily doses that was published recently to widespread acclaim 60,61. This landmark trial reported a 14% reduction for the primary major adverse cardiovascular events outcome (HR, 0.86; 95% CI, 0.74–0.99; P=0.04 for superiority) over a median follow-up period of 3.1 years. Although there were no significant between-group differences in rates of myocardial infarction or stroke in the empagliflozin group, there were significantly lower rates of death from cardiovascular causes (3.7 vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7 and 4.1%, respectively; 35% relative risk reduction) and all-cause death (5.7 and 8.3%, respectively; 32% relative risk reduction) 60. Systolic BP was reduced by ~4 mmHg. There was extensive use of antihypertensive medications in both groups 60,62. The mechanism of empagliflozin-associated cardiovascular risk reduction, including reduced heart failure, remains unclear 61. The haemodynamic and renal effects of empagliflozin are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. It has been argued that the net result of these effects is an improvement in cardiac systolic and diastolic function resulting in a lower risk of heart failure and sudden cardiac death 63. Other effects, including altered myocardial substrate utilization, may also be relevant and require further exploration 64. SGLT-2 inhibitor-mediated BP reduction is considered to reflect a combination of diuresis, nephron remodelling, a reduction in arterial stiffness and weight loss 65. Improvements in arterial stiffness with empagliflozin have been shown in patients with type 2 diabetes 66. Empagliflozin also provided clear evidence of renoprotection in EMPA-REG OUTCOME 67.

Although SGLT-2 inhibitors are not approved as antihypertensive agents, they may potentially aid BP reductions in patients with diabetes 68. A review of studies of dapagliflozin and canagliflozin in both hypertensive and normotensive patients with type 2 diabetes showed a 4–10 mmHg reduction of systolic BP 69. In the aforementioned systematic review and meta-analysis, the BP-lowering effects of SGLT-2 inhibitors were greater than those of DPP-4 inhibitors for both systolic BP (mean difference, 4.44 mmHg; 95% CI, 2.67–6.22; P<0.00001) and diastolic BP (mean difference, 2.15 mmHg; 95% CI, 1.08–3.21; P<0.00001) 54. A recent study from the EMPA-REG BP investigators used 24-h ambulatory BP monitoring to assess the BP effects of empagliflozin in more than 800 patients (mean age 60 years) with type 2 diabetes who were either normotensive (<140/90 mmHg) or had stage 1 hypertension (≥140/90<160/99 mmHg) 70. Participants were randomized to either empagliflozin 10 mg daily, empagliflozin 25 mg daily or placebo. The co-primary endpoint along with glycaemic control was change in the mean 24-h systolic BP; the study was 90% powered to detect a 4 mmHg difference from placebo. The investigators reported a significant reduction in 24-h systolic and diastolic BPs of 4/2 mmHg compared with placebo at the 25 mg dose of empagliflozin 70.

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GLP-1 receptor agonists

Glucagon-like peptide-1 receptor (GLP-1) agonists and incretin-based therapies are used to treat hyperglycaemia in patients with type 2 diabetes 71. Exenatide was approved in 2015 as a twice-daily subcutaneous injection. Liraglutide was approved in 2010 17. The longer half-life (12 vs. 2.4 h for exenatide) allows for once-daily dosing with liraglutide 72. Albiglutide, lixisenatide and dulaglutide are also available 73. Liraglutide is also approved for the treatment of obesity at a dose of 3.0 mg daily 74. Whereas DPP-4 inhibitors boost patient levels of endogenously produced GLP-1 (and glucose-dependent insulinotropic peptide) by preventing its metabolism by DPP-4 enzymatic activity, GLP-1 receptor agonists are either synthetic analogues of human GLP-1 or exendin-4-based molecules 75. They are tailored to resist hydrolysis by DPP-4 activity and to provide longer durability in the circulation compared with native GLP-1 76. Several roles for incretin-based diabetes therapies, including GLP-1 receptor agonists, beyond the endocrine pancreas and their glycaemic-lowering properties have been described. Preclinical studies reported cardioprotective and vasodilatory actions of these agents 77. Favourable actions were also observed primarily on systolic BP, but with some studies showing reductions in diastolic pressure as well 78,79. Exenatide was shown to lower BP both in its daily and in its extended-release once-weekly formulations. A pooled data analysis from six clinical trials investigating twice-daily exenatide in more than 2000 patients with type 2 diabetes studied for at least 6 months showed significantly greater reductions in systolic BP compared with either placebo (difference –2.8 mmHg) or insulin (difference –3.7 mmHg) 80. A weak correlation was found between weight loss and reductions in systolic BP (r=0.09, P=0.02). No significant changes were observed in diastolic BP. In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION) trials, exenatide QW significantly reduced systolic BP, with mean reductions ranging from –3 to –5 mmHg 81. In general, chronic administration of GLP-1 agonists reduces clinic systolic BP by ∼2 mmHg when evaluated as a secondary endpoint in studies of glycaemia while simultaneously increasing heart rate 82. The increases in heart rate generated some concern about the net cardiovascular effects of GLP-1 agonists in the light of evidence that resting heart rate is an independent predictor of cardiovascular and all-cause mortality 83. In a systemic review and meta-analysis of exenatide and liraglutide, increases in heart rate of 1.86 beats/min (bpm) (95% CI, 0.85– 2.87) versus placebo and 1.90 bpm (1.30–2.50) versus active controls were observed 84. The mechanisms by which GLP-1 receptor agonists affect BP and heart rate remain uncertain. BP-lowering effects have been observed in mouse models of hypertension with a variety of agents in this class. In rodents, GLP-1-mediated increases in heart rate and BP appear to involve both central and peripheral nervous system pathways, requiring intact vagus nerve transmission 77. Renal effects of GLP-1 receptor agonists may include diuretic and natriuretic effects, whereas cardiac effects may involve the release of atrial natiuretic peptide 77. It is unclear whether the same pathways mediate BP effects of GLP-1 receptor agonists in humans.

In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) study, 9340 patients were randomized to the once-daily GLP-1 receptor agonist liraglutide or placebo. The median follow-up period was 3.8 years. Liraglutide significantly reduced cardiovascular events (HR, 0.87; 95% CI, 0.78–0.97; P<0.001 for noninferiority; P=0.01 for superiority), cardiovascular deaths (HR, 0.78; 95% CI, 0.66–0.93; P=0.007) and all-cause mortality. 85. The results of LEADER contrast with those of Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA), in which lixisenatide failed to reduce cardiovascular event rates 86. Whether this discrepancy represents differences in the medications, including the shorter half-life of lixisenatide, differences in potency between liraglutide and lixisenatide or differences in the trial populations remains uncertain. As in the case of EMPA-REG OUTCOME, although classic cardiovascular risk factors, for example, glycaemic control, body weight and BP, were improved or mitigated by liraglutide, the mechanisms of cardiovascular benefit in LEADER are uncertain 85. The pattern of cardiovascular benefits associated with liraglutide differed from that observed in EMPA-REG OUTCOME. As discussed above, the early benefits with empagliflozin may be more closely linked to haemodynamic or myocardial metabolic effects, whereas in LEADER, the observed benefits are considered to be compatible with modified progression of atherosclerotic vascular disease 85.

In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6), the effect of the once-weekly GLP-1 receptor agonist semaglutide at doses of 0.5 and 1.0 mg was assessed in patients with type 2 diabetes and elevated cardiovascular risk 87. At baseline, 83.0% had established cardiovascular disease, chronic kidney disease or both. The primary composite outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) occurred in 6.6% of the participants in the semaglutide group and in 8.9% of the participants in the placebo group (HR, 0.74; 95% CI, 0.58–0.95; P<0.001 for noninferiority; P=0.02 for superiority, although not a prespecified endpoint). Nonfatal myocardial infarction occurred in 2.9% of patients receiving semaglutide and in 3.9% of those receiving placebo (HR, 0.74; 95% CI, 0.51–1.08; P=0.12); nonfatal stroke occurred in 1.6 and 2.7%, respectively (HR, 0.61; 95% CI, 0.38–0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower with semaglutide. However, rates of retinopathy complications, that is, vitreous haemorrhage, blindness or conditions requiring treatment with an intravitreal agent or photocoagulation, were significantly higher (HR, 1.76; 95% CI, 1.11–2.78; P=0.02) with semaglutide. Estimated treatment differences versus placebo at week 104 for systolic BP were −1.27 (P=not significant) and −2.59 (P<0.005) mmHg for the 0.5 and 1.0 doses, respectively; changes in diastolic BP were negligible. As for LEADER, minor increases in heart rate were observed with semaglutide. In another similarity to LEADER, the timescale for the emergence of cardiovascular benefit in SUSTAIN-6 has led to the suggestion that atherosclerosis may be favourably impacted by semaglutide. In support of this hypothesis, coronary and peripheral arterial revascularization rates were reduced by semaglutide (P=0.003). There was no effect of semaglutide on hospitalization rates for adjudicated heart failure 87. The adverse effects of semaglutide on retinal events in SUSTAIN-6 require further investigation.

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Insulin

Insulin has complex physiological actions that are of relevance to vascular function and BP regulation in patients with and without type 2 diabetes 88,89. Insulin resistance is implicated in the pathogenesis of hypertension 90. Under experimental conditions, acute elevation of plasma insulin attained by exogenous infusions has a vasodilator action that is considered to be nitric-oxide dependent 91. Insulin therapy can lead to weight gain and increases in BP 91,92. However, insulin therapy per se is generally considered to have neutral effects on BP when used in patients with type 2 diabetes if no weight gain is induced. In the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, 2537 patients (mean age: 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, IGT or type 2 diabetes received insulin glargine (with a target fasting blood glucose level 5.3 mmol/l) or standard care. Patients treated with insulin glargine gained weight (median: +1.6 kg), whereas standard care was associated with a small reduction in body weight (−0.5 kg) over 6.5 years. However, BP was similar between the groups 93,94.

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Summary and conclusion

The debate on BP targets in patients with type 2 diabetes continues 95. When considering a role for glucose-lowering drugs as an adjunctive medication for the attainment of BP control, only limited evidence is available to guide physicians. More robust studies are required. Future studies should utilize ambulatory BP recordings that have superior reproducibility, provide additional data on BP variability and more accurately predict cardiovascular outcomes 96.

Of the available classes of glucose-lowering drugs, current data support clinically significant reductions in BP with GLP-1 receptor agonists and SGLT-2 inhibitors. Moreover, examples from both classes have been shown to reduce cardiovascular mortality in CVOTs, ushering in a new era of treatment for type 2 diabetes. In a recently published network meta-analysis of treatments for type 2 diabetes mellitus following failure with metformin plus sulfonylurea, only SGLT-2 inhibitors and GLP-1 receptor agonists led to a decrease in systolic BP (−3.73 and −2.90 mmHg, respectively); other glucose-lowering therapies showed either an increase or no change in systolic BP 97. It is noteworthy that SGLT-2 inhibitors and GLP-1 agonists were the only classes of glucose-lowering drugs associated with significant reductions in body weight 97. The selection of glucose-lowering drugs should be guided by safety and tolerability considerations in individual patients. In the context of precision therapy in type 2 diabetes, the nonglycaemic effects of some diabetes drugs, notably BP reduction, may usefully complement those of antihypertensive medications.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

antihypertensive medication; cardiovascular outcome trials; glucose-lowering drugs; hypertension; type 2 diabetes

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